Growth Control in Multiple Myeloma

描述(申请人提供)：目前，P01‘S的资助已进入第10个年头，其目标是通过临床和基础科学家进行的高度整合的转化研究，实现多发性骨髓瘤(MM)的持久生长控制。总的假设是，骨髓微环境(ME)的各种成分通过(以MM基因型特有的方式)提供过多的生存和增殖信号而导致最终的治疗失败，而将MM和ME结合在一起的新治疗策略将加强对生长的控制。通过结合自体移植支持的大剂量马法兰和共同针对MM和ME的治疗，将采用治疗策略来最大限度地实现持续的完全反应。新的免疫治疗方法旨在通过接种癌症/睾丸抗原疫苗和使用同种异体自然杀伤细胞和细胞毒性T淋巴细胞来增强自体宿主的反应。基因表达谱分析(GEP)应该改进预后模型，并与项目4相结合，识别与MM和ME之间的致病串扰有关的基因。由于可溶性Syndecan-1具有捕捉细胞因子的特性，研究将确定阻断硫酸乙酰肝素的功能或其生物利用度是否可以抑制肿瘤的生长和扩散。为了成功地实施这些项目，需要4个核心：A)行政、数据管理和生物统计学；B)功能成像；C)分子遗传学；以及D)细胞分析/组织银行。由于可以接触到大量MM患者，这些患者在假设驱动的临床试验环境中接受治疗，并进行全面的随访，这一P01将阐明疾病发展/进展的分子和生物学机制，以及目前维持完全缓解的障碍。

DESCRIPTION (provided by applicant): Currently in its 10th year of funding, this P01's objective is to achieve durable growth control in multiple myeloma (MM) through highly integrated translational research conducted by clinical and basic scientists. The overall hypothesis will be pursued that various components of the bone marrow microenvironment (ME) contribute to eventual treatment failure by providing (in a MM genotype-specific manner) a plethora of survival and proliferation signals, and that novel therapeutic strategies, coincapacitating MM and ME, will augment growth control. Through a combination of autotransplantsupported high-dose melphalan and therapies that co-target MM and ME, therapeutic strategies will be employed to maximize sustained complete responses. Novel immunotherapeutic approaches are aimed at augmenting autologous host responses via cancer/testis antigen vaccination and employing allogeneic natural killer cells and cytotoxic T lymphocytes. Gene expression profiling (GEP) should improve prognostic models and identify, in concert with Project 4, genes involved in pathogenetic cross talk between MM and ME. Because soluble syndecan-1 has cytokine-trapping properties, studies will determine if blocking heparan sulfate function or its bioavailability may inhibit tumor growth and dissemination. To successfully implement these Projects, 4 Cores are required: A) Admin., Data Mgmt., and Biostatistics; B) Functional Imaging; C) Molecular Genetics; and D) Cell Analysis/Tissue Banking. With access to a large patient population with MM, treated in a hypothesis-driven clinical trial setting with comprehensive follow-up, this P01 will shed light on the molecular and biological mechanisms of disease development/ progression and the current obstacles to sustaining complete remission.