|
1
|
Song Y, Chen M, Wei Y, Ma X, Shi H. Signaling pathways in colorectal cancer implications for the target therapies. MOLECULAR BIOMEDICINE 2024; 5:21. [PMID: 38844562 PMCID: PMC11156834 DOI: 10.1186/s43556-024-00178-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 02/29/2024] [Indexed: 06/09/2024] Open
Abstract
Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.
Collapse
Affiliation(s)
- Yanlin Song
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Ming Chen
- West China School of Medicine, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Yuhao Wei
- West China School of Medicine, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Huashan Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
| |
Collapse
|
|
2
|
Targeting EGFR and Monitoring Tumorigenesis of Human Lung Cancer Cells In Vitro and In Vivo Using Nanodiamond-Conjugated Specific EGFR Antibody. Pharmaceutics 2022; 15:pharmaceutics15010111. [PMID: 36678740 PMCID: PMC9865332 DOI: 10.3390/pharmaceutics15010111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/23/2022] [Accepted: 12/21/2022] [Indexed: 12/30/2022] Open
Abstract
Nanoprobes provide advantages for real-time monitoring of tumor markers and tumorigenesis during cancer progression and development. Epidermal growth factor receptor (EGFR) is a key protein that plays crucial roles for tumorigenesis and cancer therapy of lung cancers. Here, we show a carbon-based nanoprobe, nanodiamond (ND), which can be applied for targeting EGFR and monitoring tumorigenesis of human lung cancer cells in vitro and in vivo. The optimal fluorescent intensities of ND particles were observed in the human lung cancer cells and nude mice under in vivo imaging system. The fluorescence signal of ND particles can be real-time detected in the xenografted human lung tumor formation of nude mice. Moreover, the ND-conjugated specific EGFR antibody cetuximab (Cet) can track the location and distribution of EGFR proteins of lung cancer cells in vitro and in vivo. ND-Cet treatment increased cellular uptake ability of nanocomposites in the EGFR-expressed cells but not in the EGFR-negative lung cancer cells. Interestingly, single ND-Cet complex can be directly observed on the protein G bead by immunoprecipitation and confocal microscopy. Besides, the EGFR proteins were transported to lysosomes for degradation. Together, this study demonstrates that ND-conjugated Cet can apply for targeting EGFR and monitoring tumorigenesis during lung cancer progression and therapy.
Collapse
|
|
3
|
Fadaka AO, Bakare OO, Pretorius A, Klein A. Genomic profiling of microRNA target genes in colorectal cancer. Tumour Biol 2020; 42:1010428320933512. [PMID: 32552466 DOI: 10.1177/1010428320933512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Colorectal cancer is the second and third most common cancer in men and women, respectively, worldwide. Alterations such as genetic and epigenetic are common in colorectal cancer and are the basis of tumor formation. The exploration of the molecular basis of colorectal cancer can drive a better understanding of the disease as well as guide the prognosis, therapeutics, and disease management. This study is aimed at investigating the genetic mutation profile of five candidate microRNAs (hsa-miR-513b-3p, hsa-miR-500b-3p, hsa-miR-500a-3p, hsa-miR-450b-3p, hsa-miR-193a-5p) targeted by seven genes (APC, KRAS, TCF7L2, EGFR, IGF1R, CASP8, and GNAS)) using in silico approaches. Two datasets (dataset 1 from our previous study and dataset two (The Cancer Genome Atlas, Nature 2012) were considered for this study. Protein-protein interaction, expression analysis, and genetic profiling were carried out using STRING, FireBrowse, and cBioPortal, respectively. Protein-protein interaction network showed that epidermal growth factor receptor has the highest connection among the target genes and this can be considered as the hub gene. Relative to other solid tumors, in colorectal cancer, six of the target genes were downregulated and only CASP8 was upregulated. Genes with protein tyrosine kinases domain were frequently altered in colorectal cancer and the most common alteration in these genes/domain are missense mutation. These results could serve as a lead in the identification of driver genes responsible for colorectal cancer initiation and progression. However, the intense mechanism of these results remains unclear and further experimental validation and molecular approaches are the focal points in the nearest future.
Collapse
Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Science and Technology/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa.,Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Olalekan Olanrewaju Bakare
- Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashley Pretorius
- Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashwil Klein
- Plant Omics Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| |
Collapse
|
|
4
|
Fadaka AO, Klein A, Pretorius A. In silico identification of microRNAs as candidate colorectal cancer biomarkers. Tumour Biol 2019; 41:1010428319883721. [PMID: 31718480 DOI: 10.1177/1010428319883721] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The involvement of microRNA in cancers plays a significant role in their pathogenesis. Specific expressions of these non-coding RNAs also serve as biomarkers for early colorectal cancer diagnosis, but their laboratory/molecular identification is challenging and expensive. The aim of this study was to identify potential microRNAs for colorectal cancer diagnosis using in silico approach. Sequence similarity search was employed to obtain the candidate microRNA from the datasets, and three target prediction software were employed to determine their target genes. To determine the involvement of these microRNAs in colorectal cancer, the microRNA gene list obtained was used alongside with colorectal cancer expressed genes from gbCRC and CoReCG databases for gene intersection analysis. The involvement of these genes in the cancer subtype was further strengthened with the DAVID database. KEGG and Gene Ontology were used for the pathway and functional analysis, while STRING was employed for the interactions of protein network and further visualized by Cytoscape. The cBioPortal database was used to prioritize the target genes; prognostic and expression analysis were finally performed on the candidate microRNAs and the prioritized targets. This study, therefore, identified five candidate microRNAs, two hub genes (CTNNB1 and epidermal growth factor receptor), and seven significant target genes associated with colorectal cancer. The molecular validation studies are ongoing to ascertain the biological fitness of these findings.
Collapse
Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashwil Klein
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashley Pretorius
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| |
Collapse
|
|
5
|
Kansy BA, Shayan G, Jie HB, Gibson SP, Lei YL, Brandau S, Lang S, Schmitt NC, Ding F, Lin Y, Ferris RL. T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response. Oncoimmunology 2018; 7:e1494112. [PMID: 30377562 PMCID: PMC6205044 DOI: 10.1080/2162402x.2018.1494112] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/24/2018] [Indexed: 12/13/2022] Open
Abstract
The role of T cell receptor (TCR) signaling for adaptive immune responses is essential. The ability to respond to a broad spectrum of tumor antigens requires an adaptive selection of various TCR. So far, little is known about the role of TCR richness and clonality in the cellular immune response to head and neck cancer (HNC), though the Endothelial Growth Factor Receptor (EGFR)-specific CD8+ T cell response can be enhanced by cetuximab therapy. Therefore, we investigated differences in TCR sequences between human papillomavirus (HPV)+ and HPV- HNC patients, as well as differences in TCR sequence characteristics between T cells of peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL). Additionally, we were able to investigate the TCR richness and clonality in samples pre- and post- treatment in a prospective clinical trial of neoadjuvant cetuximab. Interestingly, HPV+ and HPV- HNSCC did not significantly differ in the extent of TCR clonality and richness in PBMC or TIL. However, neoadjuvant cetuximab treatment increased the number of unique TCR sequences in PBMC (p = 0.0003), which was more prominent in the clinical responder patients compared to non-responders (p = 0.04). A trend toward TCR gene focusing was observed in TIL (p = 0.1) post-treatment. Thus, an increase in richness of TCR sequences in the periphery with a focusing at the tumor site is associated with an improved treatment response, suggesting an influence of peripheral quantity and intratumoral quality on adaptive immunity in cetuximab treated patients.
Collapse
Affiliation(s)
- Benjamin A Kansy
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | - Gulidanna Shayan
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hyun-Bae Jie
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sandra P Gibson
- Cancer Immunology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Yu L Lei
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Periodontics and Oral Medicine, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Sven Brandau
- Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | - Stephan Lang
- Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | - Nicole C Schmitt
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Fei Ding
- Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Yan Lin
- Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Robert L Ferris
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.,Cancer Immunology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| |
Collapse
|
|
6
|
Abstract
We report here on the state of our knowledge of the target - namely, the epidermal growth factor (EGF) and its receptor - and the challenges related to the methods of determination of the epidermal growth factor receptor (EGFR) and associated molecular pathways. A critical review of the anti-EGFR therapeutic strategies is also outlined. The chimeric anti-EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease (FDA). Cetuximab has the potential to provide an improvement of clinical outcome also in other indications and tumor types, particularly when used as first-line therapy combined with standard chemotherapy for metastatic disease or in the adjuvant setting. Possible strategies to improve the effectiveness of anti-EGFR agents are suggested and include (i) the use of predictive tools capable of making a more rational selection of patients; (ii) the development of standardized predictive biomarkers as surrogates for early monitoring of drug efficacy; and (iii) adequate study design, statistical analysis and proper end points of efficacy to be applied in future prospective trials.
Collapse
Affiliation(s)
- M.R. D'Andrea
- Division of Medical Oncology, Azienda Complesso Ospedaliero S. Filippo Neri, Rome - Italy
| | - G. Gasparini
- Division of Medical Oncology, Azienda Complesso Ospedaliero S. Filippo Neri, Rome - Italy
| |
Collapse
|
|
7
|
Khan SA, Zeng Z, Shia J, Paty PB. EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer. Pathol Oncol Res 2016; 23:673-677. [PMID: 28025786 DOI: 10.1007/s12253-016-0166-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 12/14/2016] [Indexed: 12/27/2022]
Abstract
Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.
Collapse
Affiliation(s)
- Sajid A Khan
- Department of Surgery, Section of Surgical Oncology, Yale University School of Medicine, 310 Cedar Street, FMB 130, New Haven, CT, 06520, USA.
| | - Zhaoshi Zeng
- Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Colorectal Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Philip B Paty
- Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| |
Collapse
|
|
8
|
De Pauw I, Wouters A, Van den Bossche J, Peeters M, Pauwels P, Deschoolmeester V, Vermorken JB, Lardon F. Preclinical and clinical studies on afatinib in monotherapy and in combination regimens: Potential impact in colorectal cancer. Pharmacol Ther 2016; 166:71-83. [PMID: 27373506 DOI: 10.1016/j.pharmthera.2016.06.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2016] [Indexed: 12/15/2022]
Abstract
Targeting the epidermal growth factor receptor (EGFR) with monoclonal antibodies (mAbs) or tyrosine kinase inhibitors (TKI) has been an interesting therapeutic strategy because aberrant activation of this receptor plays an important role in the tumorgenesis of many cancer types, including colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies, therapeutic resistance is a major clinical problem. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. In contrast to first generation EGFR inhibitors, afatinib (BIBW2992) is a second-generation irreversible ErbB family blocker that inhibits EGFR as well as HER2 and HER4. Consequently, treatment with afatinib may result in a distinct and more pronounced therapeutic benefit. Preclinical studies have reported promising results for afatinib in monotherapy as well as in combination with other drugs in CRC model systems. Furthermore, clinical studies examining afatinib as single agent and in combination therapy demonstrated manageable safety profile. Nevertheless, only limited antitumor activity has been observed in CRC patients. Although several combination treatments with afatinib have already been investigated, no optimal combination has been identified for CRC patients yet. As molecular tumor characteristics have gained increased importance in the choice of treatment, additional studies with biomarker-driven patient recruitment are required to further explore afatinib efficacy in CRC.
Collapse
Affiliation(s)
- I De Pauw
- Center for Oncological Research (CORE), University of Antwerp, Belgium.
| | - A Wouters
- Center for Oncological Research (CORE), University of Antwerp, Belgium
| | - J Van den Bossche
- Center for Oncological Research (CORE), University of Antwerp, Belgium
| | - M Peeters
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Oncology, Antwerp University Hospital, Belgium
| | - P Pauwels
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Belgium
| | - V Deschoolmeester
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Belgium
| | - J B Vermorken
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Oncology, Antwerp University Hospital, Belgium
| | - F Lardon
- Center for Oncological Research (CORE), University of Antwerp, Belgium
| |
Collapse
|
|
9
|
Zhu Q, Izumchenko E, Aliper AM, Makarev E, Paz K, Buzdin AA, Zhavoronkov AA, Sidransky D. Pathway activation strength is a novel independent prognostic biomarker for cetuximab sensitivity in colorectal cancer patients. Hum Genome Var 2015; 2:15009. [PMID: 27081524 PMCID: PMC4785572 DOI: 10.1038/hgv.2015.9] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 01/06/2015] [Accepted: 01/11/2015] [Indexed: 12/21/2022] Open
Abstract
Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), was shown to be active in colorectal cancer. Although some patients who harbor K-ras wild-type tumors benefit from cetuximab treatment, 40 to 60% of patients with wild-type K-ras tumors do not respond to cetuximab. Currently, there is no universal marker or method of clinical utility that could guide the treatment of cetuximab in colorectal cancer. Here, we demonstrate a method to predict response to cetuximab in patients with colorectal cancer using OncoFinder pathway activation strength (PAS), based on the transcriptomic data of the tumors. We first evaluated our OncoFinder pathway activation strength model in a set of transcriptomic data obtained from patient-derived xenograft (PDx) models established from colorectal cancer biopsies. Then, the approach and models were validated using a clinical trial data set. PAS could efficiently predict patients’ response to cetuximab, and thus holds promise as a selection criterion for cetuximab treatment in metastatic colorectal cancer.
Collapse
Affiliation(s)
| | - Evgeny Izumchenko
- Department of Otolaryngology-Head & Neck Surgery, Johns Hopkins University School of Medicine , Baltimore, MD, USA
| | - Alexander M Aliper
- InSilico Medicine, Inc., Baltimore, MD, USA; Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR
| | | | - Keren Paz
- Champions Oncology, Inc. , Baltimore, MD, USA
| | - Anton A Buzdin
- Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR; Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Alex A Zhavoronkov
- InSilico Medicine, Inc., Baltimore, MD, USA; Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR
| | - David Sidransky
- Department of Otolaryngology-Head & Neck Surgery, Johns Hopkins University School of Medicine , Baltimore, MD, USA
| |
Collapse
|
|
10
|
Bloy N, Pol J, Manic G, Vitale I, Eggermont A, Galon J, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Radioimmunotherapy for oncological indications. Oncoimmunology 2014; 3:e954929. [PMID: 25941606 DOI: 10.4161/21624011.2014.954929] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 07/18/2014] [Indexed: 02/06/2023] Open
Abstract
During the past two decades, it has become increasingly clear that the antineoplastic effects of radiation therapy do not simply reflect the ability of X-, β- and γ-rays to damage transformed cells and directly cause their permanent proliferative arrest or demise, but also involve cancer cell-extrinsic mechanisms. Indeed, among other activities, radiotherapy has been shown to favor the establishment of tumor-specific immune responses that operate systemically, underpinning the so-called 'out-of-field' or 'abscopal' effect. Thus, ionizing rays appear to elicit immunogenic cell death, a functionally peculiar variant of apoptosis associated with the emission of a particularly immunostimulatory combination of damage-associated molecular patterns. In line with this notion, radiation therapy fosters, and thus exacerbates, the antineoplastic effects of various treatment modalities, including surgery, chemotherapy and various immunotherapeutic agents. Here, we summarize recent advances in the use of ionizing rays as a means to induce or potentiate therapeutically relevant anticancer immune responses. In addition, we present clinical trials initiated during the past 12 months to test the actual benefit of radioimmunotherapy in cancer patients.
Collapse
Affiliation(s)
- Norma Bloy
- Gustave Roussy Cancer Campus ; Villejuif, France ; INSERM, U1138 ; Paris, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers ; Paris, France ; Université Paris-Sud/Paris XI ; Paris, France
| | - Jonathan Pol
- Gustave Roussy Cancer Campus ; Villejuif, France ; INSERM, U1138 ; Paris, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers ; Paris, France
| | - Gwenola Manic
- Regina Elena National Cancer Institute ; Rome, Italy
| | - Ilio Vitale
- Regina Elena National Cancer Institute ; Rome, Italy
| | | | - Jérôme Galon
- INSERM, U1138 ; Paris, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité ; Paris, France ; Université Pierre et Marie Curie/Paris VI ; Paris, France ; Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers ; Paris, France
| | - Eric Tartour
- Université Paris Descartes/Paris V; Sorbonne Paris Cité ; Paris, France ; INSERM, U970 ; Paris, France ; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP ; Paris, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus ; Villejuif, France ; INSERM, U1015; CICBT507 ; Villejuif, France
| | - Guido Kroemer
- INSERM, U1138 ; Paris, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers ; Paris, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité ; Paris, France ; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP ; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy Cancer Campus ; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers ; Paris, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité ; Paris, France
| |
Collapse
|
|
11
|
Bergmann F, Aulmann S, Sipos B, Kloor M, von Heydebreck A, Schweipert J, Harjung A, Mayer P, Hartwig W, Moldenhauer G, Capper D, Dyckhoff G, Freier K, Herpel E, Schleider A, Schirmacher P, Mechtersheimer G, Klöppel G, Bläker H. Acinar cell carcinomas of the pancreas: a molecular analysis in a series of 57 cases. Virchows Arch 2014; 465:661-72. [PMID: 25298229 DOI: 10.1007/s00428-014-1657-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 08/15/2014] [Accepted: 09/12/2014] [Indexed: 12/14/2022]
Abstract
Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c-MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs.
Collapse
Affiliation(s)
- Frank Bergmann
- Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, D-69120, Heidelberg, Germany,
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Gaber R, Watermann I, Kugler C, Reinmuth N, Huber RM, Schnabel PA, Vollmer E, Reck M, Goldmann T. Correlation of EGFR expression, gene copy number and clinicopathological status in NSCLC. Diagn Pathol 2014; 9:165. [PMID: 25227424 PMCID: PMC4176848 DOI: 10.1186/s13000-014-0165-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 08/16/2014] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Epidermal Growth Factor Receptor (EGFR) targeting therapies are currently of great relevance for the treatment of lung cancer. For this reason, in addition to mutational analysis immunohistochemistry (IHC) of EGFR in lung cancer has been discussed for the decision making of according therapeutic strategies. The aim of this study was to obtain standardization of EGFR-expression methods for the selection of patients who might benefit of EGFR targeting therapies. METHODS As a starting point of a broad investigation, aimed at elucidating the expression of EGFR on different biological levels, four EGFR specific antibodies were analyzed concerning potential differences in expression levels by Immunohistochemistry (IHC) and correlated with fluorescence in situ hybridization (FISH) analysis and clinicopathological data. 206 tumor tissues were analyzed in a tissue microarray format employing immunohistochemistry with four different antibodies including Dako PharmDx kit (clone 2-18C9), clone 31G7, clone 2.1E1 and clone SP84 using three different scoring methods. Protein expression was compared to FISH utilizing two different probes. RESULTS EGFR protein expression determined by IHC with Dako PharmDx kit, clone 31G7 and clone 2.1E1 (p ≤ 0.05) correlated significantly with both FISH probes independently of the three scoring methods; best correlation is shown for 31G7 using the scoring method that defined EGFR positivity when ≥ 10% of the tumor cells show membranous staining of moderate and severe intensity (p=0.001). CONCLUSION Overall, our data show differences in EGFR expression determined by IHC, due to the applied antibody. Highest concordance with FISH is shown for antibody clone 31G7, evaluated with score B (p=0.001). On this account, this antibody clone might by utilized for standard evaluation of EGFR expression by IHC. VIRTUAL SLIDES The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_165.
Collapse
|
|
13
|
Luo HY, Xu RH. Predictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer. World J Gastroenterol 2014; 20:3858-3874. [PMID: 24744578 PMCID: PMC3983442 DOI: 10.3748/wjg.v20.i14.3858] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/11/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide. The treatment of advanced CRC has improved significantly in recent years. With the emergence of two targeted antibodies, cetuximab (Erbitux), an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab (Avastin), a vascular endothelial growth factor monoclonal antibody, the treatment of metastatic CRC has entered the era of personalized therapy. Predictive and prognostic biomarkers have, and will continue to, facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC (mCRC). In this review, we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.
Collapse
|
|
14
|
Goffin JR, Zbuk K. Epidermal growth factor receptor: pathway, therapies, and pipeline. Clin Ther 2014; 35:1282-303. [PMID: 24054705 DOI: 10.1016/j.clinthera.2013.08.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 08/16/2013] [Accepted: 08/21/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND The epidermal growth factor receptor (EGFR) pathway is important in tumor growth, survival, and metastasis and is now the target of several therapeutic agents. OBJECTIVES This paper seeks to review the EGFR pathway, the study and use of EGFR-directed agents in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC), and related new drug development. METHODS PubMed was searched for English-language articles by MeSH and title terms of EGFR published from 2006 to 2013, using the limits of clinical trials as well as reviews. Reference lists were assessed for relevant articles, and guidelines were searched. Clinicaltrials.gov and meeting abstracts were queried for investigational agents. Eligible papers included those concerning EGFR biology, NSCLC or CRC studies involving EGFR-directed agents, and/or investigational drugs targeting EGFR and/or associated pathways. RESULTS The activity of oral tyrosine kinase inhibitors (TKIs) against EGFR has improved survival in NSCLC, and these agents particularly effective in cancers with an EGFR mutation. Resistance to TKIs is most commonly related to a second, T790M, mutation, or to MET amplification, with newer agents directed against these mechanisms. Conversely, in CRC, TKIs have been ineffective, whereas monoclonal antibodies have improved survival. Both primary and secondary KRAS mutations in CRC abrogate mAb effectiveness. Several targets, including MET, BRAF, and PI3K, may serve useful in combination with anti-EGFR drugs. CONCLUSIONS Exploitation of EGFR-directed therapies has offered improvement in survival and quality of life in NSCLC and CRC. New therapies directed at EGFR may offer further improvements. However, resistance mechanisms suggest that combination therapies or multitargeted agents will be crucial in making significant future advances.
Collapse
Affiliation(s)
- John R Goffin
- Department of Oncology, Faculty of Health Sciences, McMaster University, Hamilton, Canada.
| | | |
Collapse
|
|
15
|
Bellizzi AM. Contributions of molecular analysis to the diagnosis and treatment of gastrointestinal neoplasms. Semin Diagn Pathol 2013; 30:329-61. [DOI: 10.1053/j.semdp.2013.11.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
16
|
Cho J, Chen L, Sangji N, Okabe T, Yonesaka K, Francis JM, Flavin RJ, Johnson W, Kwon J, Yu S, Greulich H, Johnson BE, Eck MJ, Jänne PA, Wong KK, Meyerson M. Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res 2013; 73:6770-9. [PMID: 24063894 DOI: 10.1158/0008-5472.can-13-1145] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Kinase domain mutations of the EGF receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here, we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. We show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. In addition, treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization-dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization-independent EGFR mutants. These data imply that different EGFR mutants show differential requirements for dimerization and that disruption of dimerization may be among the antitumor mechanisms of cetuximab.
Collapse
Affiliation(s)
- Jeonghee Cho
- Authors' Affiliations: Departments of Medical Oncology and Cancer Biology; Center for Cancer Genome Discovery, Lowe Center for Thoracic Oncology, and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute; Departments of Medicine, Brigham and Women's Hospital; Departments of Biological Chemistry and Molecular Pharmacology and Pathology, Harvard Medical School, Boston, Massachusetts; Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea; and The Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Reirradiation plus EGFR inhibition in locally recurrent and unresectable head and neck cancer. Strahlenther Onkol 2013; 189:842-8. [DOI: 10.1007/s00066-013-0402-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 06/03/2013] [Indexed: 12/11/2022]
|
|
18
|
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.
Collapse
Affiliation(s)
- A Silvestri
- Division of Experimental Oncology 2, CRO-IRCCS, National Cancer Institute, Aviano, Italy
| | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Prenen H, Vecchione L, Van Cutsem E. Role of targeted agents in metastatic colorectal cancer. Target Oncol 2013; 8:83-96. [DOI: 10.1007/s11523-013-0281-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 04/23/2013] [Indexed: 12/11/2022]
|
|
20
|
Montagut C, Albanell J. Mechanisms of acquired resistance to anti-EGF receptor treatment in colorectal cancer. COLORECTAL CANCER 2012. [DOI: 10.2217/crc.12.62] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
SUMMARY The anti-EGFR monoclonal antibodies, cetuximab and panitumumab, are effective in a subset of colorectal cancer patients. However, acquisition of resistance to these drugs invariably develops. Elucidation of the molecular mechanisms underlying resistance is a crucial first step to develop therapeutic strategies to bypass secondary resistance. Three mechanisms of resistance have been characterized in patients so far: a mutation in the extracellular domain of EGFR preventing cetuximab-EGFR binding – interestingly, this mutation does not affect panitumumab effectiveness; activation of EGFR-related receptor HER2 by amplification or ligand overexpression; emergence of KRAS mutations or amplification. Importantly, already approved drugs can be used to bypass known mechanisms of resistance. Large-scale studies including biopsy at progression and prospective clinical trials are warranted.
Collapse
Affiliation(s)
- Clara Montagut
- Medical Oncology Department, Hospital del Mar; IMIM (Hospital del Mar Research Institute), Pompeu Fabra University, Passeig Marítim 25–29, Barcelona 08003, Spain
| | - Joan Albanell
- Medical Oncology Department, Hospital del Mar; IMIM (Hospital del Mar Research Institute), Pompeu Fabra University, Passeig Marítim 25–29, Barcelona 08003, Spain
| |
Collapse
|
|
21
|
Abstract
Antibody-based therapeutics against cancer are highly successful and currently enjoy unprecedented recognition of their potential; 13 monoclonal antibodies (mAbs) have been approved for clinical use in the European Union and in the United States. Bevacizumab, rituximab, and trastuzumab had sales in 2010 of more than $5 billion each. Hundreds of mAbs, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small-molecule drugs, and mAbs with optimized pharmacokinetics, are in clinical trials. However, deeper understanding of mechanisms is needed to overcome major problems including resistance to therapy, access to targets, complexity of biological systems, and individual variations.
Collapse
Affiliation(s)
- Mark J Adler
- UC San Diego Cancer Center, Department of Medicine, University of California Health Systems, 1200 Garden View, Encinitas, CA 92024, USA.
| | | |
Collapse
|
|
22
|
Legolvan MP, Taliano RJ, Resnick MB. Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol 2012; 43:1157-68. [PMID: 22658275 DOI: 10.1016/j.humpath.2012.03.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 02/29/2012] [Accepted: 03/02/2012] [Indexed: 12/13/2022]
Abstract
There has been an increasing role for molecular diagnostics in the diagnosis and management of cancer, and colorectal carcinoma is no exception. Recent molecular advances have elucidated 3 broad molecular subtypes of colorectal cancer, including chromosomal instability, microsatellite instability, and cytosine-phosphoguanine island methylator phenotype, which will be discussed. Also, the common syndromes associated with colorectal carcinoma will be reviewed with a focus on the differentiation between Lynch syndrome and microsatellite unstable tumors. Molecular biomarkers for predictive and prognostic markers are also becoming widely used, and due to the clinical use of monoclonal antibodies to the epidermal growth factor receptor, an emphasis is placed on that pathway.
Collapse
Affiliation(s)
- Mark P Legolvan
- Department of Pathology, Rhode Island Hospital, and the Alpert Medical School of Brown University, Providence, RI 02908, USA
| | | | | |
Collapse
|
|
23
|
Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: beyond KRAS mutations. Crit Rev Oncol Hematol 2012; 85:45-81. [PMID: 22647972 DOI: 10.1016/j.critrevonc.2012.05.001] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Revised: 04/10/2012] [Accepted: 05/04/2012] [Indexed: 12/27/2022] Open
Abstract
The advent of the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), cetuximab and panitumumab has expanded the range of treatment options for metastatic colorectal cancer (CRC). Despite these agents have paved the way to individualized therapy, our understanding why some patients respond to treatment whereas others do not remain poor. The realization that detection of positive EGFR expression by IHC does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of benefit to anti-EGFR mAbs. Oncologists are now facing emerging issues in the treatment of metastatic CRC, including the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients, the explanation of rare cases of patients carrying KRAS-mutated tumours who have been reported to respond to cetuximab and panitumumab and the discovery of mechanisms of secondary resistance to EGFR-targeted therapy. Current data suggest that, together with KRAS mutations, the evaluation of EGFR gene copy number (GCN), BRAF, NRAS, PIK3CA mutations or loss of PTEN expression could also be useful for selecting patients with reduced chance to benefit from anti-EGFR mAbs. This review aims to provide an updated of the most recent data on predictive and prognostic biomarkers within the EGFR pathway, the challenges this emerging field presents and the future role of these molecular markers in CRC treatment.
Collapse
|
|
24
|
Relapsing high grade mucoepidermoid carcinoma. Strahlenther Onkol 2012; 188:518-22. [DOI: 10.1007/s00066-012-0096-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Accepted: 02/15/2012] [Indexed: 12/23/2022]
|
|
25
|
Laborde RR, Wang VW, Smith TM, Olson NE, Olsen SM, García JJ, Olsen KD, Moore EJ, Kasperbauer JL, Tombers NM, Smith DI. Transcriptional profiling by sequencing of oropharyngeal cancer. Mayo Clin Proc 2012; 87:226-32. [PMID: 22386177 PMCID: PMC3538409 DOI: 10.1016/j.mayocp.2011.10.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 09/21/2011] [Accepted: 10/21/2011] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To compare full transcriptome expression levels of matched tumor and normal samples from patients with oropharyngeal carcinoma stratified by known tumor etiologic factors. PATIENTS AND METHODS Full transcriptome sequencing was analyzed for 10 matched tumor and normal tissue samples from patients with previously untreated oropharyngeal carcinoma. Transcriptomes were analyzed using massively parallel messenger RNA sequencing and validated using the NanoString nCounter system. Global gene expression levels were compared in samples grouped by smoking status and human papillomavirus status. This study was completed between June 10, 2010, and June 30, 2011. RESULTS Global gene expression analysis indicated tumor tissue from former smokers grouped more closely to the never smokers than the current smokers. Pathway analysis revealed alterations in the expression of genes involved in the p53 DNA damage-repair pathway, including CHEK2 and ATR, which display patterns of increased expression that is associated with human papillomavirus-negative current smokers rather than former or never smokers. CONCLUSION These findings support the application of messenger RNA sequencing technology as an important clinical tool for more accurately stratifying patients based on individual tumor biology with the goal of improving our understanding of tumor prognosis and treatment response, ultimately leading to individualized patient care strategies.
Collapse
Affiliation(s)
- Rebecca R. Laborde
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Vivian W. Wang
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | | | | | - Steven M. Olsen
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | | | - Kerry D. Olsen
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Eric J. Moore
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Jan L. Kasperbauer
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Nicole M. Tombers
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - David I. Smith
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN
- Correspondence: Address to David I. Smith, PhD, Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905
| |
Collapse
|
|
26
|
Clinical Implications and Quality Assurance of Molecular Testing for EGFR-Targeting Agents in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2011. [DOI: 10.1007/s11888-011-0112-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
|
|
27
|
Grossmann AH, Samowitz WS. Epidermal growth factor receptor pathway mutations and colorectal cancer therapy. Arch Pathol Lab Med 2011; 135:1278-82. [PMID: 21970483 DOI: 10.5858/arpa.2011-0047-ra] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
CONTEXT Rational anticancer therapy is beginning to expand the practice of surgical pathology beyond a primarily morphologic and immunophenotypic analysis into the molecular arena. Molecular testing of tumors can have both diagnostic and therapeutic value, which guides treatment decisions. This is true for colorectal cancer in which mutations in signaling mediators predict resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. OBJECTIVE To review the clinically relevant mutations that currently guide treatment decisions in metastatic colorectal cancer, summarize additional mutations that are expected to improve the prognostic sensitivity of molecular testing, and provide practical suggestions for submitting specimens for molecular analysis. DATA SOURCES Peer-reviewed literature reporting pertinent clinical trial data, mutation analysis, and molecular mechanisms of drug resistance, as well as comprehensive review articles germane to the topic and published testing recommendations from the College of American Pathologists. CONCLUSIONS Molecular analysis of colorectal cancer is now mandated before initiation of anti-EGFR therapy and directly impacts treatment options and outcomes. Familiarity with the mutations that determine utility and efficacy of therapy, as well as the importance of careful sample selection, will facilitate appropriate testing and optimize patient care.
Collapse
Affiliation(s)
- Allie H Grossmann
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84108, USA.
| | | |
Collapse
|
|
28
|
Hoda D, Simon GR, Garrett CR. Targeting colorectal cancer with anti-epidermal growth factor receptor antibodies: focus on panitumumab. Ther Clin Risk Manag 2011; 4:1221-7. [PMID: 19337429 PMCID: PMC2643103 DOI: 10.2147/tcrm.s4314] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Panitumumab is a fully humanized monoclonal antibody with a high degree of affinity for the extracellular domain of the epidermal growth factor receptor. Phase II clinical evaluation of this drug, when administered as a single agent, in patients with metastatic colorectal cancer refractory to chemotherapy, demonstrated a modest objective radiographic response rate with acceptable toxicity; the most frequently observed side effect is rash. A randomized phase III study in subjects with chemotherapy-refractory metastatic colorectal cancer documented a progression-free survival advantage in subjects treated with panitumumab plus best supportive care versus best supportive care alone; a difference in survival was not observed, likely due to the high cross over rate. Primary tumor KRAS mutation analysis performed in this study indicated that the benefit was confined to those patients whose tumors did not contain a KRAS mutation. Further studies with panitumumab will be required to develop biomarkers of response and to determine if panitumumab has a role in combination with cytotoxic chemotherapy. This article summarizes the current state-of-the-science knowledge on panitumumab therapy in the treatment of advanced colorectal cancer.
Collapse
Affiliation(s)
- Daanish Hoda
- Division of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | | | | |
Collapse
|
|
29
|
Peled N, Yoshida K, Wynes MW, Hirsch FR. Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer. Ther Adv Med Oncol 2011; 1:137-44. [PMID: 21789118 DOI: 10.1177/1758834009347923] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) related therapies - mainly tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, but also monoclonal antibodies targeting EGFR, for example, cetuximab - have been investigated in numerous settings in non-small cell lung cancer (NSCLC) and in different combinations. The overall clinical benefit of EGFR TKI therapy is roughly 10-30%, with higher benefit in nonsmoker Asiatic women with EGFR-mutated adenocarcinoma. Currently, there are several biomarkers that are able to direct and predict the yield of EGFR-related therapies in NSCLC. These include EGFR mutation status, EGFR protein expression, EGFR gene copy number and a serum proteomic marker (Veristrat®, Biodesix; CO). The usage of such biomarkers is important from many aspects. First, it helps clinicians to make the right treatment decisions and second, it leads to a wiser usage of financial resources. This review will focus on EGFR-related biomarkers for their prognostic power and their ability to predict clinical benefit from EGFR-related therapy.
Collapse
Affiliation(s)
- Nir Peled
- Division of Medical Oncology, University of Colorado Denver, Aurora, CO, USA
| | | | | | | |
Collapse
|
|
30
|
Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Cancer Biol Ther 2011; 11:777-92. [PMID: 21293176 DOI: 10.4161/cbt.11.9.15050] [Citation(s) in RCA: 192] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase belonging to the HER family of receptor tyrosine kinases. Receptor activation upon ligand binding leads to down stream activation of the PI3K/AKT, RAS/RAF/MEK/ERK and PLCγ/PKC pathways that influence cell proliferation, survival and the metastatic potential of tumor cells. Increased activation by gene amplification, protein overexpression or mutations of the EGFR has been identified as an etiological factor in a number of human epithelial cancers (e.g., NSCLC, CRC, glioblastoma and breast cancer). Therefore, targeting the EGFR has been intensely pursued as a cancer treatment strategy over the last two decades. To date, five EGFR inhibitors, including three small molecule tyrosine kinase inhibitors (TKIs) and two monoclonal antibodies have gained FDA approval for use in oncology. Both approaches to targeting the EGFR have shown clinical promise and the anti-EGFR antibody cetuximab is used to treat HNSCC and CRC. Despite clinical gains arising from use of cetuximab, both intrinsic resistance and the development of acquired resistance are now well recognized. In this review we focus on the biology of the EGFR, the role of EGFR in human cancer, the development of antibody-based anti-EGFR therapies and a summary of their clinical successes. Further, we provide an in depth discussion of described molecular mechanisms of resistance to cetuximab and potential strategies to circumvent this resistance.
Collapse
Affiliation(s)
- Toni M Brand
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | | | | |
Collapse
|
|
31
|
Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res 2011; 16:5972-80. [PMID: 21169250 DOI: 10.1158/1078-0432.ccr-10-1277] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We describe the development and approval of biologically targeted agents in the clinic through examples chosen from the experience with inhibitors of the epidermal growth factor (EGF) and VEGF pathways. Despite extensive biological rationale for the use of these classes of molecules, marginal clinical benefits have been observed in broad patient populations, and the agents have entered into general clinical practice. We discuss why this situation is unsatisfactory because marginal general benefit may often be at the expense of toxicity to nonbenefiting or even harmed patients. Finally, we point out that emerging technologies bring the promise of allowing the identification of patients who might potentially benefit from a therapy. However, development of this technology will not move forward without broader recognition of its need by the range of stakeholders, including patients, advocates, academic and private oncologists, drug sponsors, and those who develop drugs and diagnostic tests.
Collapse
Affiliation(s)
- Tito Fojo
- Medical Oncology Branch, Center for Cancer Research, Bethesda, Maryland, USA.
| | | |
Collapse
|
|
32
|
Rubinstein PG, Lindgren V, Setty S, Yao M, Pytynia KB, Radosevich JA, Kadkol SS, Feldman LE. Durable complete remission induced by cetuximab monotherapy in a patient infected with HIV and diagnosed with recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2011; 29:e222-5. [PMID: 21189379 DOI: 10.1200/jco.2010.32.1927] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
|
|
33
|
Lin AY, Buckley NS, Lu ATT, Kouzminova NB, Salpeter SR. Effect of KRAS Mutational Status in Advanced Colorectal Cancer on the Outcomes of Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: A Systematic Review and Meta-analysis. Clin Colorectal Cancer 2011; 10:63-9. [DOI: 10.3816/ccc.2011.n.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
34
|
Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Br J Cancer 2011; 104:488-95. [PMID: 21206494 PMCID: PMC3049558 DOI: 10.1038/sj.bjc.6606054] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment. METHODS We used RT-PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS). RESULTS Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC. CONCLUSION Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.
Collapse
|
|
35
|
Vincenzi B, Galluzzo S, Santini D, Rocci L, Loupakis F, Correale P, Addeo R, Zoccoli A, Napolitano A, Graziano F, Ruzzo A, Falcone A, Francini G, Dicuonzo G, Tonini G. Early magnesium modifications as a surrogate marker of efficacy of cetuximab-based anticancer treatment in KRAS wild-type advanced colorectal cancer patients. Ann Oncol 2010; 22:1141-1146. [PMID: 21115601 DOI: 10.1093/annonc/mdq550] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND KRAS wild-type mutational status is necessary but not sufficient to get benefit from epidermal growth factor receptor inhibition. Predictive markers are currently being evaluated. In this study, we investigated early hypomagnesemia as a predictor of efficacy and outcome in terms of time to progression (TtP) and overall survival (OS) in a cohort of patients affected by advanced colorectal adenocarcinoma KRAS wild-type cetuximab-treated. PATIENTS AND METHODS One hundred and forty-three patients affected by stage IV colorectal adenocarcinoma KRAS wild type receiving cetuximab + irinotecan (CTX+IRI) as third-line anticancer treatment and resistant to oxaliplatin- and irinotecan-based chemotherapy were retrospectively included. Magnesium plasma levels were measured before the first day and 7, 14, 21 and 28 days after CTX+IRI infusion. RESULTS The median magnesium basal value showed a statistically significant decrease after the start of CTX+IRI treatment (at 28 days, P < 0.0001). Patients with an early decrease of magnesium levels >50% compared with the basal level had a higher tumor response rate (55.8% versus 16.7%, P < 0.0001), a longer TtP (6.3 versus 3.6, P < 0.0001) and a longer median OS (11.0 versus 8.1, P = 0.002). CONCLUSIONS We have shown that early hypomagnesemia could be a predictor of efficacy and outcome in those patients. Magnesium circulating level is an easy and inexpensive biomarker to routinely be detected in patients treated with cetuximab.
Collapse
Affiliation(s)
- B Vincenzi
- Department of Medical Oncology, University Campus Bio-Medico, Rome
| | - S Galluzzo
- Department of Medical Oncology, University Campus Bio-Medico, Rome.
| | - D Santini
- Department of Medical Oncology, University Campus Bio-Medico, Rome
| | - L Rocci
- Department of Medical Oncology, University Campus Bio-Medico, Rome
| | - F Loupakis
- Unit of Medical Oncology, Azienda-Ospedaliero Universitaria Pisana, University of Pisa, Pisa
| | - P Correale
- Section of Medical Oncology, Department "Giorgio Segre" of Pharmacology, University of Siena, Siena
| | - R Addeo
- Oncology Department, "S. Giovanni di Dio" Hospital, Frattaminore
| | - A Zoccoli
- Department of Medical Oncology, University Campus Bio-Medico, Rome
| | - A Napolitano
- Department of Medical Oncology, University Campus Bio-Medico, Rome
| | - F Graziano
- Unit of Medical Oncology, Hospital of Pesaro, Pesaro
| | - A Ruzzo
- Section of Biochemistry and Molecular Biology "G. Fornaini", Department of Biomolecular Sciences, University of Urbino, Urbino
| | - A Falcone
- Section of Medical Oncology, Department "Giorgio Segre" of Pharmacology, University of Siena, Siena
| | - G Francini
- Oncology Department, "S. Giovanni di Dio" Hospital, Frattaminore
| | - G Dicuonzo
- Laboratory Medicine, University Campus Bio-Medico, Rome, Italy
| | - G Tonini
- Department of Medical Oncology, University Campus Bio-Medico, Rome
| |
Collapse
|
|
36
|
Vakiani E, Solit DB. KRAS and BRAF: drug targets and predictive biomarkers. J Pathol 2010; 223:219-29. [PMID: 21125676 DOI: 10.1002/path.2796] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Revised: 09/22/2010] [Accepted: 09/24/2010] [Indexed: 12/11/2022]
Abstract
Three decades have passed since RAS was first identified as the transformative factor in the Harvey and Kirsten strains of the mouse sarcoma virus. RAS and several of its downstream effectors, including BRAF, have since been shown to be commonly mutated in broad range of human cancers and biological studies have confirmed that RAS pathway activation promotes tumour initiation, progression and metastatic spread in many contexts. With the identification of RAS mutation as a strong predictor of clinical resistance to EGFR-targeted therapies, RAS mutational testing has been incorporated into the routine clinical care of patients with colorectal and lung cancers. This article reviews the current understanding of RAS signalling as it relates to cancer biology, current efforts to develop inhibitors of RAS and its key downstream effectors and the technical challenges of RAS mutational testing in the clinical setting.
Collapse
Affiliation(s)
- Efsevia Vakiani
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
| | | |
Collapse
|
|
37
|
Berardi R, Onofri A, Pistelli M, Maccaroni E, Scartozzi M, Pierantoni C, Cascinu S. Panitumumab: the evidence for its use in the treatment of metastatic colorectal cancer. CORE EVIDENCE 2010; 5:61-76. [PMID: 21042543 PMCID: PMC2963923 DOI: 10.2147/ce.s7035] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/25/2010] [Indexed: 01/01/2023]
Abstract
Panitumumab is the first fully human monoclonal antibody to Epidermal Growth Factor Receptor (EGFR) to enter clinical trials for the treatment of solid tumors. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal (CRC). Preclinical and clinical studies have established a role for panitumumab in metastatic colorectal cancer (mCRC) refractory to multiple chemotherapeutic regimens. Based on these encouraging findings, panitumumab was approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing mCRC refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. The improvement in progression free survival (PFS) and response rate (RR) produced by panitumumab monotherapy was significantly greater in patients with non mutated (wild-type) K-RAS than in those with mutant K-RAS. Therefore implementing routine K-RAS screening and limiting the use of EGFR inhibitors to patients with wild-type K-RAS appears the better strategy for select only the patients who could benefit from the therapy with panitumumab and also may have the potential for cost savings. The purpose of this review was to evaluate the patient-related, disease-related and economic-related evidence for the use of panitumumab in the treatment of metastatic colorectal cancer in clinical practice.
Collapse
Affiliation(s)
- Rossana Berardi
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi di Ancona, Italy
| | - Azzurra Onofri
- Scuola di Specializzazione in Oncologia Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Mirco Pistelli
- Scuola di Specializzazione in Oncologia Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Elena Maccaroni
- Scuola di Specializzazione in Oncologia Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Mario Scartozzi
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi di Ancona, Italy
| | - Chiara Pierantoni
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi di Ancona, Italy
| | - Stefano Cascinu
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi di Ancona, Italy
| |
Collapse
|
|
38
|
Marx AH, Zielinski M, Kowitz CM, Dancau AM, Thieltges S, Simon R, Choschzick M, Yekebas E, Kaifi JT, Mirlacher M, Atanackovic D, Brümmendorf TH, Fiedler W, Bokemeyer C, Izbicki JR, Sauter G. Homogeneous EGFR amplification defines a subset of aggressive Barrett’s adenocarcinomas with poor prognosis. Histopathology 2010; 57:418-26. [DOI: 10.1111/j.1365-2559.2010.03643.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
39
|
Chua W, Kho PS, Moore MM, Charles KA, Clarke SJ. Clinical, laboratory and molecular factors predicting chemotherapy efficacy and toxicity in colorectal cancer. Crit Rev Oncol Hematol 2010; 79:224-50. [PMID: 20719530 DOI: 10.1016/j.critrevonc.2010.07.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Revised: 07/05/2010] [Accepted: 07/15/2010] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) treatment has evolved significantly over the last ten years with the use of active chemotherapeutic agents including fluoropyrimidines, oxaliplatin and irinotecan plus targeted monoclonal antibodies bevacizumab, cetuximab and panitumumab. The addition of newer chemotherapeutic agents and targeted therapies has improved patient outcomes at the cost of increased toxicity with not all patients benefiting from these treatments. It is necessary for clinicians to more accurately predict clinical outcomes particularly in the predominantly elderly CRC patient population. This review aims to summarise existing data regarding the use of clinical and laboratory variables plus molecular markers in predicting response, survival and toxicity to chemotherapy agents and targeted monoclonal antibodies currently used in the treatment of CRC.
Collapse
Affiliation(s)
- Wei Chua
- Sydney Cancer Centre, Concord Repatriation General Hospital, Hospital Road, Concord, NSW 2139, Australia
| | | | | | | | | |
Collapse
|
|
40
|
Kanwar SS, Nautiyal J, Majumdar AP. EGFR(S) inhibitors in the treatment of gastro-intestinal cancers: what's new? Curr Drug Targets 2010; 11:682-98. [PMID: 20298154 PMCID: PMC3915939 DOI: 10.2174/138945010791170851] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Accepted: 12/18/2009] [Indexed: 01/01/2023]
Abstract
In the past 10 to 15 years, a considerable progress has been made in the treatment of gastrointestinal (GI) related malignancies, as number of agents expanded from only one in 1995 to seven in 2006. Current review describes the recent role of targeted therapies, specifically EGFR inhibitors in the treatment of GI cancers. Importance of dietary agents in the treatment and prevention of GI cancers is also reviewed.
Collapse
Affiliation(s)
- Shailender Singh Kanwar
- Veterans Affairs Medical Center, Wayne State University, Detroit, Ml 48201, USA
- Department of Internal Medicine, Wayne State University, Detroit, Ml 48201, USA
| | - Jyoti Nautiyal
- Veterans Affairs Medical Center, Wayne State University, Detroit, Ml 48201, USA
- Department of Internal Medicine, Wayne State University, Detroit, Ml 48201, USA
- Karmanos Cancer Institute, Wayne State University, Detroit, Ml 48201, USA
| | - Adhip P.N. Majumdar
- Veterans Affairs Medical Center, Wayne State University, Detroit, Ml 48201, USA
- Department of Internal Medicine, Wayne State University, Detroit, Ml 48201, USA
- Karmanos Cancer Institute, Wayne State University, Detroit, Ml 48201, USA
| |
Collapse
|
|
41
|
Asaoka Y, Tada M, Ikenoue T, Seto M, Imai M, Miyabayashi K, Yamamoto K, Yamamoto S, Kudo Y, Mohri D, Isomura Y, Ijichi H, Tateishi K, Kanai F, Ogawa S, Omata M, Koike K. Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion. Biochem Biophys Res Commun 2010; 394:1042-6. [PMID: 20331976 DOI: 10.1016/j.bbrc.2010.03.120] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Accepted: 03/18/2010] [Indexed: 10/19/2022]
Abstract
Receptor tyrosine kinases (RTKs) are involved in oncogenesis and disease progression for many cancers. Inhibitors targeting them are vigorously developed and some of them are tested in the clinical setting. Amplifications of certain RTKs (c-Met, FGFR2 and ErbB2) have been associated with human gastric cancer progression. According to our genome-wide scans of genetic lesions in 34 gastric cancer cell lines using high-density single-nucleotide polymorphism genotyping microarrays, we confirmed that the c-met locus was amplified in four gastric cancer cell lines (Hs746T, MKN45, NUGC4 and SNU5). It was reported that somatic mutation is occasionally detected in tumor samples of a certain type of cancer with gene amplification. Previous reports showed gastric cancers harbored mutations of FGFR2 and ErbB2, but c-Met oncogenic mutation had not yet been reported. We performed mutational analysis of the cytoplasmic domains of c-Met using the genome DNA of the gastric cancer cell lines, and found that Hs746T cells had a splice site mutation of exon 14. By cDNA sequencing and Western blotting, we showed that the mutation caused juxtamembrane domain deletion. Previously, this mutation had been detected only in lung cancer specimens and this deletion resulted in the loss of Cbl E3-ligase binding causing decreased ubiquitination and delayed down-regulation. In conclusion, four gastric cancer cell lines harbored amplification of c-met locus, and among them, Hs746T had a putative oncogenic mutation with amplification. This information will be useful for screening of inhibitors targeting gastric cancer with c-Met aberration.
Collapse
Affiliation(s)
- Yoshinari Asaoka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Chemotherapy with cetuximab or chemotherapy alone for untreated advanced non-small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer 2010; 70:57-62. [PMID: 20149474 DOI: 10.1016/j.lungcan.2010.01.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2009] [Revised: 01/10/2010] [Accepted: 01/12/2010] [Indexed: 01/11/2023]
Abstract
PURPOSE To compare the efficacy and toxicities of chemotherapy plus cetuximab (Erbitux, E; E-chemo) with chemotherapy alone (chemo alone) in patients with previously untreated advanced non-small-cell lung cancer (NSCLC). The primary endpoint was overall survival; the secondary endpoints were progression-free survival, overall response rate, one-year survival and safety. METHODS The PubMed database, the Cochrane Library, conference proceedings, database of ongoing trials and references of published trials and reviews were screened. Two reviewers independently assessed the quality of the trials and extracted data. The hazard ratios (HRs) for overall survival and progression-free survival, relative risks (RRs) for overall response rate and one-year survival, and odds ratios (ORs) for the different types of toxicity were pooled using STATA SE10.1 package. RESULTS Four trials involving 2018 patients with previously untreated NSCLC were ultimately analyzed. The pooled HR for overall survival (HR, 0.87; 95%CI, 0.79-0.96; p=0.004) was in favor of E-chemo, which also gave rise to a higher overall response rate (RR, 1.19; 95%CI, 1.04-1.37; p=0.013). The analysis failed to show benefit of E-chemo in progression-free survival (HR, 0.91; 95%CI, 0.83-1.00; p=0.06) and one-year survival (RR, 1.10; 95%CI, 0.98-1.26; p=0.172). E-chemo indeed caused more grade 3/4 rash and infusion reaction (OR, 43.86; 95%CI, 12.46-154.44; p=0.000; OR, 3.69; 95%CI, 1.89-7.25; p=0.000; respectively). CONCLUSION Our data showed that the addition of cetuximab to chemotherapy would improve overall survival and overall response rate. It may provide new option for clinical treatment for untreated advanced non-small-cell lung cancer. The side effects of E-chemo are predictable and manageable.
Collapse
|
|
43
|
Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, Dakhil S, Hermann RC, Lynch TJ, Weber MR. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28:918-27. [PMID: 20100958 DOI: 10.1200/jco.2009.25.2890] [Citation(s) in RCA: 209] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
PURPOSE The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is efficacious in multiple tumor types. Patient selection with markers predictive of benefit may enhance its therapeutic index. This retrospective, correlative analysis of the phase III trial BMS099 of cetuximab in advanced non-small-cell lung cancer (NSCLC) was conducted to identify molecular markers for the selection of patients most likely to benefit from cetuximab. METHODS In BMS099, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC of any histology or EGFR expression status were randomly assigned to taxane/carboplatin (T/C) with or without cetuximab. Biomarkers analyzed included K-Ras and EGFR mutations by direct sequencing, EGFR protein expression by immunohistochemistry (IHC), and EGFR gene copy number by fluorescent in situ hybridization (FISH). Relationships between biomarker status and progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) were assessed by log-rank tests per treatment arm for treatment-specific effects and across the total evaluable population. Results Tumor samples were available from 225 randomly assigned patients. K-Ras mutations were found in 17% of evaluable patients (35 of 202 patients), EGFR mutations were found in 10% (17 of 166 patients), EGFR positivity by IHC was found in 89% (131 of 148 patients), and FISH positivity was found in 52% (54 of 104 patients). No significant associations were found between biomarker status and PFS, OS, and ORR in the treatment-specific analyses. CONCLUSION In contrast with colorectal cancer, and within the limitations of the data set, efficacy parameters did not appear to correlate with K-Ras mutation status or with any of the EGFR-related biomarkers evaluated. Additional exploratory analyses are essential to identify predictive markers and to optimize patient selection for cetuximab therapy in NSCLC.
Collapse
Affiliation(s)
- Shirin Khambata-Ford
- Bristol-Myers Squibb, 311 Pennington-Rocky Hill Rd, 3B-2.06, Princeton, NJ 08543, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Markman B, Javier Ramos F, Capdevila J, Tabernero J. EGFR and KRAS in Colorectal Cancer. Adv Clin Chem 2010; 51:71-119. [DOI: 10.1016/s0065-2423(10)51004-7] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
45
|
Gridelli C, Morabito A, Gebbia V, Mencoboni M, Carrozza F, Viganò MG, Verusio C, Bollina R, Mattioli R, Valerio MR, Valmadre G, Maione P, Rossi A, Cascone T, Morgillo F, Di Maio M, Piccirillo MC, Gallo C, Perrone F, Ciardiello F. Cetuximab and gemcitabine in elderly or adult PS2 patients with advanced non-small-cell lung cancer: The cetuximab in advanced lung cancer (CALC1-E and CALC1-PS2) randomized phase II trials. Lung Cancer 2010; 67:86-92. [PMID: 19380175 DOI: 10.1016/j.lungcan.2009.03.021] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 03/17/2009] [Accepted: 03/18/2009] [Indexed: 11/26/2022]
Abstract
BACKGROUND Two parallel randomized phase 2 trials were performed to choose the optimal way of combining cetuximab with gemcitabine in the first-line treatment of elderly (CALC1-E) and adult PS2 (CALC1-PS2) patients with advanced NSCLC. METHODS Stage IV or IIIB NSCLC patients, aged > or =70 years with PS 0-2 for CALC1-E or aged <70 with PS2 for CALC1-PS2, not selected for EGFR expression, were eligible. Patients were randomized to concomitant (gemcitabine, for a maximum of 6 cycles, plus cetuximab until progression) or sequential (gemcitabine, for a maximum of 6 cycles, followed by cetuximab) strategy. A selection design, with 1-year survival rate as the primary endpoint, was applied, requiring 58 elderly and 42 PS2 patients. RESULTS All planned patients were randomized. In sequential arms, 34.5% and 60.0% patients were not able to receive cetuximab after gemcitabine in CALC1-E and CALC1-PS2, respectively. Survival rates (95% CI) at 1-year for concomitant and sequential arms were 41.4% (23.5-61.1) and 31.0% (15.3-50.8) in CALC1-E and 27.3% (10.7-50.2) and 35.0% (15.4-59.2) in CALC1-PS2. In both studies, survival curves crossed at about 10 months and the worse arm until that time became the better one at 1-year. Toxicity was similar across treatment groups. In concomitant arm of CALC1-E (but not of CALC1-PS2), survival was longer for patients who developed skin toxicity within the first two cycles of treatment. CONCLUSION In both groups of patients, sequential strategy cannot be proposed for future trials because of low compliance. Inconsistency of survival outcomes makes also concomitant treatment not a candidate for further testing in unselected elderly and PS2 NSCLC patients.
Collapse
Affiliation(s)
- Cesare Gridelli
- Oncologia Medica, Az. Sanitaria S. Giuseppe Moscati, Avellino, Contrada Amoretta-83100, Italy.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
García-Sáenz JA, Sastre J, Díaz-Rubio García E. Biomarkers and anti-EGFR therapies for KRAS wild-type metastatic colorectal cancer. Clin Transl Oncol 2009. [DOI: 10.1007/s12094-009-0436-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
|
|
47
|
Targeted therapies in the treatment of advanced/metastatic NSCLC. Eur J Cancer 2009; 45:2473-87. [PMID: 19596191 DOI: 10.1016/j.ejca.2009.06.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2009] [Accepted: 06/10/2009] [Indexed: 12/14/2022]
Abstract
The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially during the last years. Chemotherapy remains the cornerstone of treatment and prolongs survival with a positive impact on quality of life. However, we seem to have reached a plateau of activity in the treatment of NSCLC. Recently, the addition of bevacizumab or cetuximab to chemotherapy doublets has improved the outcome in selected patients with advanced NSCLC. Furthermore, the use of erlotinib and gefitinib is an alternative for second line treatment. Advances in our understanding of molecular biology of cancer and mechanisms of tumourigenesis have further enabled the discovery of several potential molecular targets and development of novel 'targeted therapies'. The purpose of this study is to review current data on the role of targeted therapies in the treatment of advanced NSCLC.
Collapse
|
|
48
|
Tiseo M, Bartolotti M, Gelsomino F, Ardizzoni A. First-line treatment in advanced non-small-cell lung cancer: the emerging role of the histologic subtype. Expert Rev Anticancer Ther 2009; 9:425-35. [PMID: 19374597 DOI: 10.1586/era.09.3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Lung cancer is the leading cause of cancer mortality worldwide. During the past quarter of a century, there have been definite steps forward in understanding the biology of this disease. However, progress in the treatment of advanced non-small-cell lung cancer (NSCLC) has been more elusive and has not been associated with a realistic probability of long-term survival. For this disease, platinum-based chemotherapy is currently the standard treatment. Numerous studies have compared various platinum doublets and have concluded that all such combinations are comparable in their clinical efficacy. Moreover, several trials evaluating different chemotherapy regimens in NSCLC have failed to document a difference based on histology. Recent evidence suggests that histology represents an important variable in the decision making. This review will discuss this new evidence in the first-line treatment of advanced NSCLC, focusing on different possible therapeutic approaches according to histologic subtype.
Collapse
Affiliation(s)
- Marcello Tiseo
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy.
| | | | | | | |
Collapse
|
|
49
|
Chen HX, Cleck JN, Coelho R, Dancey JE. Epidermal Growth Factor Receptor Inhibitors: Current Status and Future Directions. Curr Probl Cancer 2009; 33:245-94. [DOI: 10.1016/j.currproblcancer.2009.10.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
|
|
50
|
Abstract
In the US, colorectal cancer is the third leading cause of cancer-related death. Approximately 20% of patients present with metastatic disease, and an additional 30% to 40% develop metastasis during the course of their disease. Patients with metastatic colon cancer have a 5-year survival rate of only 11%. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant treatment is usually used in patients advanced stage disease. In particular, epidermal growth factor receptor (EGFR) inhibitor therapies have emerged as effective treatments in a subset of patients with metastatic colorectal carcinoma. Two anti-EGFR biologics, cetuximab and panitumumab, have been approved by the Food and Drug Administrations for the treatment of refractory metastatic colorectal carcinoma. Mounting evidence has shown that these therapies are ineffective in tumors with mutations of codons 12 and 13 of exon 2 of the KRAS gene. Because of this compelling data, the National Comprehensive Cancer Network and the American Society of Clinical Oncology have recommended determination of KRAS mutation status in all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy. Anatomic pathologists play an integral role in coordinating the testing for KRAS mutations, as this assay is performed on tissue samples selected by the pathologist. Herein, the authors present an up-to-date review of the biologic, clinical, and laboratory aspects of KRAS mutation testing in colorectal cancer.
Collapse
|