Abstract TMEM-021: CORRELATION BETWEEN DRUG SENSITIVITY AND METABOLOMIC SIGNATURES WITH OBJECTIVE RESPONSE (OR), TIME TO PROGRESSION (TTP), AND OVERALL SURVIVAL (OS) IN ADVANCED EPITHELIAL OVARIAN CANCER (EOC): A PHASE II STUDY

INTRODUCTION: Personalized oncology has advanced through the application of genomic, transcriptomics & proteomic platforms. BCR-abl; EGFr & ALK have provided drug-able targets & companion diagnostics in several diseases, yet many human transforming events are polygenic & incompletely understood at a genetic level. The recognition that oncogenesis reflects changes in both the cell and its micro-environment has renewed interest in whole cell experimental models that capture native-state cell-cell, -stroma & -vascular signaling. Phenotypic platforms like the Ex vivo Analysis of Programmed Cell Death (EVA-PCD) and Metabolomic Analyses have been shown to correlate significantly with response, time to progression & survival in cancer patients. PURPOSE: To correlate drug response profiles measured by EVA-PCD with Metabolomic Profiles measured by Mass Spectrometry, in patients with newly diagnosed, advanced epithelial ovarian cancer (EOC). Procedures: After signing informed consent, patients with advanced EOC undergoing cytoreductive surgery submit tumor tissue for EVA/PCD and blood samples for Mass Spectrometry. EVA/PCD analyses using morphologic (delayed loss of membrane integrity) and metabolic (ATP-content, mitochondrial metabolism) endpoints are used to generate dose-response curves, interpolated to provide LC50 values. The LC50 values for Cisplatin and the principal platinum-based combinations are used to define drug sensitive/drug resistant profiles for correlation with plasma-sample lipidomic analytes measured by Mass Spectrometry. Metabolite profiles from 21 participants are under analysis for more than 180 different circulating components including: amino acids, acylcarnitines, phosphatidylcholines, sphingomyelins and hexoses simultaneously identified/quantified in a targeted approach by UPLC/Mass Spectrometry. Associations between metabolite concentrations and drug sensitivity/resistance as well as clinical response parameters in EOC patients are being analyzed using adjusted linear regression models. Pairwise relationships among metabolites are investigated and illustrated by Gaussian graphical models (GGMs). RESULTS: To date, 21EOC patients have been accrued and are under analysis with a target accrual of 50. CONCLUSIONS: The growing recognition that malignant transformation represents changes in cellular metabolism offers the opportunity to interrogate human tumor biology at the level of metabolomics. This study will be among the first to correlate EOC drug response, time to progression and survival with metabolomic profiles and may offer new insights into ovarian carcinogenesis and cellular mechanisms of drug resistance with the potential to develop new predictive & prognostic models for advanced EOC. Funding: Sao Paulo State Research Foundation (FAPESP): grants 2014/19171-2 / 2015/16921-3 (Sao Paulo, SP, Brazil) and grants from Memorial Medical Center Foundation (Long Beach, CA, USA). Citation Format: Paulo D9Amora MD, PhD; Ismael DCG Silva MD, PhD; 142 MD, PhD; Marcia Batista Salzgeber; Manoel JBC Girao MD, PhD; Robert Bristow MD; Steven Evans BS, MA; Philip J. DiSaia MD and Robert Nagourney MD. CORRELATION BETWEEN DRUG SENSITIVITY AND METABOLOMIC SIGNATURES WITH OBJECTIVE RESPONSE (OR), TIME TO PROGRESSION (TTP), AND OVERALL SURVIVAL (OS) IN ADVANCED EPITHELIAL OVARIAN CANCER (EOC): A PHASE II STUDY [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-021.