<i>Bcl-xL</i>as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in<i>BRAF</i>-mutant stage II and III colon cancer

Dunne, Philip D.; Coleman, Helen; Bankhead, Peter; Alderdice, Matthew; Gray, Ronan T.; McQuaid, Stephen; Bingham, Victoria; Loughrey, Maurice B.; James, Jacqueline; McCorry, Amy M B; Gilmore, Alan; Holohan, Caitriona; Klingbiel, Dirk; Tejpar, Sabine; Johnston, Patrick G.; McArt, Darragh G.; Nicolantonio, Federica Di; Longley, Daniel B.; Lawler, Mark

doi:10.18632/oncotarget.24481

Cited by 10 publications

(8 citation statements)

References 24 publications

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“…The combination of the BTSA1.2 and Navitoclax demonstrated synergistic therapeutic efficacy in colorectal tumors while being remarkably tolerated in vivo, indicating that this therapeutic strategy may be highly promising for solid tumors. Previous evidence has shown that high expression levels of BCL-XL plays a key role in colorectal tumors formation and therapy resistance [47][48][49][50] . Despite such evidence, the application of Navitoclax in colorectal tumors including our work here suggests that BCL-XL inhibition is not efficient as single agent treatment and is not able to promote apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…BTSA1.2 and Navitoclax combination is efficacious in resistant colorectal xenografts. BCL-XL plays a key role in colorectal tumors formation and therapy resistance [47][48][49][50] . However, there is no clinical testing of BH3-mimetics for colorectal tumors as preclinical studies suggest that only BCL-XL inhibition is not sufficient to effectively induce apoptosis [47][48][49][50] .…”

Section: Combination Of Btsa12 and Navitoclax Is Well Tolerated In Vivomentioning

confidence: 99%

“…BCL-XL plays a key role in colorectal tumors formation and therapy resistance [47][48][49][50] . However, there is no clinical testing of BH3-mimetics for colorectal tumors as preclinical studies suggest that only BCL-XL inhibition is not sufficient to effectively induce apoptosis [47][48][49][50] . Here, we found that BN C was able to promote apoptosis in colorectal tumors in vitro.…”

Section: Combination Of Btsa12 and Navitoclax Is Well Tolerated In Vivomentioning

confidence: 99%

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Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

et al. 2022

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Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Combination Of Btsa12 and Navitoclax Is Well Tolerated In Vivomentioning

confidence: 99%

Section: Combination Of Btsa12 and Navitoclax Is Well Tolerated In Vivomentioning

confidence: 99%

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Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

et al. 2022

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“…Despite careful curation of the NCDB of most cancer patients in the US, various variables such as specific chemotherapy or systemic agent utilized, disease free survival, recurrence rates, objective assessment of response to treatment and prior history of malignancies ( 33 ). Further, missing molecular characteristics such as BRAF mutation have been established as major determinants of therapy response and survival in colorectal cancer ( 34 ). Neoadjuvant or preoperative therapy is typically used in rectal cancers with clinical stage T3N0 and greater.…”

Section: Discussionmentioning

confidence: 99%

Predictive and Prognostic Effects of Primary Tumor Size on Colorectal Cancer Survival

et al. 2021

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BackgroundPathologic staging is crucial in colorectal cancer (CRC). Unlike the majority of solid tumors, the current staging model does not use tumor size as a criterion. We evaluated the predictive and prognostic impact of primary tumor size on all stages of CRC.MethodsUsing the National Cancer Database (NCDB), we conducted an analysis of CRC patients diagnosed between 2010 and 2015 who underwent resection of their primary cancer. Univariate and multivariate analyses were used to identify predictive and prognostic factors, Kaplan-Meier analysis and Cox proportional hazards models for association between tumor size and survival.ResultsAbout 61,000 patients met the inclusion criteria. Median age was 63 years and majority of the tumors were colon primary (82.7%). AJCC stage distribution was: I - 20.1%; II - 32.1%; III - 34.7% and IV - 13.1%. The prognostic impact of tumor size was strongly associated with survival in stage III disease. Compared to patients with tumors <2cm; those with 2-5cm (HR 1.33; 1.19-1.49; p<0.001), 5-10cm (HR 1.51 (1.34-1.70; p<0.001) and >10cm (HR 1.95 (1.65-2.31; p<0.001) had worse survival independent of other variables. Stage II treated without adjuvant chemotherapy had comparable survival outcomes (HR 1.09; 0.97-1.523; p=0.148) with stage III patients who did, while Stage II patients who received adjuvant chemotherapy did much better than both groups (HR 0.76; 0.67-0.86; p<0.001). Stage III patients who did not receive adjuvant chemotherapy had the worst outcomes among the non-metastatic disease subgroups (HR 2.66; 2.48-2.86; p<0.001). Larger tumors were associated with advanced stage, MSI high, non-rectal primary and positive resection margins.ConclusionsFurther studies are needed to clarify the role of tumor size in prognostic staging models, and how to incorporate it into therapy decisions.

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“…where 212 patients had died from a CRC-specific cause. Subsets of Colo-661 have been used in previous publications and the data had therefore undergone prior manual QC operations [19,20,[48][49][50][51][52][53][54]. Researcherdefined data modalities span clinical pathology, epidemiology, mutation, and treatment and outcomes.…”

Section: Datasetmentioning

confidence: 99%

Strategies and Techniques for Quality Control and Semantic Enrichment with Multimodal Data: A Case Study in Colorectal Cancer with eHDPrep

Toner

Miller

Forster

et al. 2022

Preprint

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BACKGROUND: Integration of data from multiple domains can greatly enhance the quality and applicability of knowledge generated in analysis workflows. However, working with health data is challenging, requiring careful preparation in order to support meaningful interpretation and robust results. Ontologies encapsulate relationships between variables that can enrich the semantic content of health datasets to enhance interpretability and inform downstream analyses. FINDINGS: We developed an R package for electronic Health Data preparation "eHDPrep", demonstrated upon a multimodal colorectal cancer dataset (n=661 patients, n=155 variables; Colo-661). eHDPrep offers user-friendly methods for quality control, including internal consistency checking and redundancy removal with information-theoretic variable merging. Semantic enrichment functionality is provided, enabling generation of new informative meta-variables according to ontological common ancestry between variables, demonstrated with SNOMED CT and the Gene Ontology in the current study. eHDPrep also facilitates numerical encoding, variable extraction from free-text, completeness analysis and user review of modifications to the dataset. CONCLUSION: eHDPrep provides effective tools to assess and enhance data quality, laying the foundation for robust performance and interpretability in downstream analyses. Application to a multi-modal colorectal cancer dataset resulted in improved data quality, structuring, and robust encoding, as well as enhanced semantic information. We make eHDPrep available as an R package from CRAN https://cran.r-project.org/package=eHDPrep.

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Bcl-xLas a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically inBRAF-mutant stage II and III colon cancer

Cited by 10 publications

References 24 publications

Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

Predictive and Prognostic Effects of Primary Tumor Size on Colorectal Cancer Survival

Strategies and Techniques for Quality Control and Semantic Enrichment with Multimodal Data: A Case Study in Colorectal Cancer with eHDPrep

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