Growth Control in Multiple Myeloma

描述（由申请人提供）：目前在其第10年的资金，这P01的目标是实现持久的生长控制多发性骨髓瘤（MM）通过高度整合的转化研究进行的临床和基础科学家。 总体假设是骨髓微环境（ME）的各种成分通过提供（以MM基因型特异性方式）过多的存活和增殖信号而导致最终治疗失败，并且新的治疗策略，共失能MM和ME，将增强生长控制。通过联合自体移植支持的高剂量美法仑和共同靶向MM和ME的治疗，将采用治疗策略以最大限度地实现持续完全缓解。新的免疫方法旨在通过癌症/睾丸抗原疫苗接种和采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应答。基因表达谱（GEP）应改善预后模型，并确定，与项目4，参与MM和ME之间的致病性串扰的基因。由于可溶性syndecan-1具有生物素捕获特性，研究将确定是否阻断硫酸乙酰肝素功能或其生物利用度可能抑制肿瘤生长和传播。为了成功地实施这些项目，需要4个核心：A）管理，数据管理，和生物统计学; B）功能成像; C）分子遗传学;和D）细胞分析/组织建库。 在假设驱动的临床试验环境中接受治疗并进行全面随访的大型MM患者人群中，该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.