Proteasome/HDAC Inhibition in Leukemia/MDS; Phase I Trial and Correlative Studies

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DESCRIPTION (provided by applicant): The central goal of this GO RC2 application is to leverage the collective resources of three institutions (VCU/Massey Cancer Center, MD Anderson Cancer Center, H. Lee Moffitt Cancer Center) and various associated support mechanisms (i.e., R01, P01, N01, and SPORE) to conduct a mechanism-based Phase I trial of the histone deacetylase inhibitor (HDACI) belinostat (PXD-101) and the proteasome inhibitor (PI) bortezomib in patients with refractory AML, high-risk MDS, CML-blast crisis, and ALL. The second goal is to perform correlative laboratory studies to test the adequacy of methods for monitoring candidate surrogate markers that may predict for disease responsiveness and help to define mechanisms of resistance to this regimen in future efficacy-based trials (e.g., Phase II). Previous studies from our laboratories documented pronounced synergism between HDACIs and PIs in malignant hematopoietic cells, including human leukemia cells. Mechanisms responsible for synergistic interactions are likely to be multi-factorial, including PI-mediated inhibition of HDACI-induced NF-:B activation, down-regulation of NF-:B-dependent anti-apoptotic proteins (Bcl-xL, XIAP), HDACI-mediated up-regulation of Bim, and disruption of aggresome function. In addition, evidence suggests that HDACIs disrupt proteasome function, raising the possibility that combined treatment with these agents may result in enhanced proteasome inhibition. Notably, recent preclinical evidence from our laboratories indicates that very low (e.g., nM) concentrations of belinostat and bortezomib interact in a highly synergistic manner in cultured and primary AML blasts to induce apoptosis in association with diminished nuclear p65/RelA localization, down-regulation of NF-:B-dependent proteins (Bcl-xL and XIAP), and up- regulation of Bim. Despite this preclinical evidence, a strategy combining HDACIs with PIs has not yet been evaluated in AML, MDS, and related acute leukemias. Specific Aim #1 of this proposal is to conduct a Phase I trial of belinostat given IVP days 1-5 and 8-12 of a 3-wk schedule in conjunction with bortezomib given IVP twice weekly x two weeks and to identify the RPTD (recommended Phase II doses) for future Phase II trials. Secondary aims are to identify the dose-limiting toxicities of this regimen, and to gain preliminary insights into the potential therapeutic efficacy of this strategy. Specific Aim #2 of this proposal is to test the adequacy of methods for monitoring candidate correlative pharmacodynamic determinants in leukemic blast cells prior to and 24 hr after treatment with belinostat/bortezomib, focusing on events observed in vitro in preclinical studies e.g., diminished p65/RelA nuclear localization by digitized fluorescence microscopy; Bcl-xL/XIAP down- regulation and Bim up-regulation by Western blot analysis; and inhibition of 20S proteasome activity. The successful conduct of this trial and performance of correlative laboratory studies could serve as a prototype for future partnerships between the NCI, academia, and the pharmaceutical industry in the development of novel, mechanism-based anti-cancer therapeutic strategies involving two or more investigational agents. PUBLIC HEALTH RELEVANCE: Acute myelogenous leukemia and related diseases (myelodysplasic syndrome, acute lymphocytic leukemia, chronic myelogenous leukemia in blast crisis) are responsible for significant morbidity and mortality. If successful, the current proposal could lead to the development of a new and potentially more effective treatment strategy for these diseases, and could also help to identify laboratory correlates that might predict for disease responsiveness in individual patients.