ANGIOPREDICT. ICORG 12-16, V3
Ontology highlight
ABSTRACT:
DISEASE(S): Colon Cancer,Colorectal Cancer,Colorectal Neoplasms,Advanced Colorectal Cancer
PROVIDER: 2142430 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:The combination of FOLFOX and bevacizumab (FOLFOX-Bev) is a promising treatment for advanced colorectal cancer (CRC). To gain insights into the cellular changes associated with FOLFOX-Bev treatment, we conducted single-cell transcriptomic analysis of CRC samples derived from a patient before and after treatment. Our results show that cancer cells with high proliferative, metastatic, and pro-angiogenic properties respond better to FOLFOX-Bev treatment. Moreover, FOLFOX-Bev enhances CD8+ T cell cytotoxicity, thereby boosting the anti-tumor immune response. Conversely, FOLFOX-Bev impairs the functionality of tumor-associated macrophages, plasma cells, and cancer-associated fibroblasts, leading to a decrease in VEGFB-mediated angiogenesis. Furthermore, FOLFOX-Bev treatment reset intercellular communication, which could potentially affect the function of non-cancer cells. Our findings provide valuable insights into the molecular mechanisms underlying the response of advanced CRC to FOLFOX-Bev treatment and highlight potential targets for improving the efficacy of this treatment strategy.
2023-07-20 | GSE232525 | GEO
Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
2023-07-05 | GSE235917 | GEO
Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
2023-07-05 | GSE235919 | GEO
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumour tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.
2024-02-06 | GSE255058 | GEO
Project description:The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. For instance, patients harbouring oncogenic mutations in RAS signalling do not respond to anti-EGFR targeted treatment. Therefore, RAS-independent therapies are needed. Interestingly nilotinib, a clinically approved drug for chronic myeloid leukaemia, inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining -catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines.
2018-01-31 | PXD008546 | Pride
Project description:The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. For instance, patients harbouring oncogenic mutations in RAS signalling do not respond to anti-EGFR targeted treatment. Therefore, RAS-independent therapies are needed. Interestingly nilotinib, a clinically approved drug for chronic myeloid leukaemia, inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining -catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines.
2018-01-31 | PXD008582 | Pride
Project description:Herein, we assembled a cohort composed of 254 CRC patients, including discovery cohort (N = 124) and validation cohort (N = 130), which received either chemotherapy (mainly FOLFOX therapy), chemoradiotherapy (mainly FOLFOX combined with radiotherapy), or targeted combination therapy (mainly FOLFOX combined with cetuximab).
2023-10-30 | PXD046566 |
Project description:Abstract Objective: JianPiHuaTan Formula (JPHTF), a traditional Chinese medicine (TCM), has been utilized as an adjunctive therapy for colorectal cancer (CRC). The study aims to evaluate the potential clinical benefits of JPHTF and its effectiveness in inhibiting tumor growth. Methods: 300 stage II/III CRC patients and 412 advanced CRC patients were enrolled to verify the clinical value of JPHTF in CRC treatment. Furthermore, CRC patient-derived xenograft (PDX) mice were utilized to investigate the regulatory mechanisms of JPHTF. Results: JPHTF significantly improved abdominal distension, shortness of breath, drowsiness, loss of appetite, sleep, and tiredness in stage II/III CRC patients, thereby improving their quality of life. Simultaneously, JPHTF served as a supportive therapy in extending the overall survival (OS) of stage IV CRC patients with RAS/RAF mutations undergoing chemotherapy. Additionally, JPHTF effectively impeded tumor progression in CRC PDX models with RAS mutation, accompanied by a reduction in tumor cell content in the JPHTF group. Transcriptomic analysis revealed the involvement of the Hippo and Hedgehog signaling pathways in JPHTF-mediated CRC inhibition. Furthermore, mice in the JPHTF group exhibited increased immune cell infiltration. Conclusions: These findings suggested that JPHTF may inhibits tumor growth in CRC with RAS mutation by modulating RAS/RAF downstream signaling pathways, specifically the Hippo and Hedgehog signaling, leading to increased immune cell infiltration.
2024-06-15 | GSE269502 | GEO
Project description:The challenge of preventing colorectal cancer (CRC) is the early identification of individuals whose apparently normal colorectal mucosa will develop cancer, because of inherited trait or environmental exposure. We sought to use genome-wide expression profiling of endoscopic biopsies to detect a signature of propensity for cancer. We performed oligonucleotide microarray analysis of normal appearing mucosa of the following cases: healthy individuals (NOR), disease-free carriers predisposed to HNPCC (hereditary non-polyposis CRC), disease-free patients who underwent curative large bowel resection for CRC 1 to 15 years earlier and patients with CRC (MCRC) (GSE23011). As test set we run on affymetrix arrays an independent set of mucosal biopsies of MCRC and NOR samples. This profiling is based on the analysis of 5 patients who underwent curative large bowel resection for CRC from 1 to 15 years before (MCRC samples), and 12 endoscopy-negative, asymptomatic individuals (NOR samples)
2013-11-30 | E-GEOD-23194 | biostudies-arrayexpress
Project description:Aberrant RAS/MAPK signaling, a common driver of oncogenesis, can be therapeutically targeted with clinically approved MEK inhibitors. Single agent therapy ultimately results in tumor outgrowth in most settings and combination therapies are required to achieve significant clinical benefit in most advanced cancers. Here we focus on identifying MEK inhibitor-based combination therapies in RAS-mutant neuroblastoma. Mutations that activate the RAS/MAPK signaling pathway, while rare at diagnosis, are more frequent in relapsed neuroblastoma. More than 50% of children with high-risk neuroblastoma ultimately relapse and treatment options for relapsed neuroblastoma are limited so most children with relapsed disease do not survive. Here we use a genome-scale CRISPR-Cas9 functional genomic screen to identify genes that, when lost, sensitize RAS-mutant neuroblastoma to MEK inhibition. We discover that loss of either CCNC or CDK8, two members of the mediator kinase module, sensitizes neuroblastoma to MEK inhibition. Furthermore, we demonstrate that small molecule kinase inhibitors of CDK8 improve response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors, suggesting that the addition of CDK8 inhibitors could improve clinical outcome. Using transcriptional profiling, we unexpectedly find that loss of CDK8 or CCNC antagonizes the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevents the compensatory upregulation of pro-growth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies.
2023-02-22 | GSE190178 | GEO