Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma

Abstract

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

“…This includes PC neoplasia restricted to the BM, bone destruction, and monoclonal gammopathy (28). Vk*MYC mice were shown to respond to most of the conventional antimyeloma drugs and thus represent a valuable preclinical tool to test new MM therapies in immune-competent hosts (30,31).…”

Manipulation of B-cell responses with histone deacetylase inhibitors

“…We next investigated whether panobinostat could be used to eliminate auto-antibody-producing plasma cells using the MRL/lpr mouse autoimmunity model that exhibits systemic immune activation and auto-antibody production 37 . Groups of MRL/lpr mice 12-13 weeks old were treated daily with a reduced dose of panobinostat compared with preclinical studies with multiple myeloma 38 . Mice were monitored daily by a researcher masked to treatment groups and consistent with the recent panobinostat clinical trials 39 , no adverse effects were noted on the general wellbeing of mice.…”

A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

“…59 Thus, the MOAs of HDACIs (eg, Bim upregulation) and BH3 mimetics (eg, unleashing Bim from Bcl-2/Bcl-xL) provide a specific rationale for combining these two classes of agents. Although we and other groups have described synergistic interactions between HDACIs and BH3 mimetics in various hematopoietic malignant cells, 29,[60][61][62] the ability of such a Bim-targeting strategy to re-prime bortezomibresistant MM cells toward death has not previously been examined. Significantly, HDACIs, particularly when combined with BH3 mimetics, increased Bim expression and sharply increased BH3-mimetic lethality in bortezomib-resistant cells.…”