Growth Control in Multiple Myeloma

描述（由申请人提供）：目前是其资助的第10个年头，该P01的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。总体假设是，骨髓微环境（ME）的各种成分通过（以MM基因型特异性的方式）提供过多的生存和增殖信号，从而导致最终的治疗失败，而新的治疗策略，同时激活骨髓微环境和ME，将增强生长控制。通过自体移植支持的大剂量美法兰和联合靶向MM和ME的治疗，治疗策略将被用来最大化持续的完全缓解。新的免疫治疗方法旨在通过癌症/睾丸抗原疫苗接种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反应。基因表达谱（GEP）应该改善预后模型，并与项目4一起识别参与MM和ME之间致病串扰的基因。由于可溶性syndecan-1具有细胞因子捕获特性，研究将确定阻断硫酸肝素的功能或其生物利用度是否会抑制肿瘤的生长和传播。要成功实施这些项目，需要4个核心：A)管理。数据管理生物统计学；B)功能成像；C)分子遗传学；D)细胞分析/组织库。该P01纳入了大量MM患者群体，在假设驱动的临床试验环境中进行治疗，并进行了全面的随访，将揭示疾病发展/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.