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Xu Z, Guan L, Wang Y, Niu MM, Ruan Y, Xu C, Yang L. Discovery of a novel PLK1 inhibitor with high inhibitory potency using a combined virtual screening strategy. J Enzyme Inhib Med Chem 2025; 40:2467798. [PMID: 40052927 DOI: 10.1080/14756366.2025.2467798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 03/12/2025] Open
Abstract
PLK1 is essential for cell cycle regulation and proliferation, and its elevated expression in prostate cancer is associated with high tumour grade. Therefore, PLK1 inhibition is considered a promising strategy for the treatment of prostate cancer. Here, we identified five compounds (Hits 1-5) targeting the kinase domain (KD) of PLK1 using a combined virtual screening approach. Hits 1-5 all had picomolar (pM) inhibitory potency against PLK1. Notably, Hit-4 showed the strongest inhibitory activity against PLK1 (IC50 = 22.61 ± 1.12 pM) and displayed high selectivity for PLK1. Meanwhile, molecular dynamics (MD) simulations revealed that the complex formed by Hit-4 and PLK1 remained stable. Importantly, Hit-4 exhibited potent inhibitory effects on the proliferation of DU-145 prostate cancer cells (IC50 = 0.09 ± 0.01 nM). In conclusion, Hit-4 is a potent and highly selective antitumor candidate with therapeutic potential for prostate cancer.
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Affiliation(s)
- Zhen Xu
- Department of Oncology, Urology and Reproductive Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Lixia Guan
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Yuting Wang
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Miao-Miao Niu
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Yashi Ruan
- Department of Oncology, Urology and Reproductive Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Cen Xu
- Department of Oncology, Urology and Reproductive Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Li Yang
- Department of Oncology, Urology and Reproductive Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
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Fernández-Sainz J, Herrera-Ochoa D, Pacheco-Liñán PJ, Darder M, Albaladejo J, Bravo I, Garzón-Ruiz A. Spectroscopic study on volasertib: Highly stable complexes with albumin and encapsulation into alginate/montmorillonite bionanocomposites. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 322:124823. [PMID: 39033609 DOI: 10.1016/j.saa.2024.124823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/05/2024] [Accepted: 07/13/2024] [Indexed: 07/23/2024]
Abstract
In the present work, we study different physicochemical properties related to LADME processes of volasertib, a Polo-like kinase 1 inhibitor in advanced clinical trials. Firstly, the protonation equilibria, the extent of ionization at the physiological pH and pKa values of this drug are studied combining spectroscopic techniques and computational calculations. Secondly, the binding process of volasertib to the human serum albumin (HSA) protein is analyzed by fluorescence spectroscopy. We report a high binding constant to HSA (Ka = 4.10 × 106 M-1) and their pharmacokinetic implications are discussed accordingly. The negative enthalpy and entropy (ΔH0 = -54.49 kJ/mol; ΔS0 = -58.90 J K-1 mol-1) determined for the binding process suggests the implication of hydrogen bonds and van der Waals interactions in the formation of the HSA-volasertib complex. Additionally, volasertib is encapsulated in an alginate/montmorillonite bionanocomposite as a proof of concept for an oral delivery nanocarrier. The physical properties of that nanocomposite as well as volasertib delivery kinetics are analyzed.
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Affiliation(s)
- Jesús Fernández-Sainz
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02071 Albacete, Spain
| | - Diego Herrera-Ochoa
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02071 Albacete, Spain
| | - Pedro J Pacheco-Liñán
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02071 Albacete, Spain
| | - Margarita Darder
- Instituto de Ciencia de Materiales de Madrid (ICMM), CSIC, Cantoblanco, 28049 Madrid, Spain
| | - José Albaladejo
- Departamento de Química Física, Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10, 13071 Ciudad Real, Spain
| | - Iván Bravo
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02071 Albacete, Spain
| | - Andrés Garzón-Ruiz
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02071 Albacete, Spain.
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Herrera-Ochoa D, Bravo I, Garzón-Ruiz A. Monitoring cancer treatments in melanoma cells using a fluorescence lifetime nanoprobe based on a CdSe/ZnS quantum dot functionalized with a peptide containing D-penicillamine and histidine. Colloids Surf B Biointerfaces 2024; 245:114265. [PMID: 39321721 DOI: 10.1016/j.colsurfb.2024.114265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/12/2024] [Accepted: 09/21/2024] [Indexed: 09/27/2024]
Abstract
Anticancer therapies with cisplatin and volasertib (BI-6727) were monitored by fluorescence lifetime imaging microscopy (FLIM) in live SK-Mel-2 melanoma cells. A CdSe/ZnS quantum dot functionalized with a peptide containing D-penicillamine and histidine (CdSe/ZnS-PH) was used as intracellular pH fluorescent probe. A faster cytosol acidification was observed for cells treated with cisplatin when compared to volasertib. The first changes in the intracellular pH were found after 2 hours of treatment with cisplatin and 8 hours with volasertib. Additionally, the relationship between cytosol acidification and apoptosis was investigated using an innovative methodology based on time-resolved fluorescence measurements. Similar low percentages of apoptotic cells were observed after short incubation periods (2 - 8 hours) with both drugs. In contrast, late apoptosis and death were found for a large fraction of cells during 24-hour incubation with cisplatin but not volasertib. Thus, the early acidification observed in cisplatin treatment could accelerate apoptosis and cell death. Despite volasertib treatment shows slower mechanism of action than cisplatin, similar inhibitory effects were found for both drugs at longer incubation periods (72 hours). This study proves the potential of CdSe/ZnS-PH nanoparticle as a fluorescence lifetime probe in the study of the mechanism of action of antitumor drugs.
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Affiliation(s)
- Diego Herrera-Ochoa
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, Albacete 02071, Spain
| | - Iván Bravo
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, Albacete 02071, Spain; Centro Regional de Investigaciones Biomédicas (CRIB), Unidad Asociada de Biomedicina (UCLM-CSIC), C/ Almansa, 14, Albacete 02008, Spain
| | - Andrés Garzón-Ruiz
- Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, Albacete 02071, Spain.
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Hosea R, Hillary S, Naqvi S, Wu S, Kasim V. The two sides of chromosomal instability: drivers and brakes in cancer. Signal Transduct Target Ther 2024; 9:75. [PMID: 38553459 PMCID: PMC10980778 DOI: 10.1038/s41392-024-01767-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/18/2024] [Accepted: 02/06/2024] [Indexed: 04/02/2024] Open
Abstract
Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule-kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the "just-right" model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.
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Affiliation(s)
- Rendy Hosea
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Sharon Hillary
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Sumera Naqvi
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Shourong Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China.
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China.
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China.
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China.
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Masci D, Naro C, Puxeddu M, Urbani A, Sette C, La Regina G, Silvestri R. Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment. Molecules 2023; 28:7513. [PMID: 38005235 PMCID: PMC10672974 DOI: 10.3390/molecules28227513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most heterogeneous and aggressive breast cancer subtypes with a high risk of death on recurrence. To date, TNBC is very difficult to treat due to the lack of an effective targeted therapy. However, recent advances in the molecular characterization of TNBC are encouraging the development of novel drugs and therapeutic combinations for its therapeutic management. In the present review, we will provide an overview of the currently available standard therapies and new emerging therapeutic strategies against TNBC, highlighting the promises that newly developed small molecules, repositioned drugs, and combination therapies have of improving treatment efficacy against these tumors.
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Affiliation(s)
- Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (D.M.); (A.U.)
| | - Chiara Naro
- Department of Neurosciences, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (C.N.); (C.S.)
- GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Michela Puxeddu
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
| | - Andrea Urbani
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (D.M.); (A.U.)
| | - Claudio Sette
- Department of Neurosciences, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (C.N.); (C.S.)
- GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Giuseppe La Regina
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
| | - Romano Silvestri
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
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Li Q, Qian W, Zhang Y, Hu L, Chen S, Xia Y. A new wave of innovations within the DNA damage response. Signal Transduct Target Ther 2023; 8:338. [PMID: 37679326 PMCID: PMC10485079 DOI: 10.1038/s41392-023-01548-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/01/2023] [Accepted: 06/27/2023] [Indexed: 09/09/2023] Open
Abstract
Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes could induce excessive DNA damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit to patients with breast cancer gene (BRCA) mutation or homologous recombination deficiency (HRD), which proves the concept of synthetic lethality in cancer treatment. Moreover, the other two scenarios of DDR inhibitor application, replication stress and combination with chemo- or radio- therapy, are under active clinical exploration. In this review, we revisited the progress of DDR targeting therapy beyond the launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, which could maintain the efficacy while mitigating side effects, may diversify the application scenarios of PARP inhibitor in clinic. Albeit with unavoidable on-mechanism toxicities, several small molecules targeting DNA damage checkpoints (gatekeepers) have shown great promise in preliminary clinical results, which may warrant further evaluations. In addition, inhibitors for other DNA repair pathways (caretakers) are also under active preclinical or clinical development. With these progresses and efforts, we envision that a new wave of innovations within DDR has come of age.
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Affiliation(s)
- Qi Li
- Domestic Discovery Service Unit, WuXi AppTec, 200131, Shanghai, China
| | - Wenyuan Qian
- Domestic Discovery Service Unit, WuXi AppTec, 200131, Shanghai, China
| | - Yang Zhang
- Domestic Discovery Service Unit, WuXi AppTec, 200131, Shanghai, China
| | - Lihong Hu
- Domestic Discovery Service Unit, WuXi AppTec, 200131, Shanghai, China
| | - Shuhui Chen
- Domestic Discovery Service Unit, WuXi AppTec, 200131, Shanghai, China
| | - Yuanfeng Xia
- Domestic Discovery Service Unit, WuXi AppTec, 200131, Shanghai, China.
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7
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Eggermont C, Gutierrez GJ, De Grève J, Giron P. Inhibition of PLK1 Destabilizes EGFR and Sensitizes EGFR-Mutated Lung Cancer Cells to Small Molecule Inhibitor Osimertinib. Cancers (Basel) 2023; 15:cancers15092589. [PMID: 37174055 PMCID: PMC10177332 DOI: 10.3390/cancers15092589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) have significantly prolonged survival in EGFR-mutant non-small cell lung cancer patients. However, the development of resistance mechanisms prohibits the curative potential of EGFR TKIs. Combination therapies emerge as a valuable approach to preventing or delaying disease progression. Here, we investigated the combined inhibition of polo-like kinase 1 (PLK1) and EGFR in TKI-sensitive EGFR-mutant NSCLC cells. The pharmacological inhibition of PLK1 destabilized EGFR levels and sensitized NSCLC cells to Osimertinib through induction of apoptosis. In addition, we found that c-Cbl, a ubiquitin ligase of EGFR, is a direct phosphorylation target of PLK1 and PLK1 impacts the stability of c-Cbl in a kinase-dependent manner. In conclusion, we describe a novel interaction between mutant EGFR and PLK1 that may be exploited in the clinic. Co-targeting PLK1 and EGFR may improve and prolong the clinical response to EGFR TKI in patients with an EGFR-mutated NSCLC.
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Affiliation(s)
- Carolien Eggermont
- Laboratory of Medical and Molecular Oncology, Oncology Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Gustavo J Gutierrez
- Laboratory of Pathophysiological Cell Signaling, Department of Biology, Faculty of Science and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
| | - Jacques De Grève
- Laboratory of Medical and Molecular Oncology, Oncology Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
- Centre for Medical Genetics, Research Group Reproduction and Genetics, Clinical Sciences, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Philippe Giron
- Laboratory of Medical and Molecular Oncology, Oncology Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
- Centre for Medical Genetics, Research Group Reproduction and Genetics, Clinical Sciences, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
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Valinciute G, Ecker J, Selt F, Hielscher T, Sigaud R, Ridinger J, Thatikonda V, Gatzweiler C, Robinson S, Talbot J, Bernardi F, Picard D, Blattner-Johnson M, Schmid S, Jones DT, van Tilburg CM, Capper D, Kool M, Remke M, Oehme I, Pfister SM, Roussel MF, Ayrault O, Witt O, Milde T. Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells. J Neurooncol 2023; 163:143-158. [PMID: 37183219 PMCID: PMC10232604 DOI: 10.1007/s11060-023-04319-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 04/19/2023] [Indexed: 05/16/2023]
Abstract
PURPOSE We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy. METHODS We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou-Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment. RESULTS MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination. CONCLUSION The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood-brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.
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Affiliation(s)
- Gintvile Valinciute
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
- Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jonas Ecker
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
- KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Florian Selt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
- KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Hielscher
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Romain Sigaud
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
| | - Johannes Ridinger
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
| | - Venu Thatikonda
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim RCV GmbH, Co KG, Doktor-Boehringer-Gasse 5-11, 1120, Vienna, Austria
| | - Charlotte Gatzweiler
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
| | - Sarah Robinson
- Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Julie Talbot
- Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France
- Université Paris Sud, Université Paris-Saclay, CNRS-UMR 3347 INSERM U1021, Orsay, France
| | - Flavia Bernardi
- Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France
- Université Paris Sud, Université Paris-Saclay, CNRS-UMR 3347 INSERM U1021, Orsay, France
| | - Daniel Picard
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
| | - Mirjam Blattner-Johnson
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Simone Schmid
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- DKTK Partner Site, Berlin, Germany
| | - David T Jones
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Cornelis M van Tilburg
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
- KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - David Capper
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- DKTK Partner Site, Berlin, Germany
| | - Marcel Kool
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Marc Remke
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
| | - Ina Oehme
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
| | - Stefan M Pfister
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
| | - Martine F Roussel
- Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Olivier Ayrault
- Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France
- Université Paris Sud, Université Paris-Saclay, CNRS-UMR 3347 INSERM U1021, Orsay, France
| | - Olaf Witt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany
- KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Till Milde
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Research (DKTK), Heidelberg, Germany.
- KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
- Hopp Children's Cancer Center Heidelberg (KiTZ), CCU Pediatric Oncology B310, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
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Wei X, Song M, Huang C, Yu Q, Jiang G, Jin G, Jia X, Shi Z. Effectiveness, safety and pharmacokinetics of Polo-like kinase 1 inhibitors in tumor therapy: A systematic review and meta-analysis. Front Oncol 2023; 13:1062885. [PMID: 36845678 PMCID: PMC9947705 DOI: 10.3389/fonc.2023.1062885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 01/24/2023] [Indexed: 02/11/2023] Open
Abstract
Objective To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis. Methods The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies. Results A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, I2 =0.0%, P<0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, I2 =77.6%, P=0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state. Conclusions Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.
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Affiliation(s)
- Xiao Wei
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Mingzhu Song
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Chan Huang
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Qiao Yu
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Guirong Jiang
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Guanghao Jin
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Xibiao Jia
- Key Laboratory of Ministry of Education of Birth Defects and Related Maternal and Child Diseases, West China Second Hospital, Sichuan University, Chengdu, China
| | - Zheng Shi
- Clinical Genetics Laboratory, Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, China
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10
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Javed A, Özduman G, Altun S, Duran D, Yerli D, Özar T, Şimşek F, Korkmaz KS. Mitotic Kinase Inhibitors as Therapeutic Interventions for Prostate Cancer: Evidence from In Vitro Studies. Endocr Metab Immune Disord Drug Targets 2023; 23:1699-1712. [PMID: 36872354 DOI: 10.2174/1871530323666230303092243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 03/07/2023]
Abstract
Prostate cancer is one of the devastating diseases characterized by genetic changes leading to uncontrolled growth and metastasis of the cells of the prostate gland and affects men worldwide. Conventional hormonal and chemotherapeutic agents are effective in mitigating the disease if diagnosed at an early stage. All dividing eukaryotic cells require mitotic progression for the maintenance of genomic integrity in progeny populations. The protein kinases, upon activation and de-activation in an ordered fashion, lead to spatial and temporal regulation of the cell division process. The entry into mitosis along with the progression into sub-phases of mitosis is ensured due to the activity of mitotic kinases. These kinases include Polo-Like-Kinase 1 (PLK1), Aurora kinases, and Cyclin-Dependent- Kinase 1 (CDK1), among others. The mitotic kinases, among others, are usually overexpressed in many cancers and can be targeted using small molecule inhibitors to reduce the effects of these regulators on mechanisms, such as regulation of genomic integrity and mitotic fidelity. In this review, we attempted to discuss the appropriate functions of mitotic kinases revealed through cell culture studies and the impact of their respective inhibitors derived in pre-clinical studies. The review is designed to elucidate the growing field of small molecule inhibitors and their functional screening or mode of action at the cellular and molecular level in the context of Prostate Cancer. Therefore, studies performed specifically on cells of Prostatic-origin are narrated in this review, culminating in a comprehensive view of the specific field of mitotic kinases that can be targeted for therapy of Prostate cancer.
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Affiliation(s)
- Aadil Javed
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
| | - Gülseren Özduman
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
| | - Sevda Altun
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
| | - Doğan Duran
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
| | - Dilan Yerli
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
| | - Tilbe Özar
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
| | - Faruk Şimşek
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
| | - Kemal Sami Korkmaz
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Bornova, Izmir, Turkey
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11
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Olawale F, Iwaloye O, Elekofehinti OO. Virtual screening of natural compounds as selective inhibitors of polo-like kinase-1 at C-terminal polo box and N-terminal catalytic domain. J Biomol Struct Dyn 2022; 40:13606-13624. [PMID: 34669551 DOI: 10.1080/07391102.2021.1991476] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The over-expression of Polo-like kinase-1 (PLK1) is associated with cancer prognosis due to its pivotal role in cell proliferation. The N-terminal catalytic domain (NCD) and C-terminal polo box domain (PBD) of PLK1 are critical for the activity of the protein. Drugs that inhibit PLK1 by targeting these domains are on clinical trials, but so far, none has been approved by FDA. Thus, this study targets the two domains of PLK1 to identify compounds with inhibitory potential. Four validated e-pharmacophore models from NCD (PDB ID: 2OU7 and 4J52) and PBD (PDB ID: 5NEI and 5NN2) were used to screen over 26,000 natural compounds from NPASS database. Hits were identified after the well-fitted compounds were subjected to molecular docking study and ADME prediction. The pIC50 and electronic behaviour of the identified hits selectively targeting NCD and PBD of PLK1 were predicted via an externally validated QSAR model and quantum mechanics. The results showed that CAA180504, CAA197326, CAA74619, CAA328856 modulating PLK1 at NCD, and CBB130581, CBB230713, CBB206123, CBB12656 and CBB267117 modulating PLK1 at PBD had better molecular docking scores, pharmacokinetics and drug-like properties than NCD (volasertib) and PBD (purpurogallin) reference inhibitors. The compounds all had satisfactory inhibitory (pIC50) values which range from 6.187 to 7.157. The electronic behaviours of understudied compounds using HOMO/LUMO and global descriptive parameters revealed the atomic portion of the compounds prone to donating and accepting electrons. In conclusion, the hit compounds identified from the library of natural compounds are worthy of further experimental validation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Femi Olawale
- Nano-Gene and Drug Delivery Group, Department of Biochemistry, School of Life Science, University of Kwazulu Natal, Durban, South Africa.,Department of Biochemistry, University of Lagos, Lagos, Nigeria
| | - Opeyemi Iwaloye
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Akure, Nigeria
| | - Olusola Olalekan Elekofehinti
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Akure, Nigeria
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12
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HER-2-mediated nano-delivery of molecular targeted drug potently suppresses orthotopic epithelial ovarian cancer and metastasis. Int J Pharm 2022; 625:122126. [PMID: 35995316 DOI: 10.1016/j.ijpharm.2022.122126] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/04/2022] [Accepted: 08/16/2022] [Indexed: 11/23/2022]
Abstract
The treatment of epithelial ovarian cancer (EOC) has made slow progress due to absence of effective adjuvant chemotherapy that is capable of preventing tumor relapse and metastasis. Molecular targeted drugs such as PARP and PLK1 inhibitors appear to be promising new treatments for EOC. The low EOC cell uptake, poor selectivity and pronounced toxicity, however, greatly compromise their clinical efficacy. Herein, we report that HER-2-mediated nano-delivery of clinical PLK1-targeted drug, volasertib (Vol), while causing little toxicity potently suppresses orthotopic EOC and metastasis. Anti-HER-2 antibody, trastuzumab (Tra), was conjugated onto Vol-loaded polymersomes via click chemistry yielding Tra-PVol with a size of 33 nm and optimally about 5 Tra per polymersome. Tra-PVol exhibited clearly stronger uptake and anti-tumor activity (IC50 = 59 nM) in HER-2 overexpressing SKOV-3 cells than free Vol and non-targeted PVol controls. Both biodistribution and therapeutic studies in orthotopic SKOV-3-Luc tumor-bearing mice displayed that Tra-PVol induced significantly better tumor deposition and retardation than PVol and that intraperitoneal administration outperformed intravenous administration. More interestingly, Tra-PVol was shown to effectively suppress the intraperitoneal metastasis and to markedly prolong the survival time of SKOV-3-Luc tumor-bearing mice. This HER-2 directed molecular therapy emerges as a potential treatment strategy toward EOC.
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13
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Nardou K, Nicolas M, Kuttler F, Cisarova K, Celik E, Quinodoz M, Riggi N, Michielin O, Rivolta C, Turcatti G, Moulin AP. Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening. Cancers (Basel) 2022; 14:cancers14061575. [PMID: 35326726 PMCID: PMC8946509 DOI: 10.3390/cancers14061575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 02/05/2023] Open
Abstract
Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor.
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Affiliation(s)
- Katya Nardou
- Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland; (K.N.); (M.N.)
| | - Michael Nicolas
- Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland; (K.N.); (M.N.)
| | - Fabien Kuttler
- Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; (F.K.); (G.T.)
| | - Katarina Cisarova
- Medical Genetics Unit, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland;
| | - Elifnaz Celik
- Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; (E.C.); (M.Q.); (C.R.)
- Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland
| | - Mathieu Quinodoz
- Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; (E.C.); (M.Q.); (C.R.)
- Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Nicolo Riggi
- Experimental Pathology, Institute of Pathology, Lausanne University, 1011 Lausanne, Switzerland;
| | - Olivier Michielin
- Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland;
| | - Carlo Rivolta
- Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; (E.C.); (M.Q.); (C.R.)
- Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Gerardo Turcatti
- Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; (F.K.); (G.T.)
| | - Alexandre Pierre Moulin
- Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland; (K.N.); (M.N.)
- Correspondence:
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14
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Choi W, Lee ES. Therapeutic Targeting of DNA Damage Response in Cancer. Int J Mol Sci 2022; 23:ijms23031701. [PMID: 35163621 PMCID: PMC8836062 DOI: 10.3390/ijms23031701] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/25/2022] [Accepted: 01/29/2022] [Indexed: 02/07/2023] Open
Abstract
DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.
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Affiliation(s)
- Wonyoung Choi
- Research Institute, National Cancer Center, Goyang 10408, Korea;
- Center for Clinical Trials, National Cancer Center, Goyang 10408, Korea
| | - Eun Sook Lee
- Research Institute, National Cancer Center, Goyang 10408, Korea;
- Center for Breast Cancer, National Cancer Center, Goyang 10408, Korea
- Correspondence: ; Tel.: +82-31-920-1633
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15
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Adjunctive Volasertib in Patients With Acute Myeloid Leukemia not Eligible for Standard Induction Therapy: A Randomized, Phase 3 Trial. Hemasphere 2021; 5:e617. [PMID: 34350385 PMCID: PMC8328241 DOI: 10.1097/hs9.0000000000000617] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1–10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95–2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8–1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.
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16
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Wang B, Huang X, Liang H, Yang H, Guo Z, Ai M, Zhang J, Khan M, Tian Y, Sun Q, Mao Z, Zheng R, Yuan Y. PLK1 Inhibition Sensitizes Breast Cancer Cells to Radiation via Suppressing Autophagy. Int J Radiat Oncol Biol Phys 2021; 110:1234-1247. [PMID: 33621661 DOI: 10.1016/j.ijrobp.2021.02.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/13/2021] [Accepted: 02/11/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE Polo-like kinase 1 (PLK1) is a protein kinase that is overexpressed in breast cancer and may represent an attractive target for breast cancer treatment. However, few studies have investigated the relationship between PLK1 and radiosensitivity in breast cancer. Here, we attempted to explore whether PLK1 inhibition could sensitize breast cancer cells to radiation. METHODS AND MATERIALS Breast cancer cells were treated with PLK1 small interference RNA or the PLK1-inhibitor, GSK461364. Cell proliferation was assessed using a colony formation assay. Cell cycle analyses were performed by flow cytometry. DNA damage, autophagy, and reactive oxygen species induced by ionizing radiation were detected by immunofluorescence, Western blot, and flow cytometry, respectively. Microtubule-associated protein 1 light chain 3 alpha (LC3) puncta were detected using an immunofluorescence assay. A clonogenic survival assay was used to determine the effect of PLK1 inhibition on cell radiosensitivity. A xenograft mouse model of breast cancer cells was used to investigate the potential synergistic effects of PLK1 inhibition and irradiation in vivo. Finally, the expression of PLK1 and LC3 in the breast cancer tissues was evaluated by immunohistochemistry. RESULTS PLK1 inhibition significantly suppressed the proliferation and increased the radiosensitivity of breast cancer cells. Pharmacologic inhibition of PLK1 by the selective inhibitor, GSK461364, enhanced the radiosensitivity of breast cancer cells in vivo (n = 4, P = .002). Mechanistically, PLK1 inhibition led to the downregulation of radiation-induced reactive oxygen species and autophagy, thereby increasing the radiosensitivity of breast cancer cells. Additionally, we detected a positive correlation between the expression of PLK1 and LC3 in human breast cancer samples (n = 102, R = 0.486, P = .005). CONCLUSIONS Our findings indicate that PLK1 inhibition enhances the radiosensitivity of breast cancer cells in a manner associated with the suppression of radiation-induced autophagy. The inhibition of PLK1 represents a promising strategy for radiosensitizing breast cancer.
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Affiliation(s)
- Baiyao Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Xiaoting Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Huiping Liang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Hongli Yang
- Department of Radiation Oncology, Shenzhen People's Hospital, Shenzhen, Guangdong Province, People's Republic of China
| | - Zhaoze Guo
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Meiling Ai
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Jian Zhang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Muhammad Khan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Yunhong Tian
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Quanquan Sun
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, People's Republic of China
| | - Zixu Mao
- Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, Georgia
| | - Ronghui Zheng
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China.
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Novais P, Silva PMA, Amorim I, Bousbaa H. Second-Generation Antimitotics in Cancer Clinical Trials. Pharmaceutics 2021; 13:1011. [PMID: 34371703 PMCID: PMC8309102 DOI: 10.3390/pharmaceutics13071011] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/24/2021] [Accepted: 06/29/2021] [Indexed: 12/17/2022] Open
Abstract
Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA's effectiveness. With the desire to overcome some of the MTA's limitations, mitotic and SAC components have attracted great interest as promising microtubule-independent targets, leading to the so-called second-generation antimitotics (SGAs). The identification of inhibitors against most of these targets, and the promising outcomes achieved in preclinical assays, has sparked the interest of academia and industry. Many of these inhibitors have entered clinical trials; however, they exhibited limited efficacy as monotherapy, and failed to go beyond phase II trials. Combination therapies are emerging as promising strategies to give a second chance to these SGAs. Here, an updated view of the SGAs that reached clinical trials is here provided, together with future research directions, focusing on inhibitors that target the SAC components.
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Affiliation(s)
- Pedro Novais
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal; (P.N.); (P.M.A.S.)
- Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
- ICBAS, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Patrícia M. A. Silva
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal; (P.N.); (P.M.A.S.)
| | - Isabel Amorim
- GreenUPorto (Sustainable Agrifood Production) Research Center, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal;
| | - Hassan Bousbaa
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal; (P.N.); (P.M.A.S.)
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Inoue A, Robinson FS, Minelli R, Tomihara H, Rizi BS, Rose JL, Kodama T, Srinivasan S, Harris AL, Zuniga AM, Mullinax RA, Ma X, Seth S, Daniele JR, Peoples MD, Loponte S, Akdemir KC, Khor TO, Feng N, Roszik J, Sobieski MM, Brunell D, Stephan C, Giuliani V, Deem AK, Shingu T, Deribe YL, Menter DG, Heffernan TP, Viale A, Bristow CA, Kopetz S, Draetta GF, Genovese G, Carugo A. Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer. Gastroenterology 2021; 161:196-210. [PMID: 33745946 PMCID: PMC8238881 DOI: 10.1053/j.gastro.2021.03.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 02/24/2021] [Accepted: 03/05/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. METHODS To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC. RESULTS Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC. CONCLUSIONS Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.
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Affiliation(s)
- Akira Inoue
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan.
| | - Frederick S Robinson
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rosalba Minelli
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hideo Tomihara
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bahar Salimian Rizi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Johnathon L Rose
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Sanjana Srinivasan
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angela L Harris
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andy M Zuniga
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert A Mullinax
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaoyan Ma
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sahil Seth
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joseph R Daniele
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael D Peoples
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sara Loponte
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kadir C Akdemir
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tin Oo Khor
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ningping Feng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jason Roszik
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mary M Sobieski
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - David Brunell
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - Clifford Stephan
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - Virginia Giuliani
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angela K Deem
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Takashi Shingu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yonathan Lissanu Deribe
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Timothy P Heffernan
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andrea Viale
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher A Bristow
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Giulio F Draetta
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Giannicola Genovese
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Alessandro Carugo
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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19
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Ghasemishahrestani Z, Melo Mattos LM, Tilli TM, Santos ALSD, Pereira MD. Pieces of the Complex Puzzle of Cancer Cell Energy Metabolism: An Overview of Energy Metabolism and Alternatives for Targeted Cancer Therapy. Curr Med Chem 2021; 28:3514-3534. [PMID: 32814521 DOI: 10.2174/0929867327999200819123357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/17/2020] [Accepted: 07/22/2020] [Indexed: 11/22/2022]
Abstract
Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called the 'Warburg effect'. Currently, it has been accepted that the Warburg effect is not compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused on the bioenergetic and biosynthetic pathways in order to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrates, amino acids and lipids have already been reported for cancer cells and this might play an important role in cancer progression. To the best of our knowledge, these changes are mainly attributed to genetic reprogramming which leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes that are highly relevant for cellular energy are targets of oncogenes (e.g. PI3K, HIF1, and Myc) and tumor suppressor proteins (e.g. p53). As a consequence of extensive studies on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, in addition to influencing genetic reprogramming in cancer cells. In this review, we present an overview of cancer cell metabolism (carbohydrate, amino acid, and lipid), and also describe oncogenes and tumor suppressors that directly affect the metabolism. We also discuss some of the potential therapeutic candidates which have been designed to target and disrupt the main driving forces associated with cancer cell metabolism and proliferation.
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Affiliation(s)
- Zeinab Ghasemishahrestani
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Larissa Maura Melo Mattos
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tatiana Martins Tilli
- Centro de Desenvolvimento Tecnologico em Saude, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil
| | - André Luis Souza Dos Santos
- Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcos Dias Pereira
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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20
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Oh Y, Jung H, Kim H, Baek J, Jun J, Cho H, Im D, Hah JM. Design and Synthesis of a Novel PLK1 Inhibitor Scaffold Using a Hybridized 3D-QSAR Model. Int J Mol Sci 2021; 22:3865. [PMID: 33917995 PMCID: PMC8068361 DOI: 10.3390/ijms22083865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/31/2021] [Accepted: 04/06/2021] [Indexed: 12/20/2022] Open
Abstract
Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Given the hybridized 3D-QSAR models, we designed and synthesized 4-benzyloxy-1-(2-arylaminopyridin-4-yl)-1H-pyrazole-3-carboxamides, and we inspected its inhibitory activities to identify novel PLK1 inhibitors with decent potency and selectivity.
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Affiliation(s)
| | | | | | | | | | | | | | - Jung-Mi Hah
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Korea; (Y.O.); (H.J.); (H.K.); (J.B.); (J.J.); (H.C.); (D.I.)
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21
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Grieselhuber NR, Mims AS. Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches. Curr Hematol Malig Rep 2021; 16:192-206. [PMID: 33738705 DOI: 10.1007/s11899-021-00621-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow that has a poor prognosis with traditional cytotoxic chemotherapy, especially in elderly patients. In recent years, small molecule inhibitors targeting AML-associated IDH1, IDH2, and FLT3 mutations have been FDA approved. However, the majority of AML cases do not have a targetable mutation. A variety of novel agents targeting both previously untargetable mutations and general pathways in AML are currently being investigated. Herein, we review selected new targeted therapies currently in early-phase clinical investigation in AML. RECENT FINDINGS The DOT1L inhibitor pinometostat in KMT2A-rearranged AML, the menin inhibitors KO-539 and SYNDX-5613 in KMT2Ar and NPM1-mutated AML, and the mutant TP53 inhibitor APR-246 are examples of novel agents targeting specific mutations in AML. In addition, BET inhibitors, polo-like kinase inhibitors, and MDM2 inhibitors are promising new drug classes for AML which do not depend on the presence of a particular mutation. AML remains in incurable disease for many patients but advances in genomics, epigenetics, and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in ongoing clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.
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Affiliation(s)
- Nicole R Grieselhuber
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Alice S Mims
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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22
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Grohmann C, Walker F, Devlin M, Luo MX, Chüeh AC, Doherty J, Vaillant F, Ho GY, Wakefield MJ, Weeden CE, Kamili A, Murray J, Po'uha ST, Weinstock J, Kane SR, Faux MC, Broekhuizen E, Zheng Y, Shield-Artin K, Kershaw NJ, Tan CW, Witchard HM, Ebert G, Charman SA, Street I, Kavallaris M, Haber M, Fletcher JI, Asselin-Labat ML, Scott CL, Visvader JE, Lindeman GJ, Watson KG, Burgess AW, Lessene G. Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors. Cell Death Dis 2021; 12:268. [PMID: 33712556 PMCID: PMC7955127 DOI: 10.1038/s41419-020-03269-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 12/29/2022]
Abstract
Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.
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Affiliation(s)
- Christoph Grohmann
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia.
| | - Francesca Walker
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
- Ludwig Institute for Cancer Research, Melbourne, VIC, 3000, Australia
| | - Mark Devlin
- Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre building, Melbourne, 3000, Australia
- Cancer Therapeutics CRC, Melbourne, VIC, 3000, Australia
| | - Meng-Xiao Luo
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Anderly C Chüeh
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
- Cancer Therapeutics CRC, Melbourne, VIC, 3000, Australia
| | - Judy Doherty
- Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre building, Melbourne, 3000, Australia
- Cancer Therapeutics CRC, Melbourne, VIC, 3000, Australia
| | - François Vaillant
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Gwo-Yaw Ho
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Matthew J Wakefield
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
- The University of Melbourne, Department of Obstetrics and Gynaecology, Parkville, VIC, 3050, Australia
| | - Clare E Weeden
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Alvin Kamili
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia
- School of Women's and Children's Health, UNSW, Sydney, NSW, 2052, Australia
| | - Jayne Murray
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia
| | - Sela T Po'uha
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia
| | - Janet Weinstock
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
- Ludwig Institute for Cancer Research, Melbourne, VIC, 3000, Australia
| | - Serena R Kane
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Maree C Faux
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Esmee Broekhuizen
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Ye Zheng
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Kristy Shield-Artin
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Nadia J Kershaw
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
- Ludwig Institute for Cancer Research, Melbourne, VIC, 3000, Australia
| | - Chin Wee Tan
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Helen M Witchard
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
| | - Gregor Ebert
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Susan A Charman
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, VIC, 3052, Australia
| | - Ian Street
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- Cancer Therapeutics CRC, Melbourne, VIC, 3000, Australia
| | - Maria Kavallaris
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia
- ARC Centre of Excellence in Convergent Bionano Science and Technology, Australian Centre for Nanomedicine, UNSW, Sydney, NSW, 2052, Australia
| | - Michelle Haber
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia
| | - Jamie I Fletcher
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia
- School of Women's and Children's Health, UNSW, Sydney, NSW, 2052, Australia
| | - Marie-Liesse Asselin-Labat
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Clare L Scott
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
- Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre building, Melbourne, 3000, Australia
- The University of Melbourne, Department of Obstetrics and Gynaecology, Parkville, VIC, 3050, Australia
| | - Jane E Visvader
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Geoffrey J Lindeman
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
- Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre building, Melbourne, 3000, Australia
- The University of Melbourne, Department of Medicine, Parkville, VIC, 3000, Australia
| | - Keith G Watson
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia
| | - Antony W Burgess
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia.
- Ludwig Institute for Cancer Research, Melbourne, VIC, 3000, Australia.
| | - Guillaume Lessene
- Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.
- The University of Melbourne, Department of Medical Biology, Parkville, VIC, 3050, Australia.
- The University of Melbourne, Department of Pharmacology and Therapeutics, Parkville, VIC, 3050, Australia.
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23
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Shakeel I, Basheer N, Hasan GM, Afzal M, Hassan MI. Polo-like Kinase 1 as an emerging drug target: structure, function and therapeutic implications. J Drug Target 2021; 29:168-184. [PMID: 32886539 DOI: 10.1080/1061186x.2020.1818760] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/04/2020] [Accepted: 08/29/2020] [Indexed: 12/22/2022]
Abstract
Polo-like kinase 1 (PLK1) is a conserved mitotic serine-threonine protein kinase, functions as a regulatory protein, and is involved in the progression of the mitotic cycle. It plays important roles in the regulation of cell division, maintenance of genome stability, in spindle assembly, mitosis, and DNA-damage response. PLK1 is consist of a N-terminal serine-threonine kinase domain, and a C-terminal Polo-box domain (regulatory site). The expression of PLK1 is controlled by transcription repressor in the G1 stage and transcription activators in the G2 stage of the cell cycle. Overexpression of PLK1 results in undermining of checkpoints causes excessive cellular division resulting in abnormal cell growth, leading to the development of cancer. Blocking the expression of PLK1 by an antibody, RNA interference, or kinase inhibitors, causes a subsequent reduction in the proliferation of tumour cells and induction of apoptosis in tumour cells without affecting the healthy cells, suggesting an attractive target for drug development. In this review, we discuss detailed information on expression, gene and protein structures, role in different diseases, and progress in the design and development of PLK1 inhibitors. We have performed an in-depth analysis of the PLK1 inhibitors and their therapeutic implications with special focus to the cancer therapeutics.
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Affiliation(s)
- Ilma Shakeel
- Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Neha Basheer
- Institute of Neuroimmunology, Slovak Republic Bratislava, Bratislava, Slovakia
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia
| | - Mohammad Afzal
- Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
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24
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Weston LJ, Stackhouse TL, Spinelli KJ, Boutros SW, Rose EP, Osterberg VR, Luk KC, Raber J, Weissman TA, Unni VK. Genetic deletion of Polo-like kinase 2 reduces alpha-synuclein serine-129 phosphorylation in presynaptic terminals but not Lewy bodies. J Biol Chem 2021; 296:100273. [PMID: 33428941 PMCID: PMC7948797 DOI: 10.1016/j.jbc.2021.100273] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/05/2021] [Accepted: 01/07/2021] [Indexed: 12/29/2022] Open
Abstract
Phosphorylation of alpha-synuclein at serine-129 is an important marker of pathologically relevant, aggregated forms of the protein in several important human diseases, including Parkinson's disease, Dementia with Lewy bodies, and Multiple system atrophy. Although several kinases have been shown to be capable of phosphorylating alpha-synuclein in various model systems, the identity of the kinase that phosphorylates alpha-synuclein in the Lewy body remains unknown. One member of the Polo-like kinase family, PLK2, is a strong candidate for being the Lewy body kinase. To examine this possibility, we have used a combination of approaches, including biochemical, immunohistochemical, and in vivo multiphoton imaging techniques to study the consequences of PLK2 genetic deletion on alpha-synuclein phosphorylation in both the presynaptic terminal and preformed fibril-induced Lewy body pathology in mouse cortex. We find that PLK2 deletion reduces presynaptic terminal alpha-synuclein serine-129 phosphorylation, but has no effect on Lewy body phosphorylation levels. Serine-129 mutation to the phosphomimetic alanine or the unphosphorylatable analog aspartate does not change the rate of cell death of Lewy inclusion-bearing neurons in our in vivo multiphoton imaging paradigm, but PLK2 deletion does slow the rate of neuronal death. Our data indicate that inhibition of PLK2 represents a promising avenue for developing new therapeutics, but that the mechanism of neuroprotection by PLK2 inhibition is not likely due to reducing alpha-synuclein serine-129 phosphorylation and that the true Lewy body kinase still awaits discovery.
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Affiliation(s)
- Leah J Weston
- Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, USA
| | - Teresa L Stackhouse
- Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, USA
| | - Kateri J Spinelli
- Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, USA
| | - Sydney W Boutros
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA
| | - Elizabeth P Rose
- Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, USA; Neuroscience Graduate Program, Vollum Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Valerie R Osterberg
- Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, USA
| | - Kelvin C Luk
- Department of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jacob Raber
- Departments of Behavioral Neuroscience, Neurology, and Radiation Medicine and Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, Oregon, USA
| | | | - Vivek K Unni
- Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, USA; OHSU Parkinson Center, Oregon Health & Science University, Portland, Oregon, USA.
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25
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Cortes J, Podoltsev N, Kantarjian H, Borthakur G, Zeidan AM, Stahl M, Taube T, Fagan N, Rajeswari S, Uy GL. Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia. Int J Hematol 2021; 113:92-99. [PMID: 32951163 DOI: 10.1007/s12185-020-02994-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 06/19/2020] [Accepted: 09/07/2020] [Indexed: 11/30/2022]
Abstract
Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.
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Affiliation(s)
- Jorge Cortes
- Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - Nikolai Podoltsev
- Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA
| | - Hagop Kantarjian
- Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Gautam Borthakur
- Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Amer M Zeidan
- Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA
| | - Maximilian Stahl
- Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA
| | - Tillmann Taube
- Boehringer Ingelheim International GmbH, Biberach, Germany
| | - Nora Fagan
- Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | | | - Geoffrey L Uy
- Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
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26
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Bibi N, Hupp T, Kamal MA, Rashid S. Elucidation of PLK1 Linked Biomarkers in Oesophageal Cancer Cell Lines: A Step Towards Novel Signaling Pathways by p53 and PLK1-Linked Functions Crosstalk. Protein Pept Lett 2021; 28:340-358. [PMID: 32875973 DOI: 10.2174/0929866527999200901201837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 06/30/2020] [Accepted: 07/03/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Oesophgeal adenocarcinoma (OAC) is the most frequent cause of cancer death. POLO-like kinase 1 (PLK1) is overexpressed in broad spectrum of tumors and has prognostic value in many cancers including esophageal cancer, suggesting its potential as a therapeutic target. p53, the guardian of genome is the most important tumor suppressors that represses the promoter of PLK1, whereas tumor cells with inactive p53 are arrested in mitosis due to DNA damage. PLK1 expression has been linked to the elevated p53 expression and has been shown to act as a biomarker that predicts poor prognosis in OAC. OBJECTIVES The aim of the present study was identification of PLK1 associated phosphorylation targets in p53 mutant and p53 normal cells to explore the downstream signaling evets. METHODS Here we develop a proof-of-concept phospho-proteomics approach to identify possible biomarkers that can be used to identify mutant p53 or wild-type p53 pathways. We treated PLK1 asynchronously followed by mass spectrometry data analysis. Protein networking and motif analysis tools were used to identify the significant clusters and potential biomarkers. RESULTS We investigated approximately 1300 potential PLK1-dependent phosphopeptides by LCMS/ MS. In total, 2216 and 1155 high confidence phosphosites were identified in CP-A (p53+) and OE33 (p53-) cell lines owing to PLK1 inhibition. Further clustering and motif assessment uncovered many significant biomarkers with known and novel link to PLK1. CONCLUSION Taken together, our study suggests that PLK1 may serve as a potential therapeutic target in human OAC. The data highlight the efficacy and specificity of small molecule PLK1 kinase inhibitors to identify novel signaling pathways in vivo.
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Affiliation(s)
- Nousheen Bibi
- Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan
| | - Ted Hupp
- Edinburgh Cancer Research Center, University of Edinburgh, Scotland, United Kingdom
| | - Mohammad Amjad Kamal
- West China School of Nursing / Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, Saudi Arabia
| | - Sajid Rashid
- National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan
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Alverez CN, Park JE, Toti KS, Xia Y, Krausz KW, Rai G, Bang JK, Gonzalez FJ, Jacobson KA, Lee KS. Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1. J Med Chem 2020; 63:14087-14117. [PMID: 33175530 PMCID: PMC7769008 DOI: 10.1021/acs.jmedchem.0c01669] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cytotoxicity, mainly from off-target cross reactivity. The C-terminal noncatalytic polo-box domain (PBD) of Plk1 has emerged as an attractive target for generating new protein-protein interaction inhibitors. Here, we identified a 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one scaffold that efficiently inhibits Plk1 PBD but not its related Plk2 and Plk3 PBDs. Structure-activity relationship studies led to multiple inhibitors having ≥10-fold higher inhibitory activity than the previously characterized Plk1 PBD-specific phosphopeptide, PLHSpT (Kd ∼ 450 nM). In addition, S-methyl prodrugs effectively inhibited mitotic progression and cell proliferation and their metabolic stability was determined. These data describe a novel class of small-molecule inhibitors that offer a promising avenue for future drug discovery against Plk1-addicted cancers.
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Affiliation(s)
- Celeste N Alverez
- Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States
| | - Jung-Eun Park
- Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Kiran S Toti
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Yangliu Xia
- Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Kristopher W Krausz
- Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Ganesha Rai
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States
| | - Jeong K Bang
- Division of Magnetic Resonance, Korea Basic Science Institute, Cheongju 28119, Republic of Korea
| | - Frank J Gonzalez
- Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Kenneth A Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Kyung S Lee
- Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
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Lang I, Liu D, Fritsch H, Taube T, Chizhikov E, Liptai B. Potential Drug-Drug Interactions with Combination Volasertib + Itraconazole: A Phase I, Fixed-sequence Study in Patients with Solid Tumors. Clin Ther 2020; 42:2214-2224. [PMID: 33139055 DOI: 10.1016/j.clinthera.2020.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/14/2020] [Accepted: 09/30/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE This drug-drug interaction study determined whether the metabolism and distribution of the Polo-like kinase 1 inhibitor, volasertib, is affected by co-administration of the P-glycoprotein and cytochrome P-450 3A4 inhibitor, itraconazole. METHODS This was an uncontrolled, open-label, fixed-sequence trial of two 21-day treatment cycles in patients with various solid tumors. In cycle 1 (test), eligible patients were administered volasertib (day 1) plus itraconazole (days -3 to 15). In cycle 2 (reference), patients received volasertib monotherapy. The primary end point was the influence of co-administration of itraconazole on the pharmacokinetic profile (AUC0-tz; Cmax) of volasertib and its main metabolite, CD 10899, compared with that of volasertib monotherapy. Other end points included tolerability and preliminary therapeutic efficacy. FINDINGS Concurrent administration of itraconazole resulted in a slight reduction in the AUC0-tz (geometric mean ratio, 93.6%; 90% CI, 82.1%-106.8%) and a 20% reduction in Cmax (geometric mean ratio, 79.4%; 90% CI, 64.9%-97.1%) of volasertib compared with monotherapy. Of note, concurrent administration of itraconazole + volasertib had no effect on the AUC0-∞ of volasertib. More patients reported at least one drug-related adverse event in cycle 1 than in cycle 2 (75% vs 71%). The most commonly reported drug-related adverse events (cycles 1 and 2) were thrombocytopenia (68% and 33%, respectively), leukopenia (50% and 46%), and anemia (36% and 33%). No objective responses were observed. Stable disease was observed in 25 of 28 patients (89%). IMPLICATIONS While there was no clear evidence of a pharmacokinetic interaction between volasertib and itraconazole, co-administration reduced the tolerability of volasertib. Clinicaltrials.gov identifier: NCT01772563.
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Affiliation(s)
- Istvan Lang
- Medical Oncology Unit, Istenhegyi Géndiagnosztika Private Health Center, Budapest, Hungary.
| | - Dan Liu
- Boehringer Ingelheim International GmbH, Biberach, Germany
| | - Holger Fritsch
- Boehringer Ingelheim International GmbH, Biberach, Germany
| | - Tillmann Taube
- Boehringer Ingelheim International GmbH, Biberach, Germany
| | | | - Bela Liptai
- PRA Health Sciences Hungary, Budapest, Hungary
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Chow AKM, Yau SWL, Ng L. Novel molecular targets in hepatocellular carcinoma. World J Clin Oncol 2020; 11:589-605. [PMID: 32879846 PMCID: PMC7443834 DOI: 10.5306/wjco.v11.i8.589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/04/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.
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Affiliation(s)
- Ariel Ka-Man Chow
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Simon Wing-Lung Yau
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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García IA, Garro C, Fernandez E, Soria G. Therapeutic opportunities for PLK1 inhibitors: Spotlight on BRCA1-deficiency and triple negative breast cancers. Mutat Res 2020; 821:111693. [PMID: 32172132 DOI: 10.1016/j.mrfmmm.2020.111693] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/21/2020] [Accepted: 02/24/2020] [Indexed: 02/07/2023]
Abstract
Polo-Like Kinases (PLKs) are central players of mitotic progression in Eukaryotes. Given the intimate relationship between cell cycle progression and cancer development, PLKs in general and PLK1 in particular have been thoroughly studied as biomarkers and potential therapeutic targets in oncology. The oncogenic properties of PLK1 overexpression across different types of human cancers are attributed to its roles in promoting mitotic entry, centrosome maturation, spindle assembly and cytokinesis. While several academic labs and pharmaceutical companies were able to develop potent and selective inhibitors of PLK1 (PLK1i) for preclinical research, such compounds have reached only limited success in clinical trials despite their great pharmacokinetics. Even though this could be attributed to multiple causes, the housekeeping roles of PLK1 in both normal and cancer cells are most likely the main reason for clinical trials failure and withdraw due to toxicities issues. Therefore, great efforts are being invested to position PLK1i in the treatment of specific types of cancers with revised dosages schemes. In this mini review we focus on two potential niches for PLK1i that are supported by recent evidence: triple negative breast cancers (TNBCs) and BRCA1-deficient cancers. On the one hand, we recollect several lines of strong evidence indicating that TNBCs are among the cancers with highest PLK1 expression and sensitivity to PLK1i. These findings are encouraging because of the limited therapeutics options available for TNBC patients, which rely mainly on classic chemotherapy. On the other hand, we discuss recent evidence that unveils synthetic lethality induction by PLK1 inhibition in BRCA1-deficient cancers cells. This previously unforeseen therapeutic link between PLK1 and BRCA1 is promising because it defines novel therapeutic opportunities for PLK1i not only for breast cancer (i.e. TNBCs with BRCA1 deficiencies), but also for other types of cancers with BRCA1-deficiencies, such as pancreatic and prostate cancers.
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Affiliation(s)
- Iris Alejandra García
- Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas, CIDIE-CONICET. Universidad Católica de Córdoba, Córdoba, Argentina; Departamento de Bioquímica Clínica. Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Cintia Garro
- Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina; Departamento de Bioquímica Clínica. Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Elmer Fernandez
- Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas, CIDIE-CONICET. Universidad Católica de Córdoba, Córdoba, Argentina; Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Gastón Soria
- Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina; Departamento de Bioquímica Clínica. Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
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31
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Parrilla A, Barber M, Majem B, Castellví J, Morote J, Sánchez JL, Pérez-Benavente A, Segura MF, Gil-Moreno A, Santamaria A. Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer. Cancers (Basel) 2020; 12:E886. [PMID: 32268485 PMCID: PMC7226261 DOI: 10.3390/cancers12040886] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Identifying novel actionable factors that critically contribute to tumorigenesis is essential in ovarian cancer, an aggressive and disseminative tumor, with limited therapeutic options available. Here we show that Aurora Borealis (BORA), a mitotic protein that plays a key role in activating the master mitotic kinase polo-like kinase 1 (PLK1), has an oncogenic role in ovarian cancer. Gain and loss of function assays on mouse models and ex vivo patient-derived ascites cultures revealed an oncogenic role of BORA in tumor development and a transcriptome-analysis in clinically representative models depicted BORA's role in survival, dissemination and inflammatory cancer related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA displayed synergistic effect in ovarian cancer models, offering promising therapeutic value. Altogether, our findings uncovered for the first time a critical role of BORA in the viability of human cancer cells providing potential novel therapeutic opportunities for ovarian cancer management.
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Affiliation(s)
- Alfonso Parrilla
- Group of Biomedical Research in Urology, Cell Cycle and Cancer Laboratory, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; (A.P.); (M.B.); (B.M.); (J.M.)
| | - Marta Barber
- Group of Biomedical Research in Urology, Cell Cycle and Cancer Laboratory, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; (A.P.); (M.B.); (B.M.); (J.M.)
| | - Blanca Majem
- Group of Biomedical Research in Urology, Cell Cycle and Cancer Laboratory, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; (A.P.); (M.B.); (B.M.); (J.M.)
| | - Josep Castellví
- Department of Pathology, Vall Hebron University Hospital, 08035 Barcelona, Spain;
| | - Juan Morote
- Group of Biomedical Research in Urology, Cell Cycle and Cancer Laboratory, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; (A.P.); (M.B.); (B.M.); (J.M.)
- Department of Urology, Vall Hebron University Hospital, 08035 Barcelona, Spain
| | - José Luis Sánchez
- Group of Biomedical Research in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), CIBERONC, 08035 Barcelona, Spain; (J.L.S.); (A.P.-B.); (A.G.-M.)
- Department of Gynecology, Vall Hebron University Hospital, 08035 Barcelona, Spain
| | - Asunción Pérez-Benavente
- Group of Biomedical Research in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), CIBERONC, 08035 Barcelona, Spain; (J.L.S.); (A.P.-B.); (A.G.-M.)
- Department of Gynecology, Vall Hebron University Hospital, 08035 Barcelona, Spain
| | - Miguel F. Segura
- Group of Translational Research in Child and Adolescent Cancer, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain;
| | - Antonio Gil-Moreno
- Group of Biomedical Research in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), CIBERONC, 08035 Barcelona, Spain; (J.L.S.); (A.P.-B.); (A.G.-M.)
- Department of Gynecology, Vall Hebron University Hospital, 08035 Barcelona, Spain
| | - Anna Santamaria
- Group of Biomedical Research in Urology, Cell Cycle and Cancer Laboratory, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; (A.P.); (M.B.); (B.M.); (J.M.)
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Reda M, Ngamcherdtrakul W, Gu S, Bejan DS, Siriwon N, Gray JW, Yantasee W. PLK1 and EGFR targeted nanoparticle as a radiation sensitizer for non-small cell lung cancer. Cancer Lett 2019; 467:9-18. [PMID: 31563561 PMCID: PMC6927399 DOI: 10.1016/j.canlet.2019.09.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/31/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023]
Abstract
Radiation sensitizers that can selectively act on cancer cells hold great promise to patients who receive radiation therapy. We developed a novel targeted therapy and radiation sensitizer for non-small cell lung cancer (NSCLC) based on cetuximab conjugated nanoparticle that targets epidermal growth factor receptor (EGFR) and delivers small interfering RNA (siRNA) against polo-like kinase 1 (PLK1). EGFR is overexpressed in 50% of lung cancer patients and a mediator of DNA repair, while PLK1 is a key mitotic regulator whose inhibition enhances radiation sensitivity. The nanoparticle construct (C-siPLK1-NP) effectively targets EGFR + NSCLC cells and reduces PLK1 expression, leading to G2/M arrest and cell death. Furthermore, we show a synergistic combination between C-siPLK1-NP and radiation, which was confirmed in vivo in A549 flank tumors. We also demonstrate the translational potential of C-siPLK1-NP as a systemic therapeutic in an orthotopic lung tumor model, where administration of C-siPLK1-NP reduced tumor growth and led to prolonged survival. Our findings demonstrate that C-siPLK1-NP is effective as a targeted therapy and as a potent radiation sensitizer for NSCLC. Potential application to other EGFR + cancer types such as colorectal and breast cancer is also demonstrated.
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Affiliation(s)
- Moataz Reda
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
| | | | - Shenda Gu
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
| | | | - Natnaree Siriwon
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Joe W Gray
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Wassana Yantasee
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA; PDX Pharmaceuticals, LLC, Portland, OR, 97239, USA.
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Giordano A, Liu Y, Armeson K, Park Y, Ridinger M, Erlander M, Reuben J, Britten C, Kappler C, Yeh E, Ethier S. Polo-like kinase 1 (Plk1) inhibition synergizes with taxanes in triple negative breast cancer. PLoS One 2019; 14:e0224420. [PMID: 31751384 PMCID: PMC6872222 DOI: 10.1371/journal.pone.0224420] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 10/14/2019] [Indexed: 12/13/2022] Open
Abstract
Within triple negative breast cancer, several molecular subtypes have been identified, underlying the heterogeneity of such an aggressive disease. The basal-like subtype is characterized by mutations in the TP53 gene, and is associated with a low pathologic complete response rate following neoadjuvant chemotherapy. In a genome-scale short hairpin RNA (shRNA) screen of breast cancer cells, polo-like kinase 1 (Plk1) was a frequent and strong hit in the basal breast cancer cell lines indicating its importance for growth and survival of these breast cancer cells. Plk1 regulates progression of cells through the G2-M phase of the cell cycle. We assessed the activity of two ATP-competitive Plk1 inhibitors, GSK461364 and onvansertib, alone and with a taxane in a set of triple negative breast cancer cell lines and in vivo. GSK461364 showed synergism with docetaxel in SUM149 (Combination Index 0.70) and SUM159 (CI, 0.62). GSK461364 in combination with docetaxel decreased the clonogenic potential (interaction test for SUM149 and SUM159, p<0.001 and p = 0.01, respectively) and the tumorsphere formation of SUM149 and SUM159 (interaction test, p = 0.01 and p< 0.001). In the SUM159 xenograft model, onvansertib plus paclitaxel significantly decreased tumor volume compared to single agent paclitaxel (p<0.0001). Inhibition of Plk1 in combination with taxanes shows promising results in a subset of triple negative breast cancer intrinsically resistant to chemotherapy. Onvansertib showed significant tumor volume shrinkage when combined with paclitaxel in vivo and should be considered in clinical trials for the treatment of triple negative cancers.
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Affiliation(s)
- Antonio Giordano
- Department of Medicine, Division of Hematology & Oncology, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Yueying Liu
- Department of Medicine, Division of Hematology & Oncology, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Kent Armeson
- Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Yeonhee Park
- Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Maya Ridinger
- Trovagene Oncology, San Diego, California, United States of America
| | - Mark Erlander
- Trovagene Oncology, San Diego, California, United States of America
| | - James Reuben
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Carolyn Britten
- Department of Medicine, Division of Hematology & Oncology, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Christiana Kappler
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Elizabeth Yeh
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indianapolis, United States of America
| | - Stephen Ethier
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
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Doz F, Locatelli F, Baruchel A, Blin N, De Moerloose B, Frappaz D, Dworzak M, Fischer M, Stary J, Fuertig R, Riemann K, Taube T, Reinhardt D. Phase I dose-escalation study of volasertib in pediatric patients with acute leukemia or advanced solid tumors. Pediatr Blood Cancer 2019; 66:e27900. [PMID: 31276318 DOI: 10.1002/pbc.27900] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 05/17/2019] [Accepted: 05/29/2019] [Indexed: 11/10/2022]
Abstract
BACKGROUND Volasertib induces mitotic arrest and apoptosis by targeting Polo-like kinases. In this phase I dose-escalation study, the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary efficacy of volasertib were determined in pediatric patients. METHODS Patients aged 2 to <18 years with relapsed/refractory acute leukemia/advanced solid tumors (ST) without available effective treatments were enrolled-cohort C1 (aged 2 to <12 years); cohort C2 (aged 12 to <18 years). The patients received volasertib intravenously (starting dose: 200 mg/m2 body surface area on day 1, every 14 days). The primary endpoint was the pediatric MTD for further development. RESULTS Twenty-two patients received treatment (C1: leukemia, n = 4; ST, n = 8; C2: leukemia, n = 3; ST, n = 7). No dose-limiting toxicities (DLTs) occurred up to 300 mg/m2 volasertib in C1; two patients in C2, at 250 mg/m2 volasertib, had DLTs in cycle 1, one of which led to death; therefore, the MTD of volasertib in C2 was 200 mg/m2 . The most common grade 3/4 adverse events (all patients) were febrile neutropenia, thrombocytopenia, and neutropenia (41% each). Stable disease (SD) was the best objective response (leukemia, n = 5; ST, n = 2); the duration of SD was short in all patients, except in one with an ST. PK profiles were generally comparable across dose groups and were consistent with those in adults. CONCLUSION The pediatric MTD/dose for further development was identified. There were no unexpected safety or PK findings; limited antitumor/antileukemic activity was demonstrated.
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Affiliation(s)
- François Doz
- Oncology Center SIREDO (Care Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institute Curie and University Paris Descartes, Paris, France
| | - Franco Locatelli
- Department of Paediatric Haematology and Oncology, IRCCS (Istituto di Recovero e Cura a Carattere Scientifico), Bambino Gesù Children's Hospital, Sapienza University of Rome, Rome, Italy
| | - André Baruchel
- Department of Paediatric Haemato-immunology, Hôpital Robert Debré (APHP), University Paris Diderot, Paris, France
| | - Nicolas Blin
- Paediatric Haematology and Oncology, Hôpital Mère-Enfant, CHU de Nantes, Nantes, France
| | - Barbara De Moerloose
- Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Didier Frappaz
- Paediatric Oncology Department, Léon Bérard Centre, Lyon, France
| | - Michael Dworzak
- St. Anna Children's Hospital, Department of Paediatrics, Medical University of Vienna, Vienna, Austria
| | - Matthias Fischer
- Department of Experimental Paediatric Oncology, University Children's Hospital Cologne, Centre of Molecular Medicine, Medical Faculty, University of Cologne, Cologne, Germany
| | - Jan Stary
- Department of Paediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic
| | - Rene Fuertig
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Kathrin Riemann
- Clinical Operations, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Tillmann Taube
- Medical Oncology, Boehringer Ingelheim International GmbH, Biberach, Germany
| | - Dirk Reinhardt
- Department of Paediatrics, University Hospital Essen, Essen, Germany
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Kannan S, Aitken MJL, Herbrich SM, Golfman LS, Hall MG, Mak DH, Burks JK, Song G, Konopleva M, Mullighan CG, Chandra J, Zweidler-McKay PA. Antileukemia Effects of Notch-Mediated Inhibition of Oncogenic PLK1 in B-Cell Acute Lymphoblastic Leukemia. Mol Cancer Ther 2019; 18:1615-1627. [PMID: 31227645 PMCID: PMC6726528 DOI: 10.1158/1535-7163.mct-18-0706] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 11/08/2018] [Accepted: 06/17/2019] [Indexed: 02/03/2023]
Abstract
In B-cell acute lymphoblastic leukemia (B-ALL), activation of Notch signaling leads to cell-cycle arrest and apoptosis. We aimed to harness knowledge acquired by understanding a mechanism of Notch-induced cell death to elucidate a therapeutically viable target in B-ALL. To this end, we identified that Notch activation suppresses Polo-like kinase 1 (PLK1) in a B-ALL-specific manner. We identified that PLK1 is expressed in all subsets of B-ALL and is highest in Philadelphia-like (Ph-like) ALL, a high-risk subtype of disease. We biochemically delineated a mechanism of Notch-induced PLK1 downregulation that elucidated stark regulation of p53 in this setting. Our findings identified a novel posttranslational cascade initiated by Notch in which CHFR was activated via PARP1-mediated PARylation, resulting in ubiquitination and degradation of PLK1. This led to hypophosphorylation of MDM2Ser260, culminating in p53 stabilization and upregulation of BAX. shRNA knockdown or pharmacologic inhibition of PLK1 using BI2536 or BI6727 (volasertib) in B-ALL cell lines and patient samples led to p53 stabilization and cell death. These effects were seen in primary human B-ALL samples in vitro and in patient-derived xenograft models in vivo These results highlight PLK1 as a viable therapeutic target in B-ALL. Efficacy of clinically relevant PLK1 inhibitors in B-ALL patient-derived xenograft mouse models suggests that use of these agents may be tailored as an additional therapeutic strategy in future clinical studies.
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Affiliation(s)
| | - Marisa J L Aitken
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas
| | - Shelley M Herbrich
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas
| | - Leonard S Golfman
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mandy G Hall
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Duncan H Mak
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jared K Burks
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Guangchun Song
- Department of Pathology, St. Jude's Children's Research Hospital, Memphis, Tennessee
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Charles G Mullighan
- Department of Pathology, St. Jude's Children's Research Hospital, Memphis, Tennessee
| | - Joya Chandra
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Bergquist JR, Leiting JL, Habermann EB, Cleary SP, Kendrick ML, Smoot RL, Nagorney DM, Truty MJ, Grotz TE. Early-onset gastric cancer is a distinct disease with worrisome trends and oncogenic features. Surgery 2019; 166:547-555. [PMID: 31331685 DOI: 10.1016/j.surg.2019.04.036] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/11/2019] [Accepted: 04/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Overall the incidence of gastric cancer is declining in the United States; however, the incidence of early-onset gastric cancer is increasing. We sought to elucidate clinical and genomic characteristics and risk factors for early-onset gastric cancer compared with late-onset gastric cancer. METHODS We utilized the Surveillance, Epidemiology, and End Results database (1973-2015), the Behavioral Risk Factor Surveillance Survey, and The Cancer Genome Atlas to characterize early-onset gastric cancer. RESULTS The incidence of early-onset gastric cancer increased during the study period and now comprises >30% of all gastric cancer in the United States. Early-onset gastric cancer was associated with higher grade (55.2 vs 46.9%), signet-ring cells (19.0 vs 10.4%), diffuse histology (25.7 vs 15.0%), and metastatic disease (49.5 vs 40.9%, all P < .01) compared with late-onset gastric cancer. Early-onset gastric cancer was more likely to be Epstein-Barr virus (7.7 vs 5.1%) or genomically stable (22.5 vs 8.1%) subtype, whereas late-onset gastric cancer was more likely to be microsatellite instability subtype (18.6 vs 5.6%; all P < .01). Risk factors for gastric cancer were less correlated with early-onset gastric cancer compared with late-onset gastric cancer. CONCLUSION The incidence of early-onset gastric cancer has been steadily increasing in the United States, comprising >30% of new gastric cancer cases today. Early-onset gastric cancer is genetically and clinically distinct from traditional gastric cancer. Additional investigations are warranted to better understand this alarming phenomenon.
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Affiliation(s)
- John R Bergquist
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN; Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Surgical Outcomes Program, Rochester, MN
| | - Jennifer L Leiting
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Elizabeth B Habermann
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Surgical Outcomes Program, Rochester, MN
| | - Sean P Cleary
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Michael L Kendrick
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Rory L Smoot
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - David M Nagorney
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Mark J Truty
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Travis E Grotz
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN.
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Stratmann JA, Sebastian M. Polo-like kinase 1 inhibition in NSCLC: mechanism of action and emerging predictive biomarkers. LUNG CANCER-TARGETS AND THERAPY 2019; 10:67-80. [PMID: 31308774 PMCID: PMC6612950 DOI: 10.2147/lctt.s177618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 05/24/2019] [Indexed: 12/16/2022]
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Due to often unspecific disease symptoms, locally advanced or metastatic disease is diagnosed in the majority of all cases. Palliative treatment options comprise of conventional cytotoxic agents, immunotherapy with checkpoint inhibitors and the use of specific small-molecule tyrosine kinase inhibitors (TKI). However, these TKIs are mainly restricted to a small proportion of patients with lung cancer that harbor activating driver mutations. Still, the effectiveness and favorable safety profile of these compounds have prompted a systematic search for specific driver mechanisms of tumorigenesis and moreover the development of corresponding kinase inhibitors. In recent years, the Polo-like kinase (PLK) family has emerged as a key regulator in mitotic regulation. Its role in cell proliferation and the frequently observed overexpression in various tumor entities have raised much interest in basic and clinical oncology aiming to attenuate tumor growth by targeting the PLK. In this review, we give a comprehensive summary on the (pre-) clinical development of the different types of PLK inhibitors in lung cancer and summarize their mechanisms of action, safety and efficacy data and give an overview on translational research aiming to identify predictive biomarkers for a rational use of PLK inhibitors.
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Affiliation(s)
- Jan A Stratmann
- Department of Internal Medicine II, University Clinic of Frankfurt, 60596 Frankfurt, Germany
| | - Martin Sebastian
- Department of Internal Medicine II, University Clinic of Frankfurt, 60596 Frankfurt, Germany
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Singh R, Peng S, Viswanath P, Sambandam V, Shen L, Rao X, Fang B, Wang J, Johnson FM. Non-canonical cMet regulation by vimentin mediates Plk1 inhibitor-induced apoptosis. EMBO Mol Med 2019; 11:e9960. [PMID: 31040125 PMCID: PMC6505578 DOI: 10.15252/emmm.201809960] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 02/28/2019] [Accepted: 03/12/2019] [Indexed: 12/26/2022] Open
Abstract
To address the need for improved systemic therapy for non-small-cell lung cancer (NSCLC), we previously demonstrated that mesenchymal NSCLC was sensitive to polo-like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cMet was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cMet phosphorylation only in mesenchymal cells. Constitutively active cMet abrogates Plk1 inhibitor-induced apoptosis. Likewise, cMet silencing or inhibition enhances Plk1 inhibitor-induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cMet activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cMet and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cMet phosphorylation via β1-integrin. This research defines a heretofore unknown mechanism of ligand-independent activation of cMet downstream of Plk1 and an effective combination therapy.
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Affiliation(s)
- Ratnakar Singh
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shaohua Peng
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pavitra Viswanath
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Vaishnavi Sambandam
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Li Shen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiayu Rao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bingliang Fang
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jing Wang
- The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Faye M Johnson
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA
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Xin X, Lin F, Wang Q, Yin L, Mahato RI. ROS-Responsive Polymeric Micelles for Triggered Simultaneous Delivery of PLK1 Inhibitor/miR-34a and Effective Synergistic Therapy in Pancreatic Cancer. ACS APPLIED MATERIALS & INTERFACES 2019; 11:14647-14659. [PMID: 30933478 PMCID: PMC6712559 DOI: 10.1021/acsami.9b02756] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Ineffective drug delivery and poor prognosis are two major challenges in the treatment of pancreatic ductal adenocarcinoma (PDAC). While there is significant downregulation of tumor suppressor microRNA-34a (miR-34a), which targets many oncogenes related to proliferation, apoptosis, and invasion, high expression level of Polo-like kinase 1 (PLK1) is closely associated with short survival rates of pancreatic cancer patients. Therefore, the objective is to codeliver miR-34a mimic and small molecule PLK1 inhibitor volasertib (BI6727) using poly(ethylene glycol)-poly[aspartamidoethyl( p-boronobenzyl)diethylammonium bromide] (PEG-B-PAEBEA). This polymer could self-assemble into micelles of ∼100 nm with 10% drug loading of volasertib and form a complex with miR-34a at the N/P ratio of 18 and higher. Combination treatment of volasertib and miR-34a displayed the synergistic effect and superior antiproliferative activity along with an enhanced G2/M phase arrest and suppression of colony formation, leading to cell death due to potential c-myc targeting therapeutics. Orthotopic pancreatic tumor bearing NSG mice were scanned for fluorescence by IVIS after systemic administration of micelles encapsulating volasertib and miR-34a at doses of 5 and 1 mg/kg, respectively. Cy5.5 concentration in plasma and major organs was determined by measuring fluorescence intensity. There was significant reduction in tumor volume, and histological examination of major organs suggested negligible systemic toxicity. In conclusion, PEG-B-PAEBEA micelles carrying volasertib and miR-34a mimic have the potential to treat pancreatic cancer.
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Affiliation(s)
- Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Feng Lin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Qiyue Wang
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Lifang Yin
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Ram I. Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
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Paier CRK, Maranhão SS, Carneiro TR, Lima LM, Rocha DD, da Silva Santos R, de Farias KM, de Moraes-Filho MO, Pessoa C. Natural products as new antimitotic compounds for anticancer drug development. Clinics (Sao Paulo) 2018; 73:e813s. [PMID: 30540125 PMCID: PMC6256996 DOI: 10.6061/clinics/2018/e813s] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/09/2018] [Indexed: 12/19/2022] Open
Abstract
Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.
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Affiliation(s)
- Carlos Roberto Koscky Paier
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
- *Corresponding author. E-mail:
| | - Sarah Sant'Anna Maranhão
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Farmacologia, Universidade Federal do Ceara, Fortaleza, CE, BR
| | - Teiliane Rodrigues Carneiro
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Biotecnologia, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Ceara, Fortaleza, CE, BR
- Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio), Instituto de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, BR
| | - Lídia Moreira Lima
- Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio), Instituto de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, BR
| | - Danilo Damasceno Rocha
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
| | - Renan da Silva Santos
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Farmacologia, Universidade Federal do Ceara, Fortaleza, CE, BR
| | - Kaio Moraes de Farias
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Biotecnologia, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Ceara, Fortaleza, CE, BR
| | - Manoel Odorico de Moraes-Filho
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Farmacologia, Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Biotecnologia, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Ceara, Fortaleza, CE, BR
| | - Claudia Pessoa
- Laboratorio de Oncologia Experimental, Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Farmacologia, Universidade Federal do Ceara, Fortaleza, CE, BR
- Programa de Pos graduacao em Biotecnologia, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Ceara, Fortaleza, CE, BR
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Wang Y, Wu L, Yao Y, Lu G, Xu L, Zhou J. Polo-like kinase 1 inhibitor BI 6727 induces DNA damage and exerts strong antitumor activity in small cell lung cancer. Cancer Lett 2018; 436:1-9. [PMID: 30118839 DOI: 10.1016/j.canlet.2018.08.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/14/2018] [Accepted: 08/09/2018] [Indexed: 11/29/2022]
Abstract
The prognosis of small cell lung cancer (SCLC) is poor despite its good initial response to chemotherapy. Polo-like kinase 1 (PLK1) is a crucial mitotic regulator that is overexpressed in many tumors, and its overexpression is associated with tumor aggressiveness and a poor prognosis. However, its role in SCLC is still poorly characterized. Based on immunohistochemistry findings, the PLK1 protein is expressed at higher levels in SCLC tumor samples than in normal lung tissue samples. The selective PLK1 inhibitor BI 6727 significantly induced the inhibition of proliferation and apoptosis in a dose-dependent manner in SCLC cell lines. FACS analysis showed an increase in the population of cells in the G2/M phase, followed by DNA damage and the consequent activation of the ataxia telangiectasia and Rad3-related (ATR)/ataxia telangiectasia mutated (ATM)-Chk1/Chk2 checkpoint pathway. In addition, BI 6727 treatment resulted in clearly attenuated growth and apoptosis in NCI-H446 xenografts. The level of histone H2AX phosphorylation at serine-139 (γH2AX) was markedly increased both in vitro and in vivo. Our findings indicate that BI 6727 has therapeutic potential for SCLC patients.
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Affiliation(s)
- Yuehong Wang
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Linying Wu
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yinan Yao
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Guohua Lu
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liming Xu
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianying Zhou
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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Carmona-Martínez V, Ruiz-Alcaraz AJ, Vera M, Guirado A, Martínez-Esparza M, García-Peñarrubia P. Therapeutic potential of pteridine derivatives: A comprehensive review. Med Res Rev 2018; 39:461-516. [PMID: 30341778 DOI: 10.1002/med.21529] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 07/07/2018] [Accepted: 07/10/2018] [Indexed: 12/19/2022]
Abstract
Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state-of-the-art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine-based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation-related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.
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Affiliation(s)
- Violeta Carmona-Martínez
- Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum," Universidad de Murcia, Murcia, Spain
| | - Antonio J Ruiz-Alcaraz
- Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum," Universidad de Murcia, Murcia, Spain
| | - María Vera
- Departamento de Química Orgánica, Universidad de Murcia, Campus de Espinardo, Murcia, Spain
| | - Antonio Guirado
- Departamento de Química Orgánica, Universidad de Murcia, Campus de Espinardo, Murcia, Spain
| | - María Martínez-Esparza
- Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum," Universidad de Murcia, Murcia, Spain
| | - Pilar García-Peñarrubia
- Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum," Universidad de Murcia, Murcia, Spain
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Wallenstein G, Walter B, Fritsch H, Taube T. Strategic and Statistical Considerations on the QT Assessment of Volasertib. Ther Innov Regul Sci 2018; 52:416-422. [PMID: 29714574 PMCID: PMC6047300 DOI: 10.1177/2168479017739826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 08/29/2017] [Indexed: 11/15/2022]
Abstract
Volasertib is a selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). A potential for prolonged QT intervals was indicated with volasertib in preclinical studies and preliminary clinical data. As a result, electrocardiograms (ECGs) have been collected in all volasertib clinical trials to monitor potential cardiac effects. This article describes strategic and statistical methods prospectively planned to perform an integrated analysis of ECG data from available trials to evaluate volasertib's effect on cardiac repolarization, as reflected by changes in the duration of QT interval and other ECG-related endpoints. Methods to effectively cope with heterogeneity between trials (ie, differences in study designs) are discussed. These strategies may be useful for other investigational drugs for which QT risk assessment is required, but a thorough QT/QTc trial is not feasible, resulting in the need for an alternative approach. Volasertib therapy relevantly prolonged adjusted mean QTcF change from administration baseline following the first and subsequent infusions. The integrated analysis revealed that the volasertib effects on the mean QTc changes from baseline were transient and had resolved at 24 hours after start of the first infusion. There was no evidence for a long-term impact on the QTcF interval following multiple infusions with volasertib.
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Affiliation(s)
| | | | - Holger Fritsch
- Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
| | - Tillmann Taube
- Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
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Ottmann OG, Müller-Tidow C, Krämer A, Schlenk RF, Lübbert M, Bug G, Krug U, Bochtler T, Voss F, Taube T, Liu D, Garin-Chesa P, Döhner H. Phase I dose-escalation trial investigating volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukaemia. Br J Haematol 2018; 184:1018-1021. [PMID: 29882583 DOI: 10.1111/bjh.15204] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Oliver G Ottmann
- Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany
| | - Carsten Müller-Tidow
- Department of Medicine, Hematology and Oncology, University Hospital Münster, Münster, Germany
| | - Alwin Krämer
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Richard F Schlenk
- Department of Internal Medicine III, University of Ulm, Ulm, Germany
| | - Michael Lübbert
- Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany
| | - Gesine Bug
- Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany
| | - Utz Krug
- Department of Medicine, Hematology and Oncology, University Hospital Münster, Münster, Germany
| | - Tilmann Bochtler
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Florian Voss
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Tillmann Taube
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Dan Liu
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Hartmut Döhner
- Department of Internal Medicine III, University of Ulm, Ulm, Germany
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Raab M, Sanhaji M, Matthess Y, Hörlin A, Lorenz I, Dötsch C, Habbe N, Waidmann O, Kurunci-Csacsko E, Firestein R, Becker S, Strebhardt K. PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells. Nat Commun 2018; 9:1106. [PMID: 29549256 PMCID: PMC5856809 DOI: 10.1038/s41467-018-03494-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 02/19/2018] [Indexed: 12/13/2022] Open
Abstract
The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.
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Affiliation(s)
- Monika Raab
- Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany
| | - Mourad Sanhaji
- Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany
| | - Yves Matthess
- Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany
- German Cancer Consortium (DKTK)/ German Cancer Research Center, 69120, Heidelberg, Germany
| | - Albrecht Hörlin
- Institute of Pathology at the Department of Pathology, Goethe-University, 60590, Frankfurt, Germany
| | - Ioana Lorenz
- Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany
| | - Christina Dötsch
- Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany
| | - Nils Habbe
- Department of General and Visceral Surgery, Goethe-University, 60590, Frankfurt, Germany
| | - Oliver Waidmann
- Department of Gastroenterology and Hepatology, Goethe-University, 60590, Frankfurt, Germany
| | | | - Ron Firestein
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, AU 31681, Australia
- Department of Molecular Translational Medicine, Monash University, Clayton, VIC, 3800, Australia
| | - Sven Becker
- Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany
| | - Klaus Strebhardt
- Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany.
- German Cancer Consortium (DKTK)/ German Cancer Research Center, 69120, Heidelberg, Germany.
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BI-2536 and BI-6727, dual Polo-like kinase/bromodomain inhibitors, effectively reactivate latent HIV-1. Sci Rep 2018; 8:3521. [PMID: 29476067 PMCID: PMC5824842 DOI: 10.1038/s41598-018-21942-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 02/07/2018] [Indexed: 11/23/2022] Open
Abstract
HIV-1 latent reservoirs harbouring silenced but replication-competent proviruses are a major obstacle against viral eradication in infected patients. The “shock and kill” strategy aims to reactivate latent provirus with latency reversing agents (LRAs) in the presence of antiretroviral drugs, necessitating the development of effective and efficient LRAs. We screened a chemical library for potential LRAs and identified two dual Polo-like kinase (PLK)/bromodomain inhibitors, BI-2536 and BI-6727 (volasertib), which are currently undergoing clinical trials against various cancers. BI-2536 and BI-6727 significantly reactivated silenced HIV-1 provirus at both the mRNA and protein level in two latently infected model cell lines (ACH2 and U1). BI-2536 dramatically reactivated transcription of latent HIV-1 provirus in peripheral blood mononuclear cells derived from infected patients. Long terminal repeat activation by the inhibitors was associated with bromodomain rather than PLK inhibition. We also found that BI-2536 synergistically activates the latent provirus in combination with SAHA, a histone deacetylase inhibitor, or the non-tumour-promoting phorbol ester prostratin. Our findings strongly suggest that BI-2536 and BI-6727 are potent LRAs for the “shock and kill” HIV-1 eradication strategy.
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Abstract
The MYC family oncogene is deregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. Although Myc inhibition would be a powerful approach for the treatment of many types of cancers, direct targeting of Myc has been a challenge for decades owing to its "undruggable" protein structure. Hence, alternatives to Myc blockade have been widely explored to achieve desirable anti-tumor effects, including Myc/Max complex disruption, MYC transcription and/or translation inhibition, and Myc destabilization as well as the synthetic lethality associated with Myc overexpression. In this review, we summarize the latest advances in targeting oncogenic Myc, particularly for cancer therapeutic purposes.
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Affiliation(s)
- Hui Chen
- 1Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.,2Medical Research Institute, Wuhan University, Wuhan, People's Republic of China
| | - Hudan Liu
- 1Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.,2Medical Research Institute, Wuhan University, Wuhan, People's Republic of China
| | - Guoliang Qing
- 1Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.,2Medical Research Institute, Wuhan University, Wuhan, People's Republic of China
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Huang WJ, Wang Y, Liu S, Yang J, Guo SX, Wang L, Wang H, Fan YF. Silencing circular RNA hsa_circ_0000977 suppresses pancreatic ductal adenocarcinoma progression by stimulating miR-874-3p and inhibiting PLK1 expression. Cancer Lett 2018; 422:70-80. [PMID: 29454093 DOI: 10.1016/j.canlet.2018.02.014] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 02/04/2018] [Accepted: 02/08/2018] [Indexed: 01/22/2023]
Abstract
Circular RNAs (CircRNAs) are a novel type of endogenous noncoding RNAs that regulate target gene expression by interacting with microRNA (miRNA). Emerging evidence shows that dysregulation of circRNAs plays important roles in biological and pathological processes, including cancer development and progression. The functional role of circRNA in PDAC (pancreatic ductal adenocarcinoma) remains to be investigated. In this study, high throughput microarray assay revealed that hsa_circ_0000977 was aberrantly up-regulated in pancreatic cancer tissues; this was also validated by qRT-PCR. Silencing hsa_circ_0000977 suppressed pancreatic cancer cell proliferation and induced cell cycle arrest, which was simulated by hsa-miR-874-3p mimics and blocked by hsa-miR-874-3p inhibitor. Bioinformatics analysis predicted that there is an hsa_circ_0000977/hsa-miR-874-3p/PLK1 (Polo like kinase 1) axis in pancreatic cancer progression. Dual-luciferase reporter system and FISH assay validated the direct interaction of hsa_circ_0000977, hsa-miR-874-3p, and PLK1. Western blot verified that inhibition of hsa_circ_0000977 decreased PLK1 expression. Furthermore, silencing hsa_circ_0000977 suppressed pancreatic cancer growth in vivo. Altogether, silencing hsa_circ_0000977 suppresses progression of pancreatic cancer by interacting with hsa-miR-874-3p and decreasing inhibiting PLK1 expression. Our results may provide a promising strategy for future diagnosis and treatment of pancreatic cancer.
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Affiliation(s)
- Wen-Jie Huang
- Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University/The Second School of Clinical Medicine, Southern Medical University, Industrial Road No.253, Guangzhou, Guangdong 510280, China; Institute of Hepatopancreatobiliary, Surgery Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, China
| | - Yunchao Wang
- Institute of Hepatopancreatobiliary, Surgery Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, China
| | - Songsong Liu
- Institute of Hepatopancreatobiliary, Surgery Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, China
| | - Jiali Yang
- Institute of Hepatopancreatobiliary, Surgery Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, China
| | - Shi-Xiang Guo
- Institute of Hepatopancreatobiliary, Surgery Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, China
| | - Lijiang Wang
- Gulliver Preparatory School, 6575 North Kendall Drive, Miami, FL, 33156, USA
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary, Surgery Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, China
| | - Ying-Fang Fan
- Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University/The Second School of Clinical Medicine, Southern Medical University, Industrial Road No.253, Guangzhou, Guangdong 510280, China
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Weiss GJ, Jameson G, Von Hoff DD, Valsasina B, Davite C, Di Giulio C, Fiorentini F, Alzani R, Carpinelli P, Di Sanzo A, Galvani A, Isacchi A, Ramanathan RK. Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors. Invest New Drugs 2018; 36:85-95. [PMID: 28726132 DOI: 10.1007/s10637-017-0491-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/07/2017] [Indexed: 12/21/2022]
Abstract
Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.
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Affiliation(s)
- Glen J Weiss
- Western Regional Medical Center, Cancer Treatment Centers of America, 14200 W Celebrate Life Way, Goodyear, AZ, 85338, USA.
- Virginia G. Piper Cancer Centers at Scottsdale Healthcare, Scottsdale, AZ, USA.
| | - Gayle Jameson
- Virginia G. Piper Cancer Centers at Scottsdale Healthcare, Scottsdale, AZ, USA
| | - Daniel D Von Hoff
- Virginia G. Piper Cancer Centers at Scottsdale Healthcare, Scottsdale, AZ, USA
| | | | - Cristina Davite
- CLInical Organization for Strategies and Solutions (CLIOSS) S.r.l, Mayo Scottsdale, Nerviano, Italy
| | - Claudia Di Giulio
- CLInical Organization for Strategies and Solutions (CLIOSS) S.r.l, Mayo Scottsdale, Nerviano, Italy
| | | | | | | | - Alessandro Di Sanzo
- CLInical Organization for Strategies and Solutions (CLIOSS) S.r.l, Mayo Scottsdale, Nerviano, Italy
| | | | | | - Ramesh K Ramanathan
- Virginia G. Piper Cancer Centers at Scottsdale Healthcare, Scottsdale, AZ, USA
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50
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Ren Z, Tao Z. Molecular Basis of Colorectal Cancer: Tumor Biology. SURGICAL TREATMENT OF COLORECTAL CANCER 2018:23-34. [DOI: 10.1007/978-981-10-5143-2_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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