An Umbrella Study to Explore Precision Treatment of Colorectal Cancer Based on Molecular Typing
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2698986 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Interventions: Cohort 1:Trastuzumab + Camrelizumab + Irinotecan;Cohort 2:Cetuximab + Pyrotinib + Irinotecan;Cohort 3:Cetuximab + MEK Inhibitor + Irinotecan;Cohort 4:PARP Inhibitor + Irinotecan
Primary outcome(s): Objective Response Rate
Study Design: Factorial
| 2688563 | ecrin-mdr-crc
Project description:Purpose: There is an unmet clinical need for biomarkers to identify breast cancer patients who are at increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with HER2+ brain metastasis. Experimental Design: Gene expression of 19 HER2+ breast cancer brain metastases was compared with HER2+ nonmetastatic primary tumors. Gene Set Enrichment Analysis was used to identify a signature, which was evaluated for correlation with BRCA1 mutation status and clinical outcome using published microarray datasets and for correlation with pharmacological inhibition by a PARP inhibitor and temozolomide using published microarray datasets of breast cancer cell lines. Results: A BRCA1 Deficient-Like (BD-L) gene signature is significantly correlated with HER2+ metastases in both our and an independent cohort. BD-L signature is enriched in BRCA1 mutation carrier primary tumors and HER2-/ER- sporadic tumors, but high values are found in a subset of ER+ and HER2+ tumors. Elevated BD-L signature in primary tumors is associated with increased risk of overall relapse, brain relapse, and decreased survival. The BD-L signature correlates with pharmacologic response to PARP inhibitor and temozolomide in two independent microarray datasets, and the signature outperformed four published gene signatures of BRCA1/2 deficiency. Conclusions: The BD-L signature is enriched in breast cancer brain metastases and identifies a subset of primary tumors with increased propensity for brain metastasis. Furthermore, this signature may serve as a biomarker to identify sporadic breast cancer patients who could benefit from a therapeutic combination of PARP inhibitor and temozolomide. Gene expression of 19 HER2+ human breast cancer brain metastases was compared with gene expression of 19 HER2+ nonmetastatic primary human breast tumors.
2014-04-24 | E-GEOD-43837 | biostudies-arrayexpress
Project description:This is a Phase II multi-center 2-sequential cohorts trial, designed to assess the objective response rate of two anti HER2 combination in advanced disease CRC patients harbouring an amplified HER2 tumor assessed according to HERACLES Diagnostic Criteria by FISH/SISH.
Cohort A: monoclonal antibody trastuzumab, used in combination with the small molecule tyrosine kinase inhibitor lapatinib.
Cohort B, monoclonal antibody pertuzumab, used in combination with the antibody drug conjugate trastuzumab-emtansine.
Please note that cohort A accrual has been closed and endpoint already reached.
| 2249965 | ecrin-mdr-crc
Project description:Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated by a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.
2024-11-06 | GSE269881 | GEO
Project description:Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated by a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.
2024-11-06 | GSE269880 | GEO
Project description:Purpose: There is an unmet clinical need for biomarkers to identify breast cancer patients who are at increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with HER2+ brain metastasis. Experimental Design: Gene expression of 19 HER2+ breast cancer brain metastases was compared with HER2+ nonmetastatic primary tumors. Gene Set Enrichment Analysis was used to identify a signature, which was evaluated for correlation with BRCA1 mutation status and clinical outcome using published microarray datasets and for correlation with pharmacological inhibition by a PARP inhibitor and temozolomide using published microarray datasets of breast cancer cell lines. Results: A BRCA1 Deficient-Like (BD-L) gene signature is significantly correlated with HER2+ metastases in both our and an independent cohort. BD-L signature is enriched in BRCA1 mutation carrier primary tumors and HER2-/ER- sporadic tumors, but high values are found in a subset of ER+ and HER2+ tumors. Elevated BD-L signature in primary tumors is associated with increased risk of overall relapse, brain relapse, and decreased survival. The BD-L signature correlates with pharmacologic response to PARP inhibitor and temozolomide in two independent microarray datasets, and the signature outperformed four published gene signatures of BRCA1/2 deficiency. Conclusions: The BD-L signature is enriched in breast cancer brain metastases and identifies a subset of primary tumors with increased propensity for brain metastasis. Furthermore, this signature may serve as a biomarker to identify sporadic breast cancer patients who could benefit from a therapeutic combination of PARP inhibitor and temozolomide.
2014-04-24 | GSE43837 | GEO
Project description:Faratian2009 - Role of PTEN in Trastuzumab
resistance
This model is described in the article:
Systems biology
reveals new strategies for personalizing cancer medicine and
confirms the role of PTEN in resistance to trastuzumab.
Faratian D, Goltsov A, Lebedeva G,
Sorokin A, Moodie S, Mullen P, Kay C, Um IH, Langdon S, Goryanin
I, Harrison DJ.
Cancer Res. 2009 Aug; 69(16):
6713-6720
Abstract:
Resistance to targeted cancer therapies such as trastuzumab
is a frequent clinical problem not solely because of
insufficient expression of HER2 receptor but also because of
the overriding activation states of cell signaling pathways.
Systems biology approaches lend themselves to rapid in silico
testing of factors, which may confer resistance to targeted
therapies. Inthis study, we aimed to develop a new kinetic
model that could be interrogated to predict resistance to
receptor tyrosine kinase (RTK) inhibitor therapies and directly
test predictions in vitro and in clinical samples. The new
mathematical model included RTK inhibitor antibody binding,
HER2/HER3 dimerization and inhibition, AKT/mitogen-activated
protein kinase cross-talk, and the regulatory properties of
PTEN. The model was parameterized using quantitative
phosphoprotein expression data from cancer cell lines using
reverse-phase protein microarrays. Quantitative PTEN protein
expression was found to be the key determinant of resistance to
anti-HER2 therapy in silico, which was predictive of unseen
experiments in vitro using the PTEN inhibitor bp(V). When
measured in cancer cell lines, PTEN expression predicts
sensitivity to anti-HER2 therapy; furthermore, this
quantitative measurement is more predictive of response
(relative risk, 3.0; 95% confidence interval, 1.6-5.5; P <
0.0001) than other pathway components taken in isolation and
when tested by multivariate analysis in a cohort of 122 breast
cancers treated with trastuzumab. For the first time, a systems
biology approach has successfully been used to stratify
patients for personalized therapy in cancer and is further
compelling evidence that PTEN, appropriately measured in the
clinical setting, refines clinical decision making in patients
treated with anti-HER2 therapies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000424.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000424 | BioModels
Project description:Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial (ClinicalTrials.gov Identifier: NCT01875666, LCCC1214) designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 transcription factor expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. Patient samples from this trial, when sufficient material was available, were also subjected to kinase enrichment using multiplexed kinase inhibitor bead affinity chromatography and LC-MS/MS. Strongly responsive transcriptional responses observed in a subset of patients corresponded to decreased binding of CDK1 and DDR1 by our proteomic approach. Taken together, our results highlight the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
2021-04-09 | PXD021865 | Pride
Project description:This study will explore the efficacy and safety of tislelizumab (PD1 inhibitor) combined with DisitamabVedotin (ADC) and pyrotinib maleate (TKI) in the treatment of HER2-positive or mutated advanced colorectal cancer who have failed standard therapy .
| 2720538 | ecrin-mdr-crc
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients do not benefit from this treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. The series comprised 24 incisional biopsies of breast carcinomas derived from patients that received neoadjuvant trastuzumab based therapy. Gene expression profiling was performed using RNA from frozen core biopsies from 24 patients with primary HER2-positive (HER2+) tumors treated with neoadjuvant chemotherapy and trastuzumab.
2016-03-31 | E-GEOD-62327 | biostudies-arrayexpress