Hababou says it’s the best way for him to find new prospects ahead of his competition. He represents the prestigious Marilyn agency in Paris. Her travelling companion, Stephane Hababou, watches the photos of would-be models scroll across the screen. Four times a year she crosses her native region by train searching for the next top models, the ones who will one day strut the catwalks of Paris or New York. She discovers new talents for the Noah Models agency in St. They are the result, she says, of years of mixed marriages by citizens from different republics of the former Soviet Union.Īnna is a scout. She wants to show her international visitor the many charms of Siberian beauties. Furthermore, the Vk*MYC model provides an excellent platform for the development of novel combinations aimed to the treatment of refractory MM disease.Anna Yuzhakova takes her laptop computer with her to the restaurant car. We conclude that the bortezomib + HDAC inhibitors is an active combination that overcomes in vivo bortezomib resistance. 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. Several preclinical models are available to assess the efficacy of novel anti-myeloma therapies, each of them with specific utilities.
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