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In metastatic colorectal cancer (mCRC) patients (pts), treatment strategies integrating liver resection with more effective therapies offer better 5-year survival rates than palliative chemotherapy alone. However, resectability is established only on clinical-morphovolumetric criteria, liver resection is a complex and costly procedure and relapse occurs in almost 2/3 of pts after potentially curative resection. Therefore, prompt identification of pts at higher risk of recurrence is critical to avoid not-beneficial, expensive procedures. Aberrant metabolism is an emerging hallmark of cancer and recent observations suggest that specific metabolic changes can be used to stratify pts for prognosis and drug-response. We evaluated by 600MHz NMR spectroscopy the metabolomics profiling on sera from 30 mCRC pts, enrolled in the Obelics trial (NCT01718873), which investigated different schedules of bevacizumab in combination with oxaliplatin plus fluoropyrimidines regimens, and subdivided on the basis of outcome, in good (R) vs bad responders (NR) according to PFS: 12 months or longer (R, n = 12) and shorter than 12 months (NR, n = 18). We compared the samples of the two mCRC pts groups, collected at response evaluation when resectability was established in case of appropriate tumor reduction and PCA, sPLS-DA and loading plots evidenced metabolites with statistically different levels between the two sub-groups. ROC curves were performed to identify the cutoff levels of these significant metabolites to be correlated with patient survival. In this way we demonstrated that low levels of 3-hydroxybutyrate and of hydroxyproline as well as high levels of histidine correlated with both poor progression free survival (PFS) and overall survival (OS). Notably, either 3-hydroxybutyrate or histidine are better predictor of both PFS and OS compared to pathologic response on resected metatastases. Lipidomics analysis confirmed clear differences between R and NR pts indicating statistically significant increase of lipids in NR pts, with both higher triglycerides and phospholipids correlating with poor PFS and OS. This latter effects, may reflect, at least in part a non specific inflammatory response; indeed a significant increase of pro-inflammatory cytokines was also demonstrated in NR pts sera by cytokinomics using multiplex ELISA approach. Finally, basal serum metabolomics analysis in both NR and R pts demonstrated that on-treatment evaluation is more informative than pre-treatment evaluation to stratify patients for outcome. Overall, these data suggest that NMR-based metabolomics is a potent and affordable method that could play a role in the prediction of mCRC outcome. Citation Format: Alfredo Budillon, Susan Costantini, Angela Sorice, Francesca Capone, Silvia Marchese, Elena Di Gennaro, Carlo Vitagliano, Fabiana Tatangelo, Alfonso De Stefano, Franco Bianco, Paolo Delrio, Francesco Izzo, Antonio Avallone. Outcome prediction of metastatic colorectal cancer patients undergoing liver resection by analyzing serum metabolomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5268.

Introduction: docetaxel (DTX) represents the standard of care first line treatment of castration-resistant prostate cancer (PCa). However, the onset of systemic side effects hampers patient's compliance and DTX resistance invariably emerges, leading to disease relapse, suggesting the need of novel combination strategies. Cancer stem cells (CSC) drive PCa survival and metastasis and are thought to be responsible for the development of resistance to DTX. The mevalonate pathway (MVP) plays a critical role in PCa progression and is implicated in cell stemness, proliferation, and organ size regulation through the YAP-TAZ signaling axis. Here, we evaluate the combination treatment of valproic acid (VPA), an histone deacetylase (HDAC) inhibitor and the cholesterol-lowering drug simvastatin (SIM), an inhibitor of HMGCoA reductase (HMGCR), the rate limiting enzyme in MVP, alone and plus DTX in PCa models. Method: synergistic antiproliferative effects were assessed on LNCAP, 22Rv1, DU145, PC3 and DU14580 SIM-resistant cell lines and normal epithelial prostate EPN cells, by calculating combination index (CI) according to Chou and Talalay method. Apoptosis was measured by FACS analysis and caspase assay. Tumor spheroids were obtained by low attach systems and scored with luminescence 3D-cell viability assay. Proteins and genes expression was assessed by western blot and real time PCR analysis. In vivo experiments were performed on xenograft models in athymic mice. Cholesterol content was evaluated by nuclear magnetic resonance (1H-NMR). Results: synergistic antiproliferative and proapoptotic effect of VPA-SIM was observed in all PCa cell lines tested, except in EPN cells and was confirmed in PCa spheroids. SIM-dependent cholesterol content downmodulation was potentiated by VPA and mevalonic acid, the product of HMGCR activity, reverts all the antitumor combined effect, suggesting the involvement of MVP in the synergistic interaction. Mechanistically, the combination is able to induce a reduction of HMGCR mRNA expression and the inhibitory phosphorylation of HMGCR and YAP, followed by a reduction of CTGF, BRCA5 and Cyr61 YAP-target genes, as well as a reduction of a CSC-marker gene such as NANOg. Notably, the VPA-SIM combination, sensitizes PCa cells to DTX treatment in sensitive and DTX-resistant cells, as shown by CI calculation, apoptosis, and CSC enriched-spheroid experiments. The synergistic interaction of the triple combination was also confirmed in vivo in both DU145R80 and 22Rv1 xenograft models. Conclusions: Overall, this study suggests that the combination of two safe generic drugs such as VPA and SIM, may improve the therapeutic index of DTX and revert DTX-resistance, representing an innovative and feasible antitumor strategy for the treatment of prostate cancer that warrants further clinical evaluation. Citation Format: Federica Iannelli, Maria Serena Roca, Chiara Ciardiello, Simona De Rienzo, Rita Lombardi, Angela Sorice, Susan Costantini, Tania Moccia, Maria Rita Milone, Biagio Pucci, Alfredo Budillon, Francesca Bruzzese. Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting cancer stem cells compartment via YAP-pathway modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2877.