379 Background: Pan-HDAC inhibitors were studied in two separate phase I pharmacokinetic solid tumor trials at Huntsman Cancer Institute. The objective of this study was to investigate the clinical efficacy of HDAC inhibition in those study subjects with UC and correlate response to molecular subtype of tumor with translational studies to validate clinical benefit. Methods: Patients with UC treated with a pan-HDAC inhibitor in two Phase I trials were included. RECIST 1.1 was used to categorize responses. Expression profiling and TCGA clustering were performed using archived tissue (obtainable for seven of the ten subjects). To elucidate the mechanisms of clinical benefit bladder cancer cell lines with varied mutational profiles and differential sensitivity to cisplatin were tested for sensitivity to panobinostat with characterization of phenotypic changes upon treatment. Results: Ten subjects with advanced UC received either belinostat or panobinostat. The best overall responses in the pooled data were: 1 complete response (CR), 1 partial response (PR), 6 stable disease (SD), 2 progressive disease (PD). The patient with CR had failed two prior lines of chemotherapy (including cisplatin), had a Cluster IV tumor and remains in CR for 3.5 years now. All tumors with SD belong to Cluster I. For those with SD, the progression free survival ranged from 6 to 7.5 months on treatment. One tumor with PR and one tumor with PD had characteristics partly consistent with Cluster III. Validating the broad spectrum of clinical activity of pan-HDAC inhibition, potent cytotoxicity with panobinostat was noted in bladder cancer cell lines with varied chromatin remodeling mutations. Panobinostat causes inhibition of colony formation, cell cycle arrest and proinflammatory cytokine release in these cells. Cisplatin-resistant HT1197 cells (with ARID1A mutation) are tenfold more sensitive. Conclusions: Pan-HDAC inhibition may be an effective treatment option in both luminal and basal subtypes of UC and in platinum-resistant setting. Translational studies suggest options for rational therapeutic combinations to enhance efficacy. HDAC inhibition may be particularly effective in UC with mutations affecting the SWI/SNF complex.
Heat shock protein expression in testis and bladder cancer cell lines exhibiting differential sensitivity to heat
