Translational Research in Multiple Myeloma

描述（由申请人提供）：除了同种异体移植外，多发性骨髓瘤仍然是一种无法治愈的疾病，因为它对细胞毒性药物具有泛抗性。不幸的是，大多数患者由于高龄、合并症或广泛的既往治疗而不适合同种异体移植。因此，需要新的方法来治疗这种疾病。该提案的目标是通过将有希望的策略从实验室转化为临床，开发新的骨髓瘤临床治疗方法，并使Huff博士成为多发性骨髓瘤领域的独立转化研究者。这一职业发展建议包括临床调查理论和方法的正式培训，在约翰霍普金斯大学公共卫生与卫生学院攻读健康科学硕士学位，同时在多发性骨髓瘤方面开展转化研究。

DESCRIPTION (provided by applicant): With the possible exception of allogeneic transplantation, multiple myeloma remains an incurable illness due to pan-resistance to cytotoxic agents. Unfortunately, most patients are ineligible for allogeneic transplantation due to advanced age, comorbid illness or extensive prior therapy. As such, novel approaches are needed to treat this disease. The objective of this proposal is to develop novel clinical treatments for myeloma by translating promising strategies from the laboratory into the clinic and to enable Dr. Huff to become an independent translational investigator in the field of multiple myeloma, included in this career development proposal is formal training in the theory and methods of clinical investigation working towards a Masters of Health Science degree at the Johns Hopkins School of Public Health and Hygiene concurrent with translational research initiatives in multiple myeloma. Clinical results suggest that the cytotoxic conditioning regimen used in allogeneic transplantation plays a limited role in controlling myeloma, while the immunologic anti-tumor effect associated with graft-versus-host appears to have strong anti-myeloma activity. As such, we are developing a new clinical trial, utilizing nonmyeloablative BMT for myeloma that will limit the toxicity of the conditioning regimen and highlight the allogeneic graft-versus-myeloma effect. Based on encouraging preliminary data from the laboratory, we plan to incorporate anti-myeloma vaccines into the post-transplant donor lymphocyte infusions that are a key component of non-myeloablative BMT. For many patients, even a nonmyeloablative allo BMT will not be possible. Thus, other treatment approaches are needed. Preliminary data from our laboratory suggest that cytokine-mediated differentiation is another possible strategy. There are a variety of growth factors and cytokines which have activity in myeloma. IL-6 appears to be the most important. Interferon- clearly has clinical anti-tumor activity in myeloma, although its role in the management of multiple myeloma remains controversial. Interferon's exact mechanism of action is unknown; one of its multiple effects, however, is an anti-proliferative activity through induction of a G1 cell cycle arrest. The net effect of growth factors and cytokines on malignant growth is determined by a balance of their pleiotropic effects on tumor cell self-renewal, survival, and differentiation. The preferential enhancement of tumor cell self-renewal and/or survival could hasten tumor progression; conversely, a predominant or selective induction of differentiation would exhaust the neoplastic clone. Our preliminary data demonstrate that agents, like interferon, that inhibit cell cycling preferentially enhance the differentiation effects of IL-6 against myeloma, as well as block its effects on tumor cell proliferation.