Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer
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ABSTRACT:
DISEASE(S): Colon Signet Ring Cell Adenocarcinoma,Adenocarcinoma,Stage Ivb Colon Cancer,Carcinoma,Carcinoma, Signet Ring Cell,Recurrent Colon Carcinoma,Colon Mucinous Adenocarcinoma,Rectal Signet Ring Cell Adenocarcinoma,Recurrent Rectal Carcinoma,Rectal Neoplasms,Cystadenocarcinoma,Stage Iva Rectal Cancer,Rectal Mucinous Adenocarcinoma,Stage Ivb Rectal Cancer,Adenocarcinoma, Mucinous,Stage Iva Colon Cancer,Colonic Neoplasms
PROVIDER: 2094842 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.
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Project description:Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient’s tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, the G13D mutation behaves differently; for unknown reasons, CRC patients with the KRAS G13D mutation (also written KRASG13D) appear to benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it appears to contradict the well-established mechanisms of EGFR signaling and of RAS mutations. Here, we identified a systems-level, mechanistic basis that explains why KRASG13D cancers respond to EGFR inhibition. We first investigated the problem with a computational model of RAS signaling, which unexpectedly revealed that the known biophysical differences between the three most common KRAS mutant proteins are sufficient to generate different sensitivities to inhibition. Computation and experimentation together revealed a non-intuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interact with NF1 drive wild-type RAS activation in an EGFR independent manner through competitive inhibition of NF1, whereas KRAS G13D cells remain dependent upon EGFR for wild-type Ras activation because they cannot competitively inhibit NF1 due to a weak interaction between these two proteins. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.
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Project description:Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and might be more relevant preclinical models to evaluate effective therapeutic agents. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer models. From 86 unsupervised surgical colon sample collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinosis and 14 metastases. Our histological and molecular characterization of patient tumors, first passage on mice and later passages includes the sequence of key genes involved in CRC (ie APC, KRAS, TP53), CGH array and transcriptomic analysis. This comprehensive characterization demonstrates that our collection recapitulates the clinical situation regarding the histopathological and molecular diversity of colorectal cancers. Moreover, patient tumors and corresponding models are clustering together which gives the opportunity to look for relevant signatures and comparison studies between clinical and preclinical data. Hence, we performed pharmacological monotherapy studies with standard of care for colon cancer (5-FU, oxaliplatin, irinotecan, cetuximab). Through this extensive in vivo analysis, we have compared the molecular profile with the drug sensitivity of each tumor models, and run an equivalent of a cetuximab phase II clinical trial in a preclinical setting. Our results confirm the key role of KRAS mutation in the cetuximab resistance and demonstrate that such collection could bring benefit to evaluate novel targeted therapeutic strategies and potentially help the stratification strategy for cancer patients according to molecular marker. This set correspond to 82 CGH profiles, with 7 samples from patient tumor and 75 samples from mouse xenograft at different passages P0 to P9. All hybridizations are performed with Human CGH 244K Agilent arrays (amadid 014693) in dual color with Human DNA Promega (sex matched) as reference. ID for biosources without an -Px suffix correspond to tumor patients. ID with a suffix correspond to xenograft with 0 for the first passage.
2012-07-27 | E-MTAB-991 | biostudies-arrayexpress
Project description:Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and might be more relevant preclinical models to evaluate effective therapeutic agents. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer models. From 86 unsupervised surgical colon sample collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinosis and 14 metastases. Our histological and molecular characterization of patient tumors, first passage on mice and later passages includes the sequence of key genes involved in CRC (ie APC, KRAS, TP53), CGH array and transcriptomic analysis. This comprehensive characterization demonstrates that our collection recapitulates the clinical situation regarding the histopathological and molecular diversity of colorectal cancers. Moreover, patient tumors and corresponding models are clustering together which gives the opportunity to look for relevant signatures and comparison studies between clinical and preclinical data. Hence, we performed pharmacological monotherapy studies with standard of care for colon cancer (5-FU, oxaliplatin, irinotecan, cetuximab). Through this extensive in vivo analysis, we have compared the molecular profile with the drug sensitivity of each tumor models, and run an equivalent of a cetuximab phase II clinical trial in a preclinical setting. Our results confirm the key role of KRAS mutation in the cetuximab resistance and demonstrate that such collection could bring benefit to evaluate novel targeted therapeutic strategies and potentially help the stratification strategy for cancer patients according to molecular marker. This set correspond to 82 CGH profiles, with 7 samples from patient tumor and 75 samples from mouse xenograft at different passages P0 to P9. All hybridizations are performed with Human CGH 244K Agilent arrays (amadid 014693) in dual color with Human DNA Promega (sex matched) as reference. ID for biosources without an -Px suffix correspond to tumor patients. ID with a suffix correspond to xenograft with 0 for the first passage.
2012-07-27 | E-MTAB-992 | biostudies-arrayexpress
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2012-07-13 | E-GEOD-23428 | biostudies-arrayexpress
Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.
2014-09-18 | E-GEOD-61495 | biostudies-arrayexpress
Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC.
2012-07-14 | GSE23428 | GEO
Project description:HCC827 cells were grown in gradually increasing concentrations of cetuximab beginning at 0.1 ug/ml. Drug concentrations were slowly increased until the resistant cells were able to proliferate in 100 ug/ml of cetuximab. Individual clones of cetuximab resistant (CR; CR1 to CR4) cells were isolated and confirmed to be drug resistant. Number of samples: 5. Parental HCC827 as a control. 4 Cetuximab resistant clones
2011-11-23 | E-GEOD-30255 | biostudies-arrayexpress
Project description:Aberrant activation of signaling pathways controlled in normal epithelial cells by the epidermal growth factor receptor (EGFR) has been linked to cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to either ligand stimulation or pharmacological inhibition of the signaling intermediaries PI-3-Kinase and MEK or transfected with EGFR, RELA/p65, or HRASVal12. The gene expression patterns that distinguished the various HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12 further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies. 58 total RNA collected from HaCaT cell lines with combinations of the following experimental conditions: forced expression of EGFR, RELA/p65, and HRAS-VAL12D; grown in PBS, serum starve, and media stimulated with TNF or EGF; treated with gefitinib, LY294002, and U1026.
2012-05-22 | E-GEOD-32975 | biostudies-arrayexpress
Project description:Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epithelial growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms underlying cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the TGF-beta signaling pathway was upregulated in the stromal cells of PDXs that progressed to cetuximab (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab, and when tumors shrunk following cetuximab treatment (CetuximabSen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that in CetuximabProg-PDX, TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs). These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of CetuximabProg-PDX. Altogether, our findings indicate, for the first time, that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.
2020-03-23 | GSE143279 | GEO