Abstract 3958: Tubulin hyper-acetylation in blood lymphocytes: pharmacodynamic (PD) biomarker for the selective histone deacetylase (HDAC) 6 inhibitors ricolinostat and ACY-241 in multiple myeloma (MM) patients

Abstract

Abstract INTRODUCTION: HDACs are a family of enzymes that remove acetyl groups from proteins and are involved in key cellular processes. Nonselective HDAC inhibitors have shown promise in treating MM in combination with standard therapies such as proteasome inhibitors (PIs) and immunomodulatory agents, but are limited by adverse effects. The selectivity profile of clinical HDAC inhibitors is critically important as the same drug may exert its effects via alternative mechanisms depending on the partner therapeutic. An example is HDAC6 inhibitors in combination with bortezomib, a proteasome inhibitor (PI). Delivery of protein-bearing vesicles to the aggresome involves HDAC6 through its role in vesicle trafficking, thus supporting a secondary survival pathway. In the case of lenalidomide or pomalidomide, inhibiting class I HDACs can suppress MYC protein levels, which potentially enhances activity in a clinical setting. Ricolinostat (ACY-1215) and ACY-241 that are currently in clinical trials have a selectivity profile tuned toward HDAC6 over HDACs 1, 2, and 3, which is hypothesized to enhance anti-cancer activity with multiple standard of care regimes while minimizing toxicity. METHODS: Peripheral blood from patients that received escalating oral doses of ricolinostat or ACY-241 that range from 40 mg to 360 mg was collected for matched PK and PD assessment. Lymphocytes were examined for tubulin and histone hyper-acetylation by flow cytometry. RESULTS & CONCLUSION: Plasma concentration for both ricolinostat and ACY-241 reach a maximal level (Cmax) 1-2 hr after administration. An exposure plateau was reached at dose levels ≥160 mg of ricolinostat, with Cmax observed to be ∼2 μM. ACY-241 exposures reached higher levels, Cmax of ∼3 μM and ∼7 μM at 180 and 360 mg, respectively, and no evidence of an exposure plateau. Correlating to the PK levels, acetyl-tubulin increases to a maximal level by 1-2 h after dosing compared to predose, and declines to basal level by >4 hr. As plasma levels increased with dose from 40 mg to 160 mg for ricolinostat so do the number of patients that have an increase in acetyl-tubulin such that at dose levels ≥80 mg all patients have a measurable increase in acetylated tubulin. Levels of acetyl-tubulin were similar at dose levels of 180 and 360 mg of ACY-241. Acetyl-histone levels were low- moderate at the 160 and 180 mg dose level for ricolinosat and ACY-241, respectively, and for ACY-241 increased with increasing exposure at doses > 180 mg similar to results observed in vitro by immunoblot analysis of MM cells treated with ACY-241. In conclusion, the PK and PD results suggest that both ricolinostat and ACY-241 have reached a pharmacologically relevant level of HDAC inhibition as determined by acetylated tubulin and histone at the clinical dose levels examined. Citation Format: David L. Tamang, Jeffery Supko, Kailash Bhol, Catherine Wheeler, Simon S. Jones, Min Yang. Tubulin hyper-acetylation in blood lymphocytes: pharmacodynamic (PD) biomarker for the selective histone deacetylase (HDAC) 6 inhibitors ricolinostat and ACY-241 in multiple myeloma (MM) patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3958.