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Although transplanted mice treated with full dose single agent bortezomib, vorinostat or panobinostat showed no response and died within three weeks post transplant, recipient mice treated with bortezomib in combination with either vorinostat or panobinostat achieved complete response and are still alive 10 weeks post-transplant. ![]() Based on this promising single agent activity, we sought to model the effects of combination therapy in the secondary myeloma models that we specifically generated to be bortezomib refractory or multidrug resistance. From this study, the most promising class of novel agents in clinical trials are the HDAC inhibitors vorinostat and panobinostat. ![]() Using the primary MM model, we have assessed the anti-myeloma activity of 30 known and novel compounds, many of which currently in clinical trials, and found that agents effective in the treatment of patients are active in this model, whereas agents ineffective in the treatment of patients are not. Furthermore, this model offers the advantage of studying both indolent, BM localized, untreated MM (primary MM), and, with the use of transplants into syngeneic hosts, advanced, more proliferative and refractory disease (secondary MM). The immuno-competent Vk*MYC mouse model of myeloma has already demonstrated high biological fidelity to the human disease, making it an ideal model to study the behavior of myeloma cells in the context of a native microenvironment and immune system. However, once again this in-vitro model does not capture the complete biology of human MM. 3) Direct cytotoxic studies on primary patients cells, alone or in co-culture with stroma cell lines, are useful in assessing a pro-apoptotic activity in a way that is completely independent on proliferation. Drug screenings performed on both these models tend inevitably to overestimate the antimyeloma activity of compounds that simply inhibit proliferation, but are ineffective in targeting the bulk of MM tumor. 2) Xenograft studies, in which HMCLs are injected into immunodeficient mice, serve the purpose of demonstrating that in-vivo target inhibition can be achieved under physiological conditions, but again fail to represent the indolence of human MM and its complex interaction with the BM stromal cells. On the other hand, they are highly proliferative and do not recapitulate the complexity of the human disease in an endogenous micro-environment. The most commonly utilized are: 1) Human myeloma cell lines (HMCLs) offer the advantage of being easily manipulated and well genetically characterized and therefore are best used to provide in-vitro target validation and to demonstrate specific target inhibition by a drug. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent onĮxpression, that drives the progression of monoclonal gammopathy to MM.Several preclinical models are available to assess the efficacy of novel anti-myeloma therapies, each of them with specific utilities. Moreover, we identified frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. We observed recurrent copy number alterations, structural variations, chromothripsis, driver mutations, APOBEC mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Here, we profile the genomic landscape of 118 genetically engineered Vk*MYC MM and reveal that it recapitulates the genomic heterogenenity and life history of human MM. MM mouse models represent an opportunity to overcome this temporal limitation. Clincal efforts designed to deconvolute such mechanisms are challenged by the long lead time between monoclonal gammopathy and its transformation to MM. ![]() Despite advancements in profiling multiple myeloma (MM) and its precursor conditions, there is limited information on mechanisms underlying disease progression.
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