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The efficacy and safety of perioperative chemotherapy for locally advanced colorectal cancer. - The phase II study-

ABSTRACT: Interventions: 1) All RAS wild-type: 6 courses of cetuximab+mFOLFOX6 or 4 courses of cetuximab+SOX is performed, followed by curative operarion. 2) All RAS mutant-type: 6 courses of FOLFOXIRI or SOXIRI is performed, followed by curative operation. Primary outcome(s): Response rate (judged by enhanced CT and MRI on 12 weeks after initiation of chemotherapy) Study Design: Single arm Non-randomized

DISEASE(S): Locally Advanced Colorectal Cancer

PROVIDER: 2639573 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Perioperative chemotherapy for locally advanced colorectal cancer.

Project description:Interventions: 1) All RAS wild-type: 6 courses of cetuximab+mFOLFOX6 or 4 courses of cetuximab+SOX is performed, followed by curative operarion. 2) All RAS mutant-type: 6 courses of FOLFOXIRI or SOXIRI is performed, followed by curative operation. Primary outcome(s): Response rate (judged by enhanced CT and MRI on 12 weeks after initiation of chemotherapy), Induction rate of curative operation Study Design: single arm study, open(masking not used), no treatment control/standard of care control, single assignment, treatment purpose

| 2615276 | ecrin-mdr-crc

Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins

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

The expression profile of Cetuximab resistance in head-and-neck squamous cell carcinoma cells.

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.

2017-03-02 | GSE63916 | GEO

Caveolin-1 and Sox-2 are Predictive Biomarkers of Cetuximab Response in Head and Neck Cancer

Project description:Expression analysis (RNA-seq) and RPPA data (see publication) of head and neck cancer patient-derived xenographs (PDXs) revealed Sox-2 and Cav-1 expression to be biomarker determinants of head and neck cancer patient tumor response to cetuximab (EGFR inhibitor) treatment.

2021-10-12 | GSE183881 | GEO

Genomic Analysis of Relapsed Pediatric Acute Lymphoblastic Leukemia

Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>

| phs001072 | dbGaP

Ecotrop-Amphibians

Project description:Study on amphibian biodiversity performed upon ECOTROP field courses

| PRJEB56284 | ENA

Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins

2014-09-18 | GSE61495 | GEO

CHIP-seq analysis of cetuximab-resistant cells in oral cancer

Project description:We conducted chromatin immunoprecipitation for H3K27ac and BRD4, followed by sequencing (ChIP-seq) to investigate super-enhancer (SE) for drug-resistant using cetuximab-resistant cells and control cells. SE analysis revealed that several unique SE-associated genes in cetuximab-resistant cells were identified.

2022-06-30 | GSE205455 | GEO

Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

Project description:Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRC). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF-1 and non-canonical RAS/RAF-aberrations with primary resistance and validated transcriptomic CRC-subtypes as non-genetic predictors of benefit. 64% of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype pre-treatment to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PDL1 and LAG3 immune-checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

| EGAS00001003367 | EGA

A Systems Mechanism for KRAS Mutant Allele Specific Responses to Targeted Therapy

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.

2020-05-27 | PXD014755 | Pride

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