Efficacy and Safety Study of Imprime PGG With Cetuximab in Subjects With Stage IV KRAS-Mutated Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2073108 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Oncogenic KRAS mutations and inactivation of the APC tumour suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus upon downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, rendering them ‘addicted’ to glutamine supporting proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino-acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via mTORC1 inhibition, cooperates with Slc7a5 deletion to abrogate growth of established KRAS-mutant tumours. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
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Project description:Oncogenic KRAS mutations and inactivation of the APC tumour suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus upon downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, rendering them ‘addicted’ to glutamine supporting proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino-acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via mTORC1 inhibition, cooperates with Slc7a5 deletion to abrogate growth of established KRAS-mutant tumours. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
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Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed.
2011-03-04 | GSE27659 | GEO
Project description:Study BT-CL-PGG-CRC1031 is a Phase 3, open-label, randomized, multi-center study. Qualified subjects, who have KRAS wild type (WT) colorectal cancer will be randomized in a 2:1 ratio to treatment with either Imprime PGG and cetuximab or cetuximab alone. Subjects will be dosed until progression or discontinuation for some other reason. Efficacy will be assessed via Response Evaluation Criteria in Early Tumors 1.1 (RECIST 1.1); computed tomography (CT) scans will be conducted every 6 weeks. Safety, pharmacokinetics (PK), quality of life, and biomarker parameters will also be assessed.
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Project description:Despite the advent of mutant-selective KRAS inhibitors, colorectal cancer (CRC) responses remain limited, with frequent stable disease and rapid recurrence. The mechanisms underlying CRC tolerance to KRAS inhibition and eventual resistance are poorly understood. Here, we explored early transcriptional and proteomic changes following KRAS silencing in 3D CRC spheroid models to identify pathways linked to sensitivity or resistance. Based on growth, cell cycle, and apoptosis responses, cell lines were classified as KRAS silencing-sensitive (HCT116, SW480) or -resistant (LS174T, SW837). Sensitive cells showed upregulation of the unfolded protein response (UPR) and WNT/β-catenin signaling, while these pathways were downregulated in resistant cells. Proteomic analysis confirmed UPR deregulation, with reduced translation-related proteins in sensitive cells. Functional assays revealed that KRAS knockdown in HCT116 reduced protein aggregation and translational capacity, consistent with UPR activation. However, inhibiting IRE1α-mediated UPR signaling did not reverse KRAS silencing-induced arrest or apoptosis. These findings suggest UPR activation as an early adaptive response in KRAS-dependent CRC cells.
2025-05-07 | PXD059013 | Pride
Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Gene expression analysis was performed on five serous borderline tumors with BRAF mutation and five serous borderline tumors without BRAF mutation randomly. RNA was extracted from microdissected tumor cells. Expression profiling was carried out with Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays
2011-03-04 | E-GEOD-27659 | biostudies-arrayexpress