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 五十岁以上男性死亡。骨是 CaP 进展患者的主要转移部位 超越器官限制。转移性 CaP 缺乏治愈性疗法强调了以下必要性： 开发用于治疗药物的靶向递送以及新颖治疗的创新技术 有效且毒性最小的策略。我们的调查团队致力于解决以下问题的不同方面 通过高度整合和集中的研究工作，CaP 骨转移将增强我们的研究成果 了解 CaP 进展的机制并改进根除治疗策略 骨转移并防止复发。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，即来自终末期的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。随后的研究证实 MDA-9 是癌症的关键促进剂 侵袭和转移，而 MDA-7/IL-24 被认为是一种广谱抗癌治疗药物。 使用新开发的 CaP 骨转移同基因临床前模型，我们将研究两者之间的相互作用 CaP 骨转移与 MDA-9 协调的骨生态位之间的关系，并评估其治疗活性 “一流”的 MDA-9 小分子抑制剂（即 PDZ1i），用于靶向转移性 CaP 细胞和骨 利基。利用T细胞的精湛能力和高效率来定位和消灭播散性癌症 细胞，特别是那些通常无法进入的部位，即骨骼，我们将改造 CaP 反应性 T 细胞来产生 MDA-7/IL-24，一种独特的癌症选择性细胞凋亡诱导细胞因子，可提高潜在攻击能力 抗原异质性骨转移。最后，基于PDZ1i重编程免疫生态位的能力 在肿瘤微环境中，我们将结合工程化 T 细胞产生下一代 MDA-7/IL-24 （“Superkine MDA-7/IL-24”、“S7M”），具有增强的分泌和稳定性，结合 MDA-9 靶向治疗 协同消除 CaP 骨病变。我们预计从这些研究中获得的见解将 能够更精确地分子了解骨转移发展，以发现目标、合理 改进的细胞免疫疗法的设计以及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 提供将这些技术和策略转化为临床以安全有效地管理的快速途径 这是 CaP 最常见的骨骼并发症。