Dataset Information

Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.

ABSTRACT:

Purpose

Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).

Experimental design

Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371).

Results

DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI.

Conclusions

These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. See related commentary by Smalley, p. 5.

SUBMITTER: Hahn AW

PROVIDER: S-EPMC10311539 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.

Hahn Andrew W AW Menk Ashley V AV Rivadeneira Dayana B DB Augustin Ryan C RC Xu Mingchu M Li Jun J Wu Xiaogang X Mishra Aditya K AK Gide Tuba N TN Quek Camelia C Zang Yan Y Spencer Christine N CN Menzies Alexander M AM Daniel Carrie R CR Hudgens Courtney W CW Nowicki Theodore T Haydu Lauren E LE Khan M A Wadud MAW Gopalakrishnan Vancheswaran V Burton Elizabeth M EM Malke Jared J Simon Julie M JM Bernatchez Chantale C Putluri Nagireddy N Woodman Scott E SE Vashisht Gopal Y N YN Guerrieri Renato R Fischer Grant M GM Wang Jian J Wani Khalida M KM Thompson John F JF Lee Jeffrey E JE Hwu Patrick P Ajami Nadim N Gershenwald Jeffrey E JE Long Georgina V GV Scolyer Richard A RA Tetzlaff Michael T MT Lazar Alexander J AJ Schadendorf Dirk D Wargo Jennifer A JA Kirkwood John M JM DeBerardinis Ralph J RJ Liang Han H Futreal Andrew A Zhang Jianhua J Wilmott James S JS Peng Weiyi W Davies Michael A MA Delgoffe Greg M GM Najjar Yana G YG McQuade Jennifer L JL

Clinical cancer research : an official journal of the American Association for Cancer Research 20230101 1

<h4>Purpose</h4>Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).<h4>Experimental design</h4>Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ ...[more]

PMID: 36166093

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Project description:BackgroundRipretinib, a broad-spectrum KIT and platelet-derived growth factor receptor A switch-control tyrosine kinase inhibitor, is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor as ≥ fourth-line therapy. We present the efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma enrolled in the expansion phase of the ripretinib phase I study.Patients and methodsPatients with KIT-altered metastatic melanoma were enrolled and treated with ripretinib at the recommended phase II dose of 150 mg once daily in 28-day cycles. Investigator-assessed responses according to Response Evaluation Criteria In Solid Tumors version 1.1 were carried out on day 1 of cycles 3, 5, 7, every three cycles thereafter, and at a final study visit.ResultsA total of 26 patients with KIT-altered metastatic melanoma (25 with KIT mutations, 1 with KIT-amplification) were enrolled. Patients had received prior immunotherapy (n = 23, 88%) and KIT inhibitor therapy (n = 9, 35%). Confirmed objective response rate (ORR) was 23% [95% confidence interval (CI) 9%-44%; one complete and five partial responses] with a median duration of response of 9.1 months (range, 6.9-31.3 months). Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months). Patients without prior KIT inhibitor therapy had a higher ORR and longer mPFS (n = 17, ORR 29%, mPFS 10.2 months) than those who had received prior KIT inhibitor treatment (n = 9, ORR 11%, mPFS 2.9 months). The most common treatment-related treatment-emergent adverse events (TEAEs) of any grade in ≥15% of patients were increased lipase, alopecia, actinic keratosis, myalgia, arthralgia, decreased appetite, fatigue, hyperkeratosis, nausea, and palmar-plantar erythrodysesthesia syndrome. There were no grade ≥4 treatment-related TEAEs.ConclusionsIn this phase I study, ripretinib demonstrated encouraging efficacy and a well-tolerated safety profile in patients with KIT-altered metastatic melanoma, suggesting ripretinib may have a clinically meaningful role in treating these patients.

Dataset Information

Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.

Purpose

Experimental design

Results

Conclusions

Publications

Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.

Similar Datasets

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