Interplay between tumor and microenvironment in bone metastasis

骨转移中肿瘤与微环境的相互作用

• 批准号: 10590697
• 负责人: PAUL B FISHER
• 金额: $ 46.15万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590697
• 关键词: Address; Adherence; Age; Androgens; Animal Model; Antigens; Autophagocytosis; Bone Marrow Cells; Cancer Etiology; Cell Communication; Cellular immunotherapy; Cessation of life; Clinic; Clinical; Complication; Comprehension; Data; Development; Diagnosis; Disease; Engineering; Environment; Genes; Goals; Hormones; Human; IL24 gene; Immune; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Induction of Apoptosis; Insulin-Like Growth-Factor-Binding Proteins; Interleukin-24; Invaded; Lesion; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Melanoma Cell; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modality; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Neoplasm Metastasis; Organ; Pathogenicity; Patients; Phenotype; Positioning Attribute; Pre-Clinical Model; Procedures; Process; Property; Prostate Cancer therapy; Proteins; Reagent; Research; Research Proposals; Role; STAT3 gene; Scheme; Signal Transduction; Site; Solid; T cell therapy; T-Cell Immunologic Specificity; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Translating; Tumor Immunity; Up-Regulation; Work; advanced prostate cancer; angiogenesis; anti-cancer; anti-cancer therapeutic; antiangiogenesis therapy; anticancer activity; anticancer research; bone; cancer cell; cancer diagnosis; carcinogenesis; combinatorial; conventional therapy; curative treatments; cytokine; effective therapy; efficacy evaluation; engineered T cells; immune checkpoint blockade; immunoregulation; improved; inhibitor; innovative technologies; insight; male; melanoma; men; metastatic process; molecular targeted therapies; mortality; mouse model; multidisciplinary; neoplastic cell; next generation; novel; novel therapeutics; pharmacologic; pre-clinical; programs; promoter; prostate cancer cell; prostate cancer metastasis; prostate cancer model; prostate cancer progression; rational design; receptor; relapse prevention; skeletal; small molecule; small molecule inhibitor; subtraction hybridization; success; synergism; targeted treatment; therapeutic target; treatment strategy; tumor; tumor microenvironment

Prostate cancer (CaP) is the most commonly diagnosed cancer and the second leading cause of cancer death in men over the age of fifty. Bone is the primary site of metastasis in patients whose CaP progresses beyond organ confinement. The absence of curative therapies for metastatic CaP emphasizes the imperative to develop innovative technologies for target-specific delivery of therapeutic agents as well as novel treatment strategies that are efficacious with minimal toxicity. Our investigative team seeks to address different aspects of CaP bone metastasis through a highly integrated and focused research effort that will enhance our comprehension of the mechanisms underlying CaP progression and improve therapeutic strategies to eradicate bone metastases and prevent relapse. Our early work using a subtraction hybridization screen identified two unique genes, i.e., melanoma differentiation associated gene-9 (mda-9) and mda-7/IL-24 from terminally differentiating human melanoma cells. Subsequent research established MDA-9 as a key promoter of cancer invasion and metastasis, whereas MDA-7/IL-24 was recognized as a broad-spectrum anti-cancer therapeutic. Using a newly developed syngeneic pre-clinical model of CaP bone metastasis, we will investigate the interplay between CaP bone metastases and the bone niche orchestrated by MDA-9 and evaluate therapeutic activity of ‘first-in-class’ small molecule inhibitor of MDA-9 (i.e., PDZ1i) for targeting both metastatic CaP cells and the bone niche. By exploiting the exquisite ability and high efficiency of T cells to locate and destroy disseminated cancer cells, especially those in normally inaccessible sites, i.e., bone, we will engineer CaP-reactive T cells to produce MDA-7/IL-24, a unique cancer-selective apoptosis-inducing cytokine, for improved capacity to attack potentially antigenically heterogenous bone metastases. Last, based on the ability of PDZ1i to reprogram the immune niche in the tumor microenvironment, we will combine engineered T cells producing next-generation MDA-7/IL-24 (“Superkine MDA-7/IL-24“, “S7M”), having enhanced secretion and stability, with MDA-9-targeted therapy for synergistic elimination of CaP bone lesions. We anticipate that the insights garnered from these studies will enable a more precise molecular understanding of bone metastasis development for target discovery, rational design of improved cellular immunotherapy, and combinatorial treatment modalities optimized to achieve a maximum therapeutic potential. Successful completion of this multidisciplinary, synergistic research program will provide a rapid path to translate these technologies and strategies into the clinic to safely and effectively manage this most common skeletal complication of CaP.

前列腺癌（CaP）是最常诊断的癌症，也是第二大癌症原因 50岁以上的男性死亡。骨是CaP进展患者转移的主要部位 超越了器官限制转移性CaP的治愈性疗法的缺乏强调了 开发创新技术，用于治疗剂的靶向特异性递送以及新型治疗 有效且毒性最小的策略。我们的调查小组寻求解决不同方面的问题， 通过高度整合和集中的研究工作，CaP骨转移，这将提高我们的 了解CaP进展的潜在机制，并改善治疗策略， 骨转移和防止复发。我们早期的工作使用减法杂交筛选确定了两个 独特的基因，即，黑色素瘤分化相关基因9（mda-9）和mda-7/IL-24 分化人类黑色素瘤细胞随后的研究确定MDA-9是癌症的关键启动子 而MDA-7/IL-24被认为是一种广谱的抗癌治疗剂。 我们将使用一个新开发的同基因的CaP骨转移临床前模型， 之间的钙磷骨转移和骨龛编排的MDA-9和评估的治疗活性 MDA-9的“一流”小分子抑制剂（即，PDZ 1 i）用于靶向转移性CaP细胞和骨 利基通过利用T细胞的精确能力和高效率来定位和摧毁扩散的癌症， 细胞，特别是那些在正常情况下不可接近的部位，即，我们将设计CaP反应性T细胞， MDA-7/IL-24，一种独特的癌症选择性凋亡诱导细胞因子，用于提高潜在的攻击能力 抗原性异种骨转移最后，基于PDZ 1 i重编程免疫生态位的能力， 在肿瘤微环境中，我们将联合收割机工程化T细胞产生下一代MDA-7/IL-24 （“Superkine MDA-7/IL-24”，“S7 M”），其具有增强的分泌和稳定性，与MDA-9靶向疗法用于 协同消除CaP骨损伤。我们预计，从这些研究中获得的见解将 能够更精确地从分子水平了解骨转移的发展， 设计改进的细胞免疫疗法和优化的组合治疗方式，以实现 最大的治疗潜力。成功完成这一多学科，协同研究计划将 提供了一条快速的途径，将这些技术和策略转化为临床，以安全有效地管理 最常见的骨骼并发症