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A putative role for ALDH inhibitors and chemoprevention of BRCA-mutation-driven tumors.

ABSTRACT: Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA-mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers.

SUBMITTER: McGonigal S

PROVIDER: S-EPMC10653209 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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A putative role for ALDH inhibitors and chemoprevention of BRCA-mutation-driven tumors.

McGonigal Stacy S Wu Rong R Grimley Ed E Turk Ekrem G EG Zhai Yali Y Cho Kathleen R KR Buckanovich Ronald J RJ

Gynecologic oncology 20230802

Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemo ...[more]

PMID: 37535994

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Project description:ImportanceAs the third most frequently mutated gene in cancers, the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors remains unclear.ObjectiveTo examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients.Design, setting, and participantsThis cohort study used multidimensional genomic data of 10 195 patients from The Cancer Genome Atlas (TCGA) across 30 solid tumor types, 56 patients from a non-small cell lung cancer (NSCLC) cohort, and 145 patients from a melanoma cohort. Genomic factors associated with ICI response covered tumor mutational burden, neoantigens, immune-related gene signatures, and tumor immune microenvironment. Both NSCLC and melanoma cohorts included ICI-treated patients. The TCGA cohort was used to examine the association of MUC16 mutation with genomic factors. Two ICI-treated cohorts were used to explore the significance of outcomes associated with MUC16 mutation, using Kaplan-Meier curves and Cox models with adjusting for potential confounders. Gene set enrichment analysis was used to identify MUC16 mutation-associated biological processes. Data were obtained from October 1 through October 10, 2019, and were analyzed from October 11 through December 31, 2019.Main outcomes and measuresGenomic factors associated with ICI response, overall survival, and clinical response.ResultsOf the 10 195 patients, 4821 (47.6%) were men (median [interquartile range {IQR}] age, 60 [50-70] years). MUC16 was mutated in 2006 of 10 195 patients (19.68%). In this pan-cancer data set, patients with MUC16 mutation had higher tumor mutational burden (median [IQR], 230 [93-595] mutations vs 48 [25-92] mutations; difference, 182 mutations; 95% CI, 164-199 mutations; P < .001) and neoantigen load (median [IQR], 179 [74-394.5] neoantigens vs 48 [24-89] neoantigens; difference, 131 antigens; 95% CI, 116.5-145 neoantigens; P < .001) than those without mutations. The tumor immune microenvironment with dual-positive CD8A and PD-L1 was overrepresented in MUC16-mutated tumors compared with wild-type ones (43.8% vs 32.4%; odds ratio, 1.63; 95% CI, 1.46-1.80; P < .001). Of the 40 immune-related genes, 37 (92.5%) exhibited differential expression between 2 states. MUC16 mutation was associated with improved overall survival in both the NSCLC (hazard ratio, 0.34; 95% CI, 0.12-0.99; P = .04) and melanoma (hazard ratio, 0.57; 95% CI, 0.36-0.90; P = .02) cohorts. The improvement persisted after adjusting for age, sex, and dominant mutational signatures in the melanoma cohort (hazard ratio, 0.57; 95% CI, 0.33-0.96; P = .04). MUC16 mutation was associated with greater response rates in the NSCLC cohort (odds ratio, 4.03; 95% CI, 1.06-16.43; P = .03) and the melanoma cohort (odds ratio, 3.38; 95% CI, 1.07-14.25; P = .03). Gene set enrichment analysis revealed that gene sets regarding cell proliferation and immune response were enriched in MUC16-mutated tumors (false discovery rate, <.001).Conclusions and relevanceMUC16 mutation appears to be associated with reported genomic factors associated with response to and improved outcomes for ICI treatment in solid tumors. It may hold promise as a marker for guiding immunotherapeutic responsiveness.

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A putative role for ALDH inhibitors and chemoprevention of BRCA-mutation-driven tumors.

Publications

A putative role for ALDH inhibitors and chemoprevention of BRCA-mutation-driven tumors.

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