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1
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Nturubika BDD, Logan J, Johnson IRD, Moore C, Li KL, Tang J, Lam G, Parkinson-Lawrence E, Williams DB, Chakiris J, Hindes M, Brooks RD, Miles MA, Selemidis S, Gregory P, Weigert R, Butler L, Ward MP, Waugh DJJ, O’Leary JJ, Brooks DA. Components of the Endosome-Lysosome Vesicular Machinery as Drivers of the Metastatic Cascade in Prostate Cancer. Cancers (Basel) 2024; 17:43. [PMID: 39796673 PMCID: PMC11718918 DOI: 10.3390/cancers17010043] [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: 11/21/2024] [Revised: 12/16/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025] Open
Abstract
Prostate cancer remains a significant global health concern, with over 1.4 million new cases diagnosed and more than 330,000 deaths each year. The primary clinical challenge that contributes to poor patient outcomes involves the failure to accurately predict and treat at the onset of metastasis, which remains an incurable stage of the disease. This review discusses the emerging paradigm that prostate cancer metastasis is driven by a dysregulation of critical molecular machinery that regulates endosome-lysosome homeostasis. Endosome and lysosome compartments have crucial roles in maintaining normal cellular function but are also involved in many hallmarks of cancer pathogenesis, including inflammation, immune response, nutrient sensing, metabolism, proliferation, signalling, and migration. Here we discuss new insight into how alterations in the complex network of trafficking machinery, responsible for the microtubule-based transport of endosomes and lysosomes, may be involved in prostate cancer progression. A better understanding of endosome-lysosome dynamics may facilitate the discovery of novel strategies to detect and manage prostate cancer metastasis and improve patient outcomes.
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Affiliation(s)
- Bukuru Dieu-Donne Nturubika
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Jessica Logan
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Ian R. D. Johnson
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Courtney Moore
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Ka Lok Li
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Jingying Tang
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Giang Lam
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia; (G.L.); (P.G.); (D.J.J.W.)
| | - Emma Parkinson-Lawrence
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Desmond B. Williams
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - James Chakiris
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Madison Hindes
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Robert D. Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Mark A. Miles
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; (M.A.M.); (S.S.)
| | - Stavros Selemidis
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; (M.A.M.); (S.S.)
| | - Philip Gregory
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia; (G.L.); (P.G.); (D.J.J.W.)
| | - Roberto Weigert
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Lisa Butler
- South Australian ImmunoGENomics Cancer Institute, Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA 5000, Australia;
- Solid Tumour Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Mark P. Ward
- Department of Pathology, The Coombe Women and Infants University Hospital, Trinity College Dublin, D08 XW7X Dublin, Ireland;
| | - David J. J. Waugh
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia; (G.L.); (P.G.); (D.J.J.W.)
| | - John J. O’Leary
- Department of Histopathology, Trinity College Dublin, D08 XW7X Dublin, Ireland;
| | - Douglas A. Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
- Department of Histopathology, Trinity College Dublin, D08 XW7X Dublin, Ireland;
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Fujiwara Y, Takahashi RU, Saito M, Umakoshi M, Shimada Y, Koyama K, Yatabe Y, Watanabe SI, Koyota S, Minamiya Y, Tahara H, Kono K, Shiraishi K, Kohno T, Goto A, Tsuchiya N. Oncofetal IGF2BP3-mediated control of microRNA structural diversity in the malignancy of early-stage lung adenocarcinoma. Proc Natl Acad Sci U S A 2024; 121:e2407016121. [PMID: 39196622 PMCID: PMC11388381 DOI: 10.1073/pnas.2407016121] [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: 04/08/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
The nature of microRNA (miRNA) dysfunction in carcinogenesis remains controversial because of the complex connection between miRNA structural diversity and biological processes. Here, we found that oncofetal IGF2BP3 regulates the selective production of a subset of 3'-isoforms (3'-isomiRs), including miR-21-5p and Let-7 family, which induces significant changes in their cellular seed occupancy and structural components, establishing a cancer-specific gene expression profile. The D-score, reflecting dominant production of a representative miR-21-5p+C (a 3'-isomiR), discriminated between clinical early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks, and was associated with molecular features of cell cycle progression, epithelial-mesenchymal transition pressure, and immune evasion. We found that IGF2BP3 controls the production of miR-21-5p+C by directing the nuclear Drosha complex to select the cleavage site. IGF2BP3 was also involved in the production of 3'-isomiRs of miR-425-5p and miR-454-3p. IGF2BP3-regulated these three miRNAs are suggested to be associated with the regulation of p53, TGF-β, and TNF pathways in LUAD. Knockdown of IGF2BP3 also induced a selective upregulation of Let-7 3'-isomiRs, leading to increased cellular Let-7 seed occupancy and broad repression of its target genes encoding cell cycle regulators. The D-score is an index that reflects this cellular situation. Our results suggest that the aberrant regulation of miRNA structural diversity is a critical component for controlling cellular networks, thus supporting the establishment of a malignant gene expression profile in early stage LUAD.
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Affiliation(s)
- Yuko Fujiwara
- Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Ryou-U Takahashi
- Department of Cellular and Molecular Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Michinobu Umakoshi
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan
| | - Yoko Shimada
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Kei Koyama
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan
| | - Yasushi Yatabe
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Shun-Ichi Watanabe
- Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Souichi Koyota
- Molecular Medicine Laboratory, Bioscience Education and Research Support Center, Akita University, Akita 010-8543, Japan
| | - Yoshihiro Minamiya
- Department of Thoracic Surgery, Akita University Hospital, Akita 010-8543, Japan
| | - Hidetoshi Tahara
- Department of Cellular and Molecular Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Akiteru Goto
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan
| | - Naoto Tsuchiya
- Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, Tokyo 104-0045, Japan
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3
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Chang H, Cheng S, Xing G, Huang C, Zhang C, Qian W, Li J. Vincristine exposure impairs mouse oocyte quality by inducing spindle defects and early apoptosis. IUBMB Life 2024; 76:345-356. [PMID: 38009728 DOI: 10.1002/iub.2797] [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: 06/15/2023] [Accepted: 11/02/2023] [Indexed: 11/29/2023]
Abstract
Vincristine (VCR) is a microtubule-destabilizing chemotherapeutic agent commonly administered for the treatment of cancers in patients, which can induce severe side effects including neurotoxicity. In context of the effects on female fertility, ovarian toxicity has been found in patients and mice model after VCR exposure. However, the influence of VCR exposure on oocyte quality has not been elucidated. We established VCR exposure in vitro and in vivo model. The results indicated in vitro VCR exposure contributed to failure of oocyte maturation through inducing defects in spindle assembly, activation of SAC, oxidative stress, mitochondrial dysfunction, and early apoptosis, which were confirmed by using in vivo exposure model. Moreover, in vivo VCR exposure caused aneuploidy, reduced oocyte-sperm binding ability, and the number of cortical granules in mouse oocyte cortex. Taken together, this study demonstrated that VCR could cause meiotic arrest and poor quality of mouse oocyte.
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Affiliation(s)
- Haoya Chang
- Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Siyu Cheng
- Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Guoqiang Xing
- Department of General Surgery, Tianjin Fifth Central Hospital (Peking University Binhai Hospital), Tianjin, China
| | - Chenyang Huang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Chunhui Zhang
- Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Weiping Qian
- Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jian Li
- Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen, China
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4
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Tufail M, Wan WD, Jiang C, Li N. Targeting PI3K/AKT/mTOR signaling to overcome drug resistance in cancer. Chem Biol Interact 2024; 396:111055. [PMID: 38763348 DOI: 10.1016/j.cbi.2024.111055] [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: 03/27/2024] [Revised: 05/06/2024] [Accepted: 05/13/2024] [Indexed: 05/21/2024]
Abstract
This review comprehensively explores the challenge of drug resistance in cancer by focusing on the pivotal PI3K/AKT/mTOR pathway, elucidating its role in oncogenesis and resistance mechanisms across various cancer types. It meticulously examines the diverse mechanisms underlying resistance, including genetic mutations, feedback loops, and microenvironmental factors, while also discussing the associated resistance patterns. Evaluating current therapeutic strategies targeting this pathway, the article highlights the hurdles encountered in drug development and clinical trials. Innovative approaches to overcome resistance, such as combination therapies and precision medicine, are critically analyzed, alongside discussions on emerging therapies like immunotherapy and molecularly targeted agents. Overall, this comprehensive review not only sheds light on the complexities of resistance in cancer but also provides a roadmap for advancing cancer treatment.
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Affiliation(s)
- Muhammad Tufail
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Dong Wan
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Canhua Jiang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China; Institute of Oral Precancerous Lesions, Central South University, Changsha, China; Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Li
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China; Institute of Oral Precancerous Lesions, Central South University, Changsha, China; Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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5
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Thomas JD, Yurkovetskiy AV, Yin M, Bodyak ND, Tang S, Protopopova M, Kelleher E, Jones B, Yang L, Custar D, Catcott KC, Demady DR, Collins SD, Xu L, Bu C, Qin L, Ter-Ovanesyan E, Damelin M, Toader D, Lowinger TB. Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates. Mol Cancer Ther 2024; 23:541-551. [PMID: 38354416 DOI: 10.1158/1535-7163.mct-23-0622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/02/2024] [Accepted: 02/08/2024] [Indexed: 02/16/2024]
Abstract
Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.
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Affiliation(s)
| | | | - Mao Yin
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | | | - Shuyi Tang
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | | | | | - Brian Jones
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | - Liping Yang
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | - Daniel Custar
- Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | | | - Damon R Demady
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | | | - Ling Xu
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | - Charlie Bu
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | - LiuLiang Qin
- Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | | | - Marc Damelin
- Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | - Dorin Toader
- Mersana Therapeutics, Inc., Cambridge, Massachusetts
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Hsieh Y, Du J, Yang P. Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance. Mol Oncol 2024; 18:386-414. [PMID: 37842807 PMCID: PMC10850822 DOI: 10.1002/1878-0261.13536] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 09/26/2023] [Accepted: 10/12/2023] [Indexed: 10/17/2023] Open
Abstract
Microtubule-targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule-targeting agents without such limitations are urgently needed. By employing a gene expression-based drug repositioning strategy, this study identifies VU-0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU-0365114 exhibits a broad-spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU-0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU-0365114 is not related to its original target, M5 mAChR. In addition, VU-0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus, it can overcome MDR. Furthermore, a kinome analysis shows that VU-0365114 did not exhibit other significant off-target effects. Taken together, our study suggests that VU-0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development.
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Affiliation(s)
- Yao‐Yu Hsieh
- Division of Hematology and OncologyTaipei Medical University Shuang Ho HospitalNew Taipei CityTaiwan
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
- Taipei Cancer CenterTaipei Medical UniversityTaipeiTaiwan
- TMU and Affiliated Hospitals Pancreatic Cancer GroupsTaipei Medical UniversityTaipeiTaiwan
| | - Jia‐Ling Du
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and TechnologyTaipei Medical UniversityNew Taipei CityTaiwan
| | - Pei‐Ming Yang
- Taipei Cancer CenterTaipei Medical UniversityTaipeiTaiwan
- TMU and Affiliated Hospitals Pancreatic Cancer GroupsTaipei Medical UniversityTaipeiTaiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and TechnologyTaipei Medical UniversityNew Taipei CityTaiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and TechnologyTaipei Medical UniversityNew Taipei CityTaiwan
- TMU Research Center of Cancer Translational MedicineTaipeiTaiwan
- Cancer Center, Wan Fang HospitalTaipei Medical UniversityTaipeiTaiwan
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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Hassan MS, Awasthi N, Ponna S, von Holzen U. Nab-Paclitaxel in the Treatment of Gastrointestinal Cancers-Improvements in Clinical Efficacy and Safety. Biomedicines 2023; 11:2000. [PMID: 37509639 PMCID: PMC10377238 DOI: 10.3390/biomedicines11072000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/03/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.
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Affiliation(s)
- Md Sazzad Hassan
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Saisantosh Ponna
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN 46556, USA
| | - Urs von Holzen
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
- Harper Cancer Research Institute, South Bend, IN 46617, USA
- Goshen Center for Cancer Care, Goshen, IN 46526, USA
- Department of Surgery, University of Basel School of Medicine, 4001 Basel, Switzerland
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9
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Sartore-Bianchi A, Lonardi S, Martino C, Fenocchio E, Tosi F, Ghezzi S, Leone F, Bergamo F, Zagonel V, Ciardiello F, Ardizzoni A, Amatu A, Bencardino K, Valtorta E, Grassi E, Torri V, Bonoldi E, Sapino A, Vanzulli A, Regge D, Cappello G, Bardelli A, Trusolino L, Marsoni S, Siena S. Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial. ESMO Open 2020; 5:e000911. [PMID: 32988996 PMCID: PMC7523198 DOI: 10.1136/esmoopen-2020-000911] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/08/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND HER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting. METHODS HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1). RESULTS Thirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue. CONCLUSIONS HERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource. TRIAL REGISTRATION NUMBER 2012-002128-33 and NCT03225937.
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Affiliation(s)
- Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Milano, Italy
| | - Sara Lonardi
- Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy
| | - Cosimo Martino
- Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy
| | - Elisabetta Fenocchio
- Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy
| | - Federica Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Silvia Ghezzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Francesco Leone
- Department of Oncology, ASL BI, Ospedale degli Infermi di Biella, Biella, Italy
| | - Francesca Bergamo
- Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy
| | - Vittorina Zagonel
- Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy
| | - Fortunato Ciardiello
- Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Caserta, Campania, Italy
| | - Andrea Ardizzoni
- UOC Oncologia Medica, Policlinico S. Orsola, Dipartimento di Medicina Specialistica, di Laboratorio e Sperimentale, Università Alma Mater, Bologna, Italy
| | - Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Emanuele Valtorta
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Elena Grassi
- Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy; Dipartimento di Scienze Mediche, Università degli Studi di Torino, Torino, Italy
| | - Valter Torri
- Dipartimento di Oncologia, IRCCS- Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
| | - Emanuela Bonoldi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Anna Sapino
- Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy; Dipartimento di Scienze Mediche, Università degli Studi di Torino, Torino, Italy
| | - Angelo Vanzulli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Milano, Italy
| | - Daniele Regge
- Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy; Dipartimento di Scienze Chirurgiche, Università degli Studi di Torino, Torino, Italy
| | - Giovanni Cappello
- Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy; Dipartimento di Scienze Chirurgiche, Università degli Studi di Torino, Torino, Italy
| | - Alberto Bardelli
- Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy
| | - Livio Trusolino
- Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy
| | - Silvia Marsoni
- Precision Oncology, IFOM-FIRC Institute of Molecular Oncology, Milano, Italy
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Milano, Italy.
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10
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Sugiyama T, Iwaizumi M, Taniguchi T, Suzuki S, Tani S, Yamade M, Hamaya Y, Osawa S, Furuta T, Miyajima H, Ohta T, Baba S, Sugimura H, Maekawa M, Sugimoto K. Microsatellite frameshift variants in SGO1 of gastric cancer are not always associated with MSI status. J Clin Pathol 2020; 74:jclinpath-2020-206934. [PMID: 32817265 DOI: 10.1136/jclinpath-2020-206934] [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: 07/09/2020] [Revised: 07/17/2020] [Accepted: 07/20/2020] [Indexed: 12/24/2022]
Abstract
AIMS Although frameshift variants in the microsatellite area of shugoshin 1 (SGO1) have been reported in the context of microsatellite instability-high (MSI-H)/deficient mismatch repair gastrointestinal cancer, most have been evaluated only in early stage I-III patients, and only two of its five microsatellite regions have been evaluated. Therefore, we investigated the frequency and MSI status of microsatellite frameshift variants in gastric cancer cases, including stage IV. METHODS In a total of 55 cases, 30 gastric cancer resection and 25 non-resection cases, DNA was extracted from both tumour and normal parts and PCR was performed. The variant was confirmed by TA cloning, and MSI was evaluated using GeneMapper software. RESULTS A frameshift variant of c.973delA was observed in 16 of the 45 evaluable cases. Its frequency was 35.6%. Of the 25 cases that could be assessed for MSI status, two cases of MSI-H were associated with the c.973delA SGO1 variant. However, c.973delA SGO1 variant was also observed in four cases of microsatellite stable. CONCLUSION Our study shows that SGO1 frameshift variants are not always associated with MSI status.
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Affiliation(s)
- Tomohiro Sugiyama
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Terumi Taniguchi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Satoshi Suzuki
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shinya Tani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tsutomu Ohta
- Department of Physical Therapy, Faculty of Health and Medical Sciences, Tokoha University, Hamamatsu, Shizuoka, Japan
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masato Maekawa
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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11
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Varela FA, Foust VL, Hyland TE, Sala-Hamrick KE, Mackinder JR, Martin CE, Murray AS, Todi SV, List K. TMPRSS13 promotes cell survival, invasion, and resistance to drug-induced apoptosis in colorectal cancer. Sci Rep 2020; 10:13896. [PMID: 32807808 PMCID: PMC7431588 DOI: 10.1038/s41598-020-70636-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 07/09/2020] [Indexed: 12/17/2022] Open
Abstract
Cancer progression is often accompanied by increased levels of extracellular proteases capable of remodeling the extracellular matrix and promoting pro-cancerous signaling pathways by activating growth factors and receptors. The type II transmembrane serine protease (TTSP) family encompasses several proteases that play critical roles in cancer progression; however, the expression or function of the TTSP TMPRSS13 in carcinogenesis has not been examined. In the present study, we found TMPRSS13 to be differentially expressed at both the transcript and protein levels in human colorectal cancer (CRC). Immunohistochemical analyses revealed consistent high expression of TMPRSS13 protein on the cancer cell surface in CRC patient samples; in contrast, the majority of normal colon samples displayed no detectable expression. On a functional level, TMPRSS13 silencing in CRC cell lines increased apoptosis and impaired invasive potential. Importantly, transgenic overexpression of TMPRSS13 in CRC cell lines increased tolerance to apoptosis-inducing agents, including paclitaxel and HA14-1. Conversely, TMPRSS13 silencing rendered CRC cells more sensitive to these agents. Together, our findings suggest that TMPRSS13 plays an important role in CRC cell survival and in promoting resistance to drug-induced apoptosis; we also identify TMPRSS13 as a potential new target for monotherapy or combination therapy with established chemotherapeutics to improve treatment outcomes in CRC patients.
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Affiliation(s)
- Fausto A Varela
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
| | - Victoria L Foust
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
| | - Thomas E Hyland
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
| | | | - Jacob R Mackinder
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
| | - Carly E Martin
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
- Department of Oncology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
| | - Andrew S Murray
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
- Department of Oncology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
| | - Sokol V Todi
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
- Department of Neurology, Wayne State University School of Medicine, Detroit, 48201, MI, USA
| | - Karin List
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, 48201, MI, USA.
- Department of Oncology, Wayne State University School of Medicine, Detroit, 48201, MI, USA.
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12
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Gymnopoulos M, Betancourt O, Blot V, Fujita R, Galvan D, Lieuw V, Nguyen S, Snedden J, Stewart C, Villicana J, Wojciak J, Wong E, Pardo R, Patel N, D'Hooge F, Vijayakrishnan B, Barry C, Hartley JA, Howard PW, Newman R, Coronella J. TR1801-ADC: a highly potent cMet antibody-drug conjugate with high activity in patient-derived xenograft models of solid tumors. Mol Oncol 2019; 14:54-68. [PMID: 31736230 PMCID: PMC6944112 DOI: 10.1002/1878-0261.12600] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 10/23/2019] [Accepted: 11/14/2019] [Indexed: 12/13/2022] Open
Abstract
cMet is a well‐characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody–drug conjugates (ADCs). However, the clinical benefit from cMet‐targeted therapy has been limited. We developed a novel cMet‐targeted ‘third‐generation’ ADC, TR1801‐ADC, that was optimized at different levels including specificity, stability, toxin–linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site‐specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin–linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet‐expressing cell lines but also in medium‐to‐low cMet cell lines (40 000–90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low–medium cMet expression were also very responsive to TR1801‐ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801‐ADC had excellent efficacy with significant antitumor activity in 90% of tested patient‐derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single‐dose administration. Altogether, TR1801‐ADC is a new generation cMet ADC with best‐in‐class preclinical efficacy and good tolerability in rats.
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Affiliation(s)
| | | | - Vincent Blot
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Ryo Fujita
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Diana Galvan
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Vincent Lieuw
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Sophie Nguyen
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | | | | | - Jose Villicana
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Jon Wojciak
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Eley Wong
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Raul Pardo
- Spirogen, a member of the AstraZeneca Group, London, UK
| | - Neki Patel
- Spirogen, a member of the AstraZeneca Group, London, UK
| | | | | | - Conor Barry
- Spirogen, a member of the AstraZeneca Group, London, UK
| | | | | | - Roland Newman
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
| | - Julia Coronella
- Tanabe Research Laboratories U.S.A., Inc., San Diego, CA, USA
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13
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Overman MJ, Adam L, Raghav K, Wang J, Kee B, Fogelman D, Eng C, Vilar E, Shroff R, Dasari A, Wolff R, Morris J, Karunasena E, Pisanic TR, Azad N, Kopetz S. Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer. Ann Oncol 2019; 29:139-144. [PMID: 29069279 DOI: 10.1093/annonc/mdx688] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. Results A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P = 0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA.
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Affiliation(s)
- M J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - L Adam
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - K Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - J Wang
- Institute for NanoBioTechnology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA
| | - B Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - D Fogelman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - C Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - E Vilar
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - R Shroff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - R Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - J Morris
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - E Karunasena
- Department of Gastrointestinal Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA
| | - T R Pisanic
- Institute for NanoBioTechnology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA
| | - N Azad
- Department of Gastrointestinal Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA
| | - S Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
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14
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Gallery M, Zhang J, Bradley DP, Brauer P, Cvet D, Estevam J, Danaee H, Greenfield E, Li P, Manfredi M, Loke HK, Rabino C, Stringer B, Williamson M, Wyant T, Yang J, Zhu Q, Abu-Yousif A, Veiby OP. A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo. PLoS One 2018; 13:e0191046. [PMID: 29370189 PMCID: PMC5784926 DOI: 10.1371/journal.pone.0191046] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 12/27/2017] [Indexed: 12/15/2022] Open
Abstract
Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors.
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Affiliation(s)
- Melissa Gallery
- Molecular & Cellular Oncology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Julie Zhang
- Cancer Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Daniel P Bradley
- Biomedical Imaging, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Pamela Brauer
- Protein Sciences, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Donna Cvet
- Biomedical Imaging, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Jose Estevam
- Biomarker Assay & Exploratory Biology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Hadi Danaee
- Biomarker Assay & Exploratory Biology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Edward Greenfield
- Protein Sciences, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Ping Li
- Protein Sciences, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Mark Manfredi
- Cancer Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Huay-Keng Loke
- Oncology Biochemistry, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Claudia Rabino
- Molecular & Cellular Oncology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Brad Stringer
- Molecular Pathology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Mark Williamson
- US Medical Affairs, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Tim Wyant
- Translational Medicine, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Johnny Yang
- DMPK, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Qing Zhu
- DMPK, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - Adnan Abu-Yousif
- Cancer Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
| | - O Petter Veiby
- Global Biotherapeutics, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America
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15
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Comprehensive Analysis of Cancer-Proteogenome to Identify Biomarkers for the Early Diagnosis and Prognosis of Cancer. Proteomes 2017; 5:proteomes5040028. [PMID: 29068423 PMCID: PMC5748563 DOI: 10.3390/proteomes5040028] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 10/13/2017] [Accepted: 10/17/2017] [Indexed: 02/07/2023] Open
Abstract
During the past century, our understanding of cancer diagnosis and treatment has been based on a monogenic approach, and as a consequence our knowledge of the clinical genetic underpinnings of cancer is incomplete. Since the completion of the human genome in 2003, it has steered us into therapeutic target discovery, enabling us to mine the genome using cutting edge proteogenomics tools. A number of novel and promising cancer targets have emerged from the genome project for diagnostics, therapeutics, and prognostic markers, which are being used to monitor response to cancer treatment. The heterogeneous nature of cancer has hindered progress in understanding the underlying mechanisms that lead to abnormal cellular growth. Since, the start of The Cancer Genome Atlas (TCGA), and the International Genome consortium projects, there has been tremendous progress in genome sequencing and immense numbers of cancer genomes have been completed, and this approach has transformed our understanding of the diagnosis and treatment of different types of cancers. By employing Genomics and proteomics technologies, an immense amount of genomic data is being generated on clinical tumors, which has transformed the cancer landscape and has the potential to transform cancer diagnosis and prognosis. A complete molecular view of the cancer landscape is necessary for understanding the underlying mechanisms of cancer initiation to improve diagnosis and prognosis, which ultimately will lead to personalized treatment. Interestingly, cancer proteome analysis has also allowed us to identify biomarkers to monitor drug and radiation resistance in patients undergoing cancer treatment. Further, TCGA-funded studies have allowed for the genomic and transcriptomic characterization of targeted cancers, this analysis aiding the development of targeted therapies for highly lethal malignancy. High-throughput technologies, such as complete proteome, epigenome, protein-protein interaction, and pharmacogenomics data, are indispensable to glean into the cancer genome and proteome and these approaches have generated multidimensional universal studies of genes and proteins (OMICS) data which has the potential to facilitate precision medicine. However, due to slow progress in computational technologies, the translation of big omics data into their clinical aspects have been slow. In this review, attempts have been made to describe the role of high-throughput genomic and proteomic technologies in identifying a panel of biomarkers which could be used for the early diagnosis and prognosis of cancer.
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López-García C, Sansregret L, Domingo E, McGranahan N, Hobor S, Birkbak NJ, Horswell S, Grönroos E, Favero F, Rowan AJ, Matthews N, Begum S, Phillimore B, Burrell R, Oukrif D, Spencer-Dene B, Kovac M, Stamp G, Stewart A, Danielsen H, Novelli M, Tomlinson I, Swanton C. BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer. Cancer Cell 2017; 31:79-93. [PMID: 28073006 PMCID: PMC5225404 DOI: 10.1016/j.ccell.2016.11.001] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 08/05/2016] [Accepted: 10/28/2016] [Indexed: 01/03/2023]
Abstract
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.
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Affiliation(s)
- Carlos López-García
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Laurent Sansregret
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Enric Domingo
- Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN UK; Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Nicholas McGranahan
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Translational Cancer Therapeutics Laboratory, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC2E 6DD, UK
| | - Sebastijan Hobor
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Nicolai Juul Birkbak
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Translational Cancer Therapeutics Laboratory, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC2E 6DD, UK
| | - Stuart Horswell
- Bioinformatics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Eva Grönroos
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Francesco Favero
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer System Biology, Centre for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark
| | - Andrew J Rowan
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Nicholas Matthews
- Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Sharmin Begum
- Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Benjamin Phillimore
- Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Rebecca Burrell
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Dahmane Oukrif
- Research Department of Pathology, University College London Medical School, University Street, London WC1E 6JJ, UK
| | - Bradley Spencer-Dene
- Experimental Histopathology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Michal Kovac
- Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN UK
| | - Gordon Stamp
- Experimental Histopathology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Aengus Stewart
- Bioinformatics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Havard Danielsen
- Institute for Cancer Genetics and Informatics, Norwegian Radium Hospital, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway
| | - Marco Novelli
- Research Department of Pathology, University College London Medical School, University Street, London WC1E 6JJ, UK
| | - Ian Tomlinson
- Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN UK
| | - Charles Swanton
- Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Translational Cancer Therapeutics Laboratory, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC2E 6DD, UK.
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Lopes-Costa E, Abreu M, Gargiulo D, Rocha E, Ramos AA. Anticancer effects of seaweed compounds fucoxanthin and phloroglucinol, alone and in combination with 5-fluorouracil in colon cells. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2017; 80:776-787. [PMID: 28850007 DOI: 10.1080/15287394.2017.1357297] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Colorectal cancer therapy with 5-fluorouracil (5-Fu) frequently become ineffective due to resistance to this drug; and thus other effective compounds are essential for therapy. It is well-known marine brown seaweeds contain antioxidant compounds the carotenoid fucoxanthin (Fx) and polyphenolic compound phloroglucinol (Ph) which exerted diverse biological activities including antioxidant and anticancer. The aim of this study was to determine the anticancer activities of Fx or Ph alone as well as combination of each chemical with 5-Fu on two human colorectal cancer cell lines (HCT116 and HT29), with comparison to responses in a normal colon cell line (CCD-18Co). Effects of these compounds on cell viability, induction of DNA damage, and cell death were evaluated using MTT assay, comet assay, nuclear condensation assay, and Western blot. 5-Fu decreased cell viability in a concentration-dependent manner in HCT116 and HT29 cells but was not cytotoxic in CCD-18Co cells. 5-Fu induced DNA damage in HCT116 cells with induction of cell death, while no marked effects on DNA damage and cell death were observed in HT29 cells. Fx or Ph alone also reduced cell viability in both cancer cell lines but no apparent cytotoxic effect in CCD-18Co cells, except for Fx at 50 and 100 µM. Diminished cell viability was accompanied by induction of DNA damage (by Fx) and induction of cell death (by Ph). In combination with 5-Fu, Fx at 10 µM (in HCT116 and HT29 cells), and Ph at 300 µM (in HT29 cells) enhanced the cytotoxic effect of 5-Fu; however, no marked cytotoxicity was noted in CCD-18Co cells. Since Fx and Ph alone reduced cancer cell line viability without an effect on normal cells and when in combination enhanced the cytotoxic effect of 5-Fu only in colon cancer cells, these compounds seem promising as anticancer agents.
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Affiliation(s)
- Eduarda Lopes-Costa
- a Group of Histomorphology, Physiopathology and Applied Toxicology, CIIMAR - Interdisciplinary Center for Marine and Environmental Research, U. Porto - University of Porto , Matosinhos , Portugal
- b Laboratory of Histology and Embryology, Department of Microscopy , ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto (U. Porto) , Porto , Portugal
| | - Mariana Abreu
- a Group of Histomorphology, Physiopathology and Applied Toxicology, CIIMAR - Interdisciplinary Center for Marine and Environmental Research, U. Porto - University of Porto , Matosinhos , Portugal
| | - Daniela Gargiulo
- a Group of Histomorphology, Physiopathology and Applied Toxicology, CIIMAR - Interdisciplinary Center for Marine and Environmental Research, U. Porto - University of Porto , Matosinhos , Portugal
- c Department of Biological Sciences and Health , UNIBH - University Center of Belo Horizonte, University of Minas Gerais , Belo Horizonte , MG , Brazil
| | - Eduardo Rocha
- a Group of Histomorphology, Physiopathology and Applied Toxicology, CIIMAR - Interdisciplinary Center for Marine and Environmental Research, U. Porto - University of Porto , Matosinhos , Portugal
- b Laboratory of Histology and Embryology, Department of Microscopy , ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto (U. Porto) , Porto , Portugal
| | - Alice A Ramos
- a Group of Histomorphology, Physiopathology and Applied Toxicology, CIIMAR - Interdisciplinary Center for Marine and Environmental Research, U. Porto - University of Porto , Matosinhos , Portugal
- b Laboratory of Histology and Embryology, Department of Microscopy , ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto (U. Porto) , Porto , Portugal
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Lopez NE, Peterson CY. Advances in Biomarkers: Going Beyond the Carcinoembryonic Antigen. Clin Colon Rectal Surg 2016; 29:196-204. [PMID: 27582644 DOI: 10.1055/s-0036-1584289] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Using biologically available markers to guide treatment decisions in colorectal cancer care is becoming increasingly common, though our understanding of these biomarkers is in its infancy. In this article, we will discuss how this area is rapidly changing, review important biomarkers being used currently, and explain how the results influence clinical decision-making. We will also briefly discuss the possibility of a liquid biopsy and explore several exciting and new options.
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Affiliation(s)
- Nicole E Lopez
- Division of Surgical Oncology, University of North Carolina, Chapel Hill, North Carolina
| | - Carrie Y Peterson
- Division of Colorectal Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
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Parayath NN, Nehoff H, Norton SE, Highton AJ, Taurin S, Kemp RA, Greish K. Styrene maleic acid-encapsulated paclitaxel micelles: antitumor activity and toxicity studies following oral administration in a murine orthotopic colon cancer model. Int J Nanomedicine 2016; 11:3979-91. [PMID: 27574427 PMCID: PMC4993259 DOI: 10.2147/ijn.s110251] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Oral administration of paclitaxel (PTX), a broad spectrum anticancer agent, is challenged by its low uptake due to its poor bioavailability, efflux through P-glycoprotein, and gastrointestinal toxicity. We synthesized PTX nanomicelles using poly(styrene-co-maleic acid) (SMA). Oral administration of SMA-PTX micelles doubled the maximum tolerated dose (60 mg/kg vs 30 mg/kg) compared to the commercially available PTX formulation (PTX [Ebewe]). In a murine orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 mg/kg and 60 mg/kg reduced tumor weight by 54% and 69%, respectively, as compared to the control group, while no significant reduction in tumor weight was observed with 30 mg/kg of PTX (Ebewe). In addition, toxicity of PTX was largely reduced by its encapsulation into SMA. Furthermore, examination of the tumors demonstrated a decrease in the number of blood vessels. Thus, oral delivery of SMA-PTX micelles may provide a safe and effective strategy for the treatment of colon cancer.
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Affiliation(s)
| | | | - Samuel E Norton
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Andrew J Highton
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Sebastien Taurin
- Department of Pharmacology and Toxicology
- Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA
| | - Roslyn A Kemp
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Khaled Greish
- Department of Pharmacology and Toxicology
- Princess Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain
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20
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Park JS, Kim JK, Yoon DS. Correlation of Early Recurrence With In Vitro Adenosine Triphosphate Based Chemotherapy Response Assay in Pancreas Cancer With Postoperative Gemcitabine Chemotherapy. J Clin Lab Anal 2016; 30:804-810. [PMID: 26991127 DOI: 10.1002/jcla.21940] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Revised: 12/13/2015] [Accepted: 12/28/2015] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION Gemcitabine-based regimens represent the standard systemic first line treatment in patients after pancreatic resection. However, the clinical impact of gemcitabine varies significantly in individuals because of chemoresistance. An in vitro adenosine triphosphate based chemotherapy response assay (ATP-CRA) was designed to evaluate the sensitivity of cancer cells to various chemotherapeutic agents. This study investigated the correlation between in vitro gemcitabine sensitivity of tumor cells and early recurrence after curative resection. METHOD From January 2007 to December 2010, the ATP-CRA for gemcitabine was tested in 64 patients surgically treated for pancreas cancer at Gangnam Severance Hospital, Seoul, Korea. We analyzed the relationship between chemosensitivity and early systemic recurrence in patients with pancreas cancer to predict disease-free survival (DFS) after curative resection in pancreas cancer. RESULT The mean cell death rate (CDR) was 20.0 (±14.5) and divided into two groups according to the mean values of the CDR. Lymphovascular invasion was more frequently shown in gemcitabine resistance group without statistical significance. In univariate and multivariate analysis, advanced tumor stage and gemcitabine sensitive group (CDR ≥ 20) were identified as independent prognostic factors for DFS. CONCLUSIONS Gemcitabine sensitivity measured by ATP-CRA was well correlated with in vivo drug responsibility to predict early recurrence following gemcitabine-based adjuvant chemotherapy in patients with pancreas cancer.
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Affiliation(s)
- Joon Seong Park
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Jae Keun Kim
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Dong Sup Yoon
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea.
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21
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Cleven AHG, Derks S, Draht MXG, Smits KM, Melotte V, Van Neste L, Tournier B, Jooste V, Chapusot C, Weijenberg MP, Herman JG, de Bruïne AP, van Engeland M. CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer. Clin Cancer Res 2015; 20:3261-71. [PMID: 24928946 DOI: 10.1158/1078-0432.ccr-12-3734] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here, we examine the prognostic impact of promoter methylation in patients with CRC treated with surgery alone in the context of microsatellite instability (MSI), BRAF and KRAS mutations. EXPERIMENTAL METHODS One hundred and seventy-three CRCs were analyzed for promoter methylation of 19 tumor suppressor and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. RESULTS Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 [CL1, 57% (98/173) of CRCs], cluster 2 [CL2, 25% (43/173) of CRCs], and cluster 3 [CL3, 18% (32/173) of CRCs]. CL3 had the highest methylation index (0.25, 0.49, and 0.69, respectively, P = <0.01) and was strongly associated with CIMP (P < 0.01). Subgroup analysis for tumor stage, MSI, and BRAF status showed no statistically significant differences in survival between CL1, CL2, and CL3 nor between CIMP and non-CIMP CRCs. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, microsatellite stability (MSS), BRAF wild-type (WT) CRCs: multivariate Cox proportional HR = 3.89 [95% confidence interval (CI), 1.58-9.60, P < 0.01; n = 66] and HR = 2.11 (95% CI, 0.95-4.69, P = 0.068, n = 136) in a second independent population-based study. CONCLUSIONS CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF WT CRCs.
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Affiliation(s)
- Arjen H G Cleven
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sarah Derks
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Muriel X G Draht
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kim M Smits
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, MarylandAuthors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Veerle Melotte
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Leander Van Neste
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Benjamin Tournier
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Valerie Jooste
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Caroline Chapusot
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Matty P Weijenberg
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - James G Herman
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Adriaan P de Bruïne
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Manon van Engeland
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
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Bargiela-Iparraguirre J, Prado-Marchal L, Pajuelo-Lozano N, Jiménez B, Perona R, Sánchez-Pérez I. Mad2 and BubR1 modulates tumourigenesis and paclitaxel response in MKN45 gastric cancer cells. Cell Cycle 2015; 13:3590-601. [PMID: 25483095 DOI: 10.4161/15384101.2014.962952] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Aneuploidy and chromosomal instability (CIN) are common features of gastric cancer (GC), but their contribution to carcinogenesis and antitumour therapy response is still poorly understood. Failures in the mitotic checkpoint induced by changes in expression levels of the spindle assembly checkpoint (SAC) proteins cause the missegregation of chromosomes in mitosis as well as aneuploidy. To evaluate the possible contribution of SAC to GC, we analyzed the expression levels of proteins of the mitotic checkpoint complex in a cohort of GC cell lines. We found that the central SAC proteins, Mad2 and BubR1, were the more prominently expressed members in disseminated GC cell lines. Silencing of Mad2 and BubR1 in MKN45 and ST2957 cells decreased their cell proliferation, migration and invasion abilities, indicating that Mad2 and BubR1 could contribute to cellular transformation and tumor progression in GC. We next evaluated whether silencing of SAC proteins could affect the response to microtubule poisons. We discovered that paclitaxel treatment increased cell survival in MKN45 cells interfered for Mad2 or BubR1 expression. However, apoptosis (assessed by caspase-3 activation, PARP proteolysis and levels of antiapoptotic Bcl 2-family members), the DNA damage response (assessed by H2Ax phosphorylation) and exit from mitosis (assessed by Cyclin B degradation and Cdk1 regulation) were activated equally between cells, independently of Mad2 or BubR1-protein levels. In contrast, we observed that the silencing of Mad2 or BubR1 in MKN45 cells showed the induction of a senescence-like phenotype accompanied by cell enlargement, increased senescence-associated β-galactosidase activity and increased IL-6 and IL-8 expression. In addition, the senescent phenotype is highly increased after treatment with PTX, indicating that senescence could prevent tumorigenesis in GC. In conclusion, the results presented here suggest that Mad2 and BubR1 could be used as prognostic markers of tumor progression and new pharmacological targets in the treatment for GC.
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Key Words
- BMC, bleomycin
- BubR1
- BubR1, budding uninhibited by benzimidazoles 1 homolog B protein (gene BUB1B)
- CDDP, cisplatin
- CIN, chromosome instability
- DDR, DNA damage response
- Mad2
- Mad2, mitotic arrest deficient-like-1 protein (gene Mad2L1)
- Monopolar Spindle kinase, MPS1
- PTX, paclitaxel
- SAC, spindle assembly checkpoint
- SASP, senescence associate secretory phenotype
- apoptosis
- gastric cancer
- mitosis
- paclitaxel
- senescence
- γH2AX, phosphorylated H2AX
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23
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Vasudevan S, Thomas SA, Sivakumar KC, Komalam RJ, Sreerekha KV, Rajasekharan KN, Sengupta S. Diaminothiazoles evade multidrug resistance in cancer cells and xenograft tumour models and develop transient specific resistance: understanding the basis of broad-spectrum versus specific resistance. Carcinogenesis 2015; 36:883-93. [PMID: 26014355 DOI: 10.1093/carcin/bgv072] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Accepted: 05/18/2015] [Indexed: 02/07/2023] Open
Abstract
Acquired drug resistance poses a challenge in cancer therapy. Drug efflux is the most common mechanism of resistance displayed by hydrophobic drugs beyond a certain size. However, target specific changes and imbalance between the pro- and anti-apoptotic proteins are also found quite often in many tumours. A number of small antimitotic agents show high potential for multidrug resistant tumours, mainly because they are able to evade the efflux pumps. However, these compounds are also likely to suffer from resistance upon prolonged treatment. Thus, it is important to find out agents that are sensitive to resistant tumours and to know the resistance mechanisms against small molecules so that proper combinations can be planned. In this report, we have studied the efficiency of diaminothiazoles, a novel class of tubulin targeting potential anticancer compounds of small size, in multidrug resistant cancer. Studies in model cell lines raised against taxol and the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole], and the xenograft tumours derived from them, show that diaminothiazoles are highly promising against multidrug resistant cancers. They were able to overcome the expression of efflux protein MDR1 and certain tubulin isotypes, could sensitize improper apoptotic machinery and ablated checkpoint proteins Bub1 and Mad2. Further, we have found that the resistance against microtubule binding compounds with higher size is broad-spectrum and emerges due to multiple factors including overexpression of transmembrane pumps. However, resistance against small molecules is transient, specific and is contributed by target specific changes and variations in apoptotic factors.
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Affiliation(s)
- Smreti Vasudevan
- Division of Cancer Research and Distributed Information Sub-Centre, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India and Department of Chemistry, University of Kerala, Trivandrum, India
| | - Sannu Ann Thomas
- Division of Cancer Research and Distributed Information Sub-Centre, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India and Department of Chemistry, University of Kerala, Trivandrum, India
| | | | - Reena J Komalam
- Department of Chemistry, University of Kerala, Trivandrum, India
| | | | | | - Suparna Sengupta
- Division of Cancer Research and Distributed Information Sub-Centre, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India and Department of Chemistry, University of Kerala, Trivandrum, India
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How C, Bruce J, So J, Pintilie M, Haibe-Kains B, Hui A, Clarke BA, Hedley DW, Hill RP, Milosevic M, Fyles A, Liu FF. Chromosomal instability as a prognostic marker in cervical cancer. BMC Cancer 2015; 15:361. [PMID: 25944123 PMCID: PMC4433070 DOI: 10.1186/s12885-015-1372-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 04/27/2015] [Indexed: 01/10/2023] Open
Abstract
Background Cervical cancer is the third most common cancer in women globally, and despite treatment, distant metastasis and nodal recurrence will still develop in approximately 30% of patients. The ability to predict which patients are likely to experience distant relapse would allow clinicians to better tailor treatment. Previous studies have investigated the role of chromosomal instability (CIN) in cancer, which can promote tumour initiation and growth; a hallmark of human malignancies. In this study, we sought to examine the published CIN70 gene signature in a cohort of cervical cancer patients treated at the Princess Margaret (PM) Cancer Centre and an independent cohort of The Cancer Genome Atlas (TCGA) cervical cancer patients, to determine if this CIN signature associated with patient outcome. Methods Cervical cancer samples were collected from 79 patients, treated between 2000–2007 at the PM, prior to undergoing curative chemo-radiation. Total RNA was extracted from each patient sample and analyzed using the GeneChip Human Genome U133 Plus 2.0 array (Affymetrix). Results High CIN70 scores were significantly related to increased chromosomal alterations in TCGA cervical cancer patients, including a higher percentage of genome altered and a higher number of copy number alterations. In addition, this same CIN70 signature was shown to be predictive of para-aortic nodal relapse in the PM Cancer Centre cohort. Conclusions These findings demonstrate that chromosomal instability plays an important role in cervical cancer, and is significantly associated with patient outcome. For the first time, this CIN70 gene signature provided prognostic value for patients with cervical cancer.
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Affiliation(s)
- Christine How
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | - Jeff Bruce
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | - Jonathan So
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
| | - Melania Pintilie
- Division of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Medical Biophysics Department, University of Toronto, Toronto, ON, Canada.
| | - Angela Hui
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | - Blaise A Clarke
- Department of Pathology, University Health Network, Toronto, ON, Canada.
| | - David W Hedley
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
| | - Richard P Hill
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | - Michael Milosevic
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
| | - Anthony Fyles
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
| | - Fei-Fei Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
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Giovinazzi S, Sirleto P, Aksenova V, Morozov VM, Zori R, Reinhold WC, Ishov AM. Usp7 protects genomic stability by regulating Bub3. Oncotarget 2015; 5:3728-42. [PMID: 25003721 PMCID: PMC4116516 DOI: 10.18632/oncotarget.1989] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
USP7 (Ubiquitin Specific processing Protease-7) is a deubiquitinase which, over the past decade emerged as a critical regulator of cellular processes. Deregulation of USP7 activity has been linked to cancer, making USP7 inhibition an appealing anti-cancer strategy. The identification of novel USP7 substrates and additional USP7-dependent cellular activities will broaden our knowledge towards potential clinical application of USP7 inhibitors. Results presented in this study uncover a novel and pivotal function of USP7 in the maintenance of genomic stability. Upon USP7 depletion we observed prolonged mitosis and mitotic abnormalities including micronuclei accumulation, lagging chromosomes and karyotype instability. Inhibition of USP7 with small molecule inhibitors stabilizes cyclin B and causes mitotic abnormalities. Our results suggest that these USP7-dependent effects are mediated by decreased levels of spindle assembly checkpoint (SAC) component Bub3, which we characterized as an interacting partner and substrate of USP7. In silico analysis across the NCI-60 panels of cell lines supports our results where lower levels of USP7 strongly correlate with genomic instability. In conclusion, we identified a novel role of USP7 as regulator of the SAC component Bub3 and genomic stability.
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Affiliation(s)
- Serena Giovinazzi
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL; University of Florida Health Cancer Center, Gainesville, FL
| | | | | | | | | | | | - Alexander M Ishov
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL; University of Florida Health Cancer Center, Gainesville, FL
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Adamia S, Kriangkum J, Belch AR, Pilarski LM. Aberrant posttranscriptional processing of hyaluronan synthase 1 in malignant transformation and tumor progression. Adv Cancer Res 2015; 123:67-94. [PMID: 25081526 DOI: 10.1016/b978-0-12-800092-2.00003-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
It is becoming increasingly apparent that splicing defects play a key role in cancer, and that alterations in genomic splicing elements promote aberrant splicing. Alternative splicing increases the diversity of the human transcriptome and increases the numbers of functional gene products. However, dysregulation that leads to aberrant pre-mRNA splicing can contribute to cancer. Hyaluronan (HA), known to be an important component of cancer progression, is synthesized by hyaluronan synthases (HASs). In cancer cells, hyaluronan synthase 1 (HAS1) pre-mRNA is abnormally spliced to generate a family of aberrant splice variants (HAS1Vs) that synthesize extracellular and intracellular HA. HAS1Vs are clinically relevant, being found almost exclusively in malignant cells. Expression of aberrant HAS1Vs predicts poor survival in multiple myeloma. In this review, we summarize the unusual properties of HAS1Vs and their relationship to cancer. HAS1Vs form heterogeneous multimers with normally spliced HAS1 as well as with each other and with HAS3. Aberrant variants of HAS1 synthesize HA. Extracellular HA synthesized by HAS1Vs is likely to promote malignant spread. We speculate that synthesis of intracellular HA plays a fundamental and early role in oncogenesis by promoting genetic instability and the emergence of viable cancer variants that lead to aggressive disease.
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Affiliation(s)
- Sophia Adamia
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
| | - Jitra Kriangkum
- Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada
| | - Andrew R Belch
- Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada
| | - Linda M Pilarski
- Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada
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Nakayama Y, Uno N, Uno K, Mizoguchi Y, Komoto S, Kazuki Y, Nanba E, Inoue T, Oshimura M. Recurrent micronucleation through cell cycle progression in the presence of microtubule inhibitors. Cell Struct Funct 2015; 40:51-9. [PMID: 25736016 DOI: 10.1247/csf.14005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Although most cell lines undergo mitotic arrest after prolonged exposure to microtubule inhibitors, some cells subsequently exit this state and become tetraploid. Among these cells, limited numbers of rodent cells are known to undergo multinucleation to generate multiple small independent nuclei, or micronuclei by prolonged colcemid treatment. Micronuclei are thought to be formed when cells shift to a pseudo G1 phase, during which the onset of chromosomal decondensation allows individual chromosomes distributed throughout the cell to serve as sites for the reassembly of nuclear membranes. To better define this process, we used long-term live cell imaging to observe micronucleation induced in mouse A9 cells by treating with the microtubule inhibitor colcemid. Our observations confirm that nuclear envelope formation occurs when mitotic-arrested cells shift to a pseudo G1 phase and adopt a tetraploid state, accompanied by chromosome decondensation. Unexpectedly, only a small number of cells containing large micronuclei were formed. We found that tetraploid micronucleated cells proceeded through an additional cell cycle, shifting to a pseudo G1 phase and forming octoploid micronucleated cells that were smaller and more numerous compared with the tetraploid micronucleated cells. Our data suggest that micronucleation occur when cells shift from mitotic arrest to a pseudo G1 phase, and demonstrate that, rather than being a single event, micronucleation is an inducible recurrent process that leads to the formation of progressively smaller and more numerous micronuclei.
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Affiliation(s)
- Yuji Nakayama
- Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University
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28
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Maletzki C, Gock M, Randow M, Klar E, Huehns M, Prall F, Linnebacher M. Establishment and characterization of cell lines from chromosomal instable colorectal cancer. World J Gastroenterol 2015; 21:164-176. [PMID: 25574089 PMCID: PMC4284332 DOI: 10.3748/wjg.v21.i1.164] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 06/26/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To generate novel tumor models for preclinical validation of biomarkers that allow drug response prediction and individual therapeutic decisions. METHODS Cell line establishment was conducted by both direct in vitro culturing and in vivo xenografting followed by in vitro culturing procedure. A comprehensive characterization was subsequently performed. This included quality control, consisting of the confirmation of human and colorectal cancer (CRC) origin by DNA fingerprint and epithelial cell adhesion molecule (EpCAM) staining, as well as mycoplasma and human virus testing. Phenotypic analysis was done by light microscopy and multicolor flow cytometry. Histopathological examination (β-catenin and cytokeratin staining) was conducted in direct comparison to parental tumor tissues. Extensive molecular-pathological profiling included mutation analysis for CRC-associated driver mutations, assessment of chromosomal and microsatellite instability, and the grade of CpG island methylation. Additionally, an array-based comparative genomic hybridization analysis was performed. Drug responsiveness was assessed for a panel of classical and novel substances in clinical use for the treatment of solid cancers. Finally, tumorigenicity of the cell lines was tested by xenografting into immunocompromised nude mice. RESULTS Herein we describe the establishment of three ultra-low passage cell lines from two individual patients suffering from sporadic CRC. One cell line was derived directly from an early stage case (HROC18), whereas two cell lines could be established both direct from patient material and after xenografting from a late stage tumor (HROC32). All cell lines were free of contaminating mycoplasma and viruses. Molecular-pathological analysis allowed all cell lines to be classified as chromosomal instable (CIN(+)). They were aneuploid, with CpG island promoter methylation and microsatellite instability being absent. The following mutational profile was observed both in the cell lines and the parental tumor tissue: HROC18: APC(mut), p53(mut), K-ras(wt); HROC32: APC(wt), p53(mut), K-ras(mut). All cell lines were characterized as epithelial (EpCAM(+)) cells, showing distinct morphology and migration speed, but comparable growth kinetics. The cell lines showed different patterns of response towards clinically approved and novel drugs, with HROC18 being more resistant than HROC32 cells. Finally, in vivo tumorigenicity was demonstrated. CONCLUSION We successfully established and characterized novel ultra-low passage patient-derived CRC models as useful instruments for analyzing biological characteristics associated with the CIN(+) phenotype.
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Inoue T, Nakayama Y, Li Y, Matsumori H, Takahashi H, Kojima H, Wanibuchi H, Katoh M, Oshimura M. SIRT2 knockdown increases basal autophagy and prevents postslippage death by abnormally prolonging the mitotic arrest that is induced by microtubule inhibitors. FEBS J 2014; 281:2623-37. [PMID: 24712640 DOI: 10.1111/febs.12810] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 03/11/2014] [Accepted: 04/07/2014] [Indexed: 12/16/2022]
Abstract
Mitotic catastrophe, a form of cell death that occurs during mitosis and after mitotic slippage to a tetraploid state, plays important roles in the efficacy of cancer cell killing by microtubule inhibitors (MTIs). Prolonged mitotic arrest by the spindle assembly checkpoint is a well-known requirement for mitotic catastrophe, and thus for conferring sensitivity to MTIs. We previously reported that turning off spindle assembly checkpoint activation after a defined period of time is another requirement for efficient postslippage death from a tetraploid state, and we identified SIRT2, a member of the sirtuin protein family, as a regulator of this process. Here, we investigated whether SIRT2 regulates basal autophagy and whether, in that case, autophagy regulation by SIRT2 is required for postslippage death, by analogy with previous insights into SIRT1 functions in autophagy. We show, by combined knockdown of autophagy genes and SIRT2, that SIRT2 serves this function at least partially by suppressing basal autophagy levels. Notably, increased autophagy induced by rapamycin and mild starvation caused mitotic arrest for an abnormally long period of time in the presence of MTIs, and this was followed by delayed postslippage death, which was also observed in cells with SIRT2 knockdown. These results underscore a causal association among increased autophagy levels, mitotic arrest for an abnormally long period of time after exposure to MTIs, and resistance to MTIs. Although autophagy acts as a tumor suppressor mechanism, this study highlights its negative aspects, as increased autophagy may cause mitotic catastrophe malfunction. Thus, SIRT2 offers a novel target for tumor therapy.
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Affiliation(s)
- Toshiaki Inoue
- Division of Human Genome Science, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, Tottori University, Japan; Chromosome Engineering Research Center, Tottori University, Japan
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30
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Moorcraft SY, Chau I, Peckitt C, Cunningham D, Rao S, Yim KL, Walther A, Jackson CGCA, Stamp G, Webb J, Smith G, Gillbanks A, Swanton C. Patupilone in patients with pretreated metastatic/locally recurrent colorectal cancer: results of the Phase II CINATRA trial. Invest New Drugs 2013; 31:1339-44. [DOI: 10.1007/s10637-013-9990-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 06/12/2013] [Indexed: 01/09/2023]
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31
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Araujo A, Baum B, Bentley P. The role of chromosome missegregation in cancer development: a theoretical approach using agent-based modelling. PLoS One 2013; 8:e72206. [PMID: 23991060 PMCID: PMC3753339 DOI: 10.1371/journal.pone.0072206] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 07/08/2013] [Indexed: 01/30/2023] Open
Abstract
Many cancers are aneuploid. However, the precise role that chromosomal instability plays in the development of cancer and in the response of tumours to treatment is still hotly debated. Here, to explore this question from a theoretical standpoint we have developed an agent-based model of tissue homeostasis in which to test the likely effects of whole chromosome mis-segregation during cancer development. In stochastic simulations, chromosome mis-segregation events at cell division lead to the generation of a diverse population of aneuploid clones that over time exhibit hyperplastic growth. Significantly, the course of cancer evolution depends on genetic linkage, as the structure of chromosomes lost or gained through mis-segregation events and the level of genetic instability function in tandem to determine the trajectory of cancer evolution. As a result, simulated cancers differ in their level of genetic stability and in their growth rates. We used this system to investigate the consequences of these differences in tumour heterogeneity for anti-cancer therapies based on surgery and anti-mitotic drugs that selectively target proliferating cells. As expected, simulated treatments induce a transient delay in tumour growth, and reveal a significant difference in the efficacy of different therapy regimes in treating genetically stable and unstable tumours. These data support clinical observations in which a poor prognosis is correlated with a high level of chromosome mis-segregation. However, stochastic simulations run in parallel also exhibit a wide range of behaviours, and the response of individual simulations (equivalent to single tumours) to anti-cancer therapy prove extremely variable. The model therefore highlights the difficulties of predicting the outcome of a given anti-cancer treatment, even in cases in which it is possible to determine the genotype of the entire set of cells within the developing tumour.
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Affiliation(s)
- Arturo Araujo
- Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, United Kingdom
| | - Buzz Baum
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
- * E-mail:
| | - Peter Bentley
- Department of Computer Science, University College London, London, United Kingdom
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32
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Silvestri A, Pin E, Huijbers A, Pellicani R, Parasido EM, Pierobon M, Petricoin E, Liotta L, Belluco C. Individualized therapy for metastatic colorectal cancer. J Intern Med 2013; 274:1-24. [PMID: 23527888 DOI: 10.1111/joim.12070] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Systemic therapeutic efficacy is central to determining the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive biomarkers to optimize efficacy whilst minimizing toxicity. The integration of a new generation of molecularly targeted drugs into the treatment of CRC, coupled with the development of sophisticated technologies for individual tumours as well as patient molecular profiling, underlines the potential for personalized medicine. In this review, we focus on the latest progress made within the genomic and proteomic fields, concerning predictive biomarkers for individualized therapy in metastatic CRC.
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Affiliation(s)
- A Silvestri
- Division of Experimental Oncology 2, CRO-IRCCS, National Cancer Institute, Aviano, Italy
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A'Hern RP, Jamal-Hanjani M, Szász AM, Johnston SRD, Reis-Filho JS, Roylance R, Swanton C. Taxane benefit in breast cancer—a role for grade and chromosomal stability. Nat Rev Clin Oncol 2013; 10:357-64. [DOI: 10.1038/nrclinonc.2013.67] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Wang Y, Liu L, Liu X, Zhang H, Liu J, Feng B, Shang Y, Zhou L, Wu K, Nie Y, Zhang H, Fan D. Shugoshin1 enhances multidrug resistance of gastric cancer cells by regulating MRP1, Bcl-2, and Bax genes. Tumour Biol 2013; 34:2205-14. [PMID: 23564482 DOI: 10.1007/s13277-013-0758-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 03/20/2013] [Indexed: 12/26/2022] Open
Abstract
Multidrug resistance (MDR) is a major clinical obstacle in treatment of gastric cancer (GC) and it accounts for the majority of cancer-related mortalities. Shugoshin1 (SGO1) is an important player in appropriate chromosome segregation and is involved in tumorigenesis. In this study, we found endogenous SGO1 overexpression in the multidrug-resistant GC cell lines SGC7901/VCR and SGC7901/ADR compared with their parental cell line SGC7901. By enhancing expression of SGO1, sensitivity of SGC7901 cells to vincristine (VCR), adriamycin, 5-fluorouracil (5-FU), and cisplatin (CDDP) was significantly diminished. Silencing its expression resulted in enhanced sensitivity of SGC7901/VCR and SGC7901/ADR cells to these antitumor drugs. Additionally, we confirmed that SGO1 increased capacity of cells to enable adriamycin (ADR) efflux and inhibit drug-induced apoptosis by regulating MRP 1, Bcl-2, and Bax genes so as to confer a MDR phenotype to GC cells. In brief, these findings suggest that SGO1 promotes MDR of GC cells and may be useful as a novel therapeutic target for preventing or reversing MDR.
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Affiliation(s)
- Yafang Wang
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
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Solier S, Zhang YW, Ballestrero A, Pommier Y, Zoppoli G. DNA damage response pathways and cell cycle checkpoints in colorectal cancer: current concepts and future perspectives for targeted treatment. Curr Cancer Drug Targets 2012; 12:356-71. [PMID: 22385513 DOI: 10.2174/156800912800190901] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 07/05/2011] [Accepted: 12/22/2011] [Indexed: 01/28/2023]
Abstract
Although several drugs have been designed in the last few years to target specific key pathways and functions in colorectal cancer (CRC), the backbone of CRC treatment is still made up of compounds which rely on DNA damage to accomplish their role. DNA damage response (DDR) and checkpoint pathways are intertwined signaling networks that arrest cell cycle, recognize and repair genetic mistakes which arise during DNA replication and transcription, as well as through the exposure to chemical and physical agents that interact with nucleic acids. The good but highly variable activity of DNA damaging agents in the treatment of CRC suggests that intrinsic alterations in DDR pathways and cell cycle checkpoints may contribute differentially to the way cancer cells react to DNA damage. In the present review, our aim is to depict the recent advances in understanding the molecular basis of the activity of DNA damaging agents used for the treatment of CRC. We focus on the known and potential drug targets that are part of these complex and intertwined pathways. We describe the potential role of the checkpoints in CRC, and how their pharmacological manipulation could lead to chemopotentiation or synergism with currently used drugs. Novel therapeutic agents playing a role in DDR and checkpoint inhibition are assessed. We discuss the possible rationale for combining PARP inhibition with DNA damaging agents, and we address the link between DDR and EGFR pathways in CRC.
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Affiliation(s)
- S Solier
- Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (MD), USA
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Bakhoum SF, Danilova OV, Kaur P, Levy NB, Compton DA. Chromosomal instability substantiates poor prognosis in patients with diffuse large B-cell lymphoma. Clin Cancer Res 2012; 17:7704-11. [PMID: 22184286 DOI: 10.1158/1078-0432.ccr-11-2049] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE The specific role of chromosomal instability (CIN) in tumorigenesis has been a matter of conjecture. In part, this is due to the challenge of directly observing chromosome mis-segregation events as well as the inability to distinguish the role of CIN, which consists of increased rates of chromosome mis-segregation, from that of aneuploidy, which is a state of nondiploid chromosome number. EXPERIMENTAL DESIGN Here, we examine the contribution of CIN to the prognosis of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) by directly surveying tumor cells, fixed while undergoing anaphase, for evidence of chromosome mis-segregation. Hematoxylin and eosin-stained samples from a cohort of 54 patients were used to examine the relationship between frequencies of chromosome mis-segregation and patient prognosis, overall survival, and response to treatment. RESULTS We show that a two-fold increase in the frequency of chromosome mis-segregation led to a 24% decrease in overall survival and 48% decrease in relapse-free survival after treatment. The HR of death in patients with increased chromosome mis-segregation was 2.31 and these patients were more likely to present with higher tumor stage, exhibit tumor bone marrow involvement, and receive a higher International Prognostic Index score. CONCLUSIONS Increased rates of chromosome mis-segregation in DLBCL substantiate inferior outcome and poor prognosis. This is likely due to increased heterogeneity of tumor cells leading to a larger predilection for adaptation in response to external pressures such as metastasis and drug treatments. We propose that targeting CIN would yield superior prognosis and improved response to chemotherapeutic drugs.
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Affiliation(s)
- Samuel F Bakhoum
- Department of Biochemistry; The Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.
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37
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Yang HY, Kwon J, Park HR, Kwon SO, Park YK, Kim HS, Chung YJ, Chang YJ, Choi HI, Chung KJ, Lee DS, Park BJ, Jeong SH, Lee TH. Comparative proteomic analysis for the insoluble fractions of colorectal cancer patients. J Proteomics 2012; 75:3639-53. [PMID: 22564821 DOI: 10.1016/j.jprot.2012.04.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Revised: 03/24/2012] [Accepted: 04/15/2012] [Indexed: 12/30/2022]
Abstract
We used label-free quantitative proteomics with the insoluble fractions from colorectal cancer (CRC) patients to gain further insight into the utility of profiling altered protein expression as a potential biomarker for cancer. The insoluble fractions were prepared from paired tumor/normal biopsies from 13 patients diagnosed with CRC (stages I to IV). Fifty-six proteins identified in data pooled from the 13 cases were differentially expressed between the tumor and adjacent normal tissue. The connections between these proteins are involved in reciprocal networks related to tumorigenesis, cancer incidence based on genetic disorder, and skeletal and muscular disorders. To assess their potential utility as biomarkers, the relative expression levels of the proteins were validated using personal proteomics and a heat map to compare five individual CRC samples with five normal tissue samples. Further validation of a panel of proteins (KRT5, JUP, TUBB, and COL6A1) using western blotting confirmed the differential expression. These proteins gave specific network information for CRC, and yielded a panel of novel markers and potential targets for treatment. It is anticipated that the experimental approach described here will increase our understanding of the membrane environment in CRC, which may provide direction for making diagnoses and prognoses through molecular biomarker targeting.
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Affiliation(s)
- Hee-Young Yang
- Department of Oral Biochemistry, Dental Science Research Institute and the BK21 Project, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
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Eschenbrenner J, Winsel S, Hammer S, Sommer A, Mittelstaedt K, Drosch M, Klar U, Sachse C, Hannus M, Seidel M, Weiss B, Merz C, Siemeister G, Hoffmann J. Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines. Front Oncol 2011; 1:44. [PMID: 22649765 PMCID: PMC3355879 DOI: 10.3389/fonc.2011.00044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Accepted: 10/31/2011] [Indexed: 12/14/2022] Open
Abstract
Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.
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Affiliation(s)
- Julia Eschenbrenner
- Global Drug Discovery, Therapeutic Research Group Oncology, Bayer Healthcare Pharmaceuticals Berlin, Germany
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Field KM, Zalcberg JR. Biological Markers in Patients with Early-Stage Colon Cancer: Consensus and Controversies. CURRENT COLORECTAL CANCER REPORTS 2011. [DOI: 10.1007/s11888-011-0102-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Niittymäki I, Gylfe A, Laine L, Laakso M, Lehtonen HJ, Kondelin J, Tolvanen J, Nousiainen K, Pouwels J, Järvinen H, Nuorva K, Mecklin JP, Mäkinen M, Ristimäki A, Ørntoft TF, Hautaniemi S, Karhu A, Kallio MJ, Aaltonen LA. High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint. Carcinogenesis 2010; 32:305-11. [PMID: 21163887 DOI: 10.1093/carcin/bgq272] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3' end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A(9)-G(4)-A(7) locus, in which the most common mutation was a mononucleotide deletion in the A(9) (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC.
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Affiliation(s)
- Iina Niittymäki
- Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland
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Abstract
IMPORTANCE OF THE FIELD Since the introduction of taxane-based chemotherapy for advanced solid tumors in the 1990s, the median overall survival of patients with metastatic breast cancer increased from 2 years to almost 5 years. Similarly, the 5-year overall survival for ovarian cancer has increased from 30% to more than 40%. AREAS COVERED IN THIS REVIEW Patupilone is a novel cytotoxic compound, with similar microtubule-binding and apoptotic properties of taxanes and is active in taxane-resistant cell lines. Over 1200 patients have been treated with patupilone in Phase I - III clinical trials and a wealth of knowledge has accumulated about this compound. This review discusses current pharmacology and data from clinical trials with patupilone from the last seven years. WHAT THE READER WILL GAIN We present a comprehensive summary of data from Phase II and III trials, as well as an overview of currently accruing trials. TAKE HOME MESSAGE Although patupilone has not demonstrated superiority over pegylated liposomal doxorubicin in a large Phase III trial in relapsed or refractory ovarian cancer, its evaluation is continuing in a range of other malignancies, especially in primary or secondary tumors of the CNS.
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Affiliation(s)
- Branislav Bystricky
- Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK.
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Tejpar S, Bertagnolli M, Bosman F, Lenz HJ, Garraway L, Waldman F, Warren R, Bild A, Collins-Brennan D, Hahn H, Harkin DP, Kennedy R, Ilyas M, Morreau H, Proutski V, Swanton C, Tomlinson I, Delorenzi M, Fiocca R, Van Cutsem E, Roth A. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist 2010; 15:390-404. [PMID: 20350999 PMCID: PMC3227961 DOI: 10.1634/theoncologist.2009-0233] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.
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Affiliation(s)
- Sabine Tejpar
- Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
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Hewish M, Lord CJ, Martin SA, Cunningham D, Ashworth A. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nat Rev Clin Oncol 2010; 7:197-208. [DOI: 10.1038/nrclinonc.2010.18] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Brosh R, Rotter V. Transcriptional control of the proliferation cluster by the tumor suppressor p53. ACTA ACUST UNITED AC 2010; 6:17-29. [DOI: 10.1039/b911416e] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro. Br J Cancer 2009; 101:1900-8. [PMID: 19935801 PMCID: PMC2788249 DOI: 10.1038/sj.bjc.6605419] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. METHODS Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. RESULTS We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2 cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2 cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2 MCF7 cell line after paclitaxel reflecting the observed increase in senescence. CONCLUSION Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.
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De Geest K, Blessing JA, Morris RT, Yamada SD, Monk BJ, Zweizig SL, Matei D, Muller CY, Richards WE. Phase II clinical trial of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant ovarian or primary peritoneal cancer: a gynecologic oncology group study. J Clin Oncol 2009; 28:149-53. [PMID: 19917861 DOI: 10.1200/jco.2009.24.1455] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Ixabepilone (BMS-247550) is a microtubule-stabilizing epothilone B analog with activity in taxane-resistant metastatic breast cancer. The Gynecologic Oncology Group conducted a phase II evaluation of the efficacy and safety of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant primary ovarian or peritoneal carcinoma. PATIENTS AND METHODS Patients with measurable platinum- and taxane-resistant ovarian or peritoneal carcinoma, defined as progression during or within 6 months of one prior course of treatment with each agent, received intravenous ixabepilone 20 mg/m(2) administered over 1 hour on days 1, 8, and 15 of a 28-day cycle. Results Of 51 patients entered, 49 were eligible. The objective response rate was 14.3% (95% CI, 5.9% to 27.2%), with three complete and four partial responses. Twenty patients (40.8%) had stable disease, whereas sixteen (32.7%) had increasing disease. The median time to progression was 4.4 months (95% CI, 0.8 to 32.6+ months); median survival was 14.8 months (95% CI, 0.8 to 50.0) months. Patients received a median of two treatment cycles (range, 1 to 29 cycles), and 18.4% of patients received > or = six cycles. Adverse effects included peripheral grade 2 (28.5%) and grade 3 (6.1%) neuropathy, grades 3 to 4 neutropenia (20.4%), grade 3 fatigue (14.3%), grade 3 nausea/emesis (22%), grade 3 diarrhea (10%), and grade 3 mucositis (4%). CONCLUSION Ixabepilone 20 mg/m(2) over 1 hour on days 1, 8, and 15 of a 28-day cycle demonstrates antitumor activity and acceptable safety in patients with platinum- and taxane-resistant recurrent or persistent ovarian or primary peritoneal carcinoma.
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Affiliation(s)
- Koen De Geest
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Suite 4630 JCP, Iowa City, IA 52242, USA.
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Huh JW, Park YA, Lee KY, Sohn SK. Heterogeneity of adenosine triphosphate-based chemotherapy response assay in colorectal cancer--secondary publication. Yonsei Med J 2009; 50:697-703. [PMID: 19881975 PMCID: PMC2768246 DOI: 10.3349/ymj.2009.50.5.697] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2008] [Revised: 01/05/2009] [Accepted: 01/05/2009] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Adenosine triphosphate-based chemotherapy response assay (ATP-CRA) is a well-documented and validated technology that can individualize chemotherapy for patients with lung, stomach, or breast cancer. This study explored the feasibility of ATP-CRA as a chemosensitivity test in patients with colorectal cancer. MATERIALS AND METHODS A total of 118 patients who underwent surgical resection for colorectal adenocarcinoma were analyzed for chemosensitivity to 6 anticancer drugs using ATP-CRA. We calculated the cell death rate (CDR) by measuring intracellular ATP levels of drug-exposed cells and untreated controls. RESULTS Interpretable results were available for 85.5% (118/138) of patients. The mean coefficient of variation for triplicate ATP measurements was 9.2%. The highest CDR was observed in irinotecan (34.0%) and the lowest CDR in etoposide (21.0%). Paclitaxel had the broadest range of CDR (0-86.7%) and 5-FU had the narrowest range of CDR (0-56.8%). The overall highest responsiveness was seen most prevalently in irinotecan (24.7%, 23/93 patients). Irinotecan had the greatest responsiveness in patients with well differentiated and moderately differentiated carcinoma. CONCLUSION Our study suggests that ATP-CRA could be used to identify patients with colorectal cancer who might benefit from treatment with a specific chemotherapeutic agent.
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Affiliation(s)
- Jung Wook Huh
- Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Gwangju, Korea
| | - Yoon Ah Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kang Young Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Kook Sohn
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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RNAi-mediated functional analysis of pathways influencing cancer cell drug resistance. Expert Rev Mol Med 2009; 11:e15. [DOI: 10.1017/s1462399409001070] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Acquired drug resistance limits the efficacy of cytotoxics used in the management of haematological and solid tumours and is responsible for the declining clinical benefit following successive treatment regimens in metastatic cancers. Treatment failure has a major impact on quality of life and survival in advanced disease. Defining pathways of intrinsic and acquired drug resistance may provide new targets to prolong drug efficacy and time to disease progression. Predicting the intrinsic drug sensitivity of human tumours in advance of cytotoxic therapy is of paramount importance in order to limit unnecessary toxicity and optimise treatment outcome. RNA interference (RNAi) provides a powerful tool to annotate gene function and systematically define drug-resistance pathways. High-throughput screening RNAi technology has provided evidence for drug-specific resistance pathways as well as novel pathways implicated in multidrug sensitivity. The challenge is how to integrate these data with biological samples to define relevant drug-resistant pathways in vivo.
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Swanton C, Caldas C. Molecular classification of solid tumours: towards pathway-driven therapeutics. Br J Cancer 2009; 100:1517-22. [PMID: 19367275 PMCID: PMC2696770 DOI: 10.1038/sj.bjc.6605031] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2008] [Revised: 03/13/2009] [Accepted: 03/19/2009] [Indexed: 12/26/2022] Open
Abstract
The last decade has witnessed unprecedented developments in the genetic and epigenetic analyses of solid tumours. Transcriptional and DNA copy-number studies have improved our understanding and classification of solid tumours and highlighted the patterns of genomic aberrations associated with outcome. The identification of altered transcriptional and translational silencing by microRNAs and epigenetic modification by methylation in tumours has showed a layer of additional intricacy to the regulation of gene expression in different tumour types. The advent of massive parallel sequencing has allowed whole cancer genomes to be sequenced with extraordinary speed and accuracy providing insight into the bewildering complexity of gene mutations present in solid tumours. Functional genomic studies using RNA interference-screening tools promises to improve the classification of solid tumours by probing the relevance of each gene to tumour phenotype. In this review, we discuss how these studies have contributed to solid tumour classification and why such studies are central to the future of oncology. We suggest that these developments are gradually leading to a change in emphasis of early clinical trials to a therapeutic model guided by the molecular classification of tumours. The investigation of drug efficacy later in development is beginning to rely on patient selection defined by predictive molecular criteria that complement solid tumour classification based on anatomic site.
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Affiliation(s)
- C Swanton
- Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
- Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, UK
| | - C Caldas
- Department of Oncology, University of Cambridge Functional Breast Cancer Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka-Shing Centre, Robinson Way, Cambridge CB2 0RE
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50
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Abstract
Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these "CIN-survival" genes is associated with poor outcome in estrogen receptor-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.
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