RATIONAL DESIGN OF PROSTATE-SPECIFIC MEMBRANE ANTIGEN DNA VACCINES

前列腺特异性膜抗原 DNA 疫苗的合理设计

• 批准号: 7550451
• 负责人: POLLY D. GREGOR
• 金额: $ 28.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7550451
• 关键词: Adjuvant; Androgen Receptor; Animal Model; Animals; Ansamycin Antineoplastic Antibiotic; Antibodies; Antigen Presentation; Antigen Presentation Pathway; Antigens; Area; Autoantigens; Binding; Biological Markers; Biology; Biometry; Biopsy Specimen; British; CD4 Positive T Lymphocytes; Cells; Classification; Clinical Data; Clinical Trials; Combined Vaccines; Commit; Core Facility; DNA; DNA Vaccines; Data; Development; Diagnostic; Differentiation Antigens; Disease; Disseminated Malignant Neoplasm; Dose; Down-Regulation; ERBB2 gene; Epitopes; Funding; Generations; Glutamate Carboxypeptidase II; Goals; HLA A*0201 antigen; Hormones; Human; Image; Immune; Immune response; Immunization; Immunologic Adjuvants; Immunologics; Immunology; Immunotherapy; Institution; Interleukin-12; Invasive; Investigation; Knockout Mice; Laboratories; Lead; Local Therapy; Localized; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of prostate; Memorial Sloan-Kettering Cancer Center; Metastatic Prostate Cancer; Modification; Molecular Genetics; Morbidity - disease rate; Mutate; Mutation; Neoplasm Metastasis; Patient observation; Patients; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Phase I Clinical Trials; Population; Positioning Attribute; Preclinical Testing; Prostate; Prostatic; Proteins; Recruitment Activity; Reproduction spores; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resistance; Rifabutin; Scientist; Selection for Treatments; T-Lymphocyte; TNFRSF5 gene; TP53 gene; Therapeutic Intervention; Tissue Microarray; Translational Research; Tumor Immunity; Vaccines; Work; base; carcinogenesis; career; cohort; cytokine; design; dosage; experience; hormone refractory prostate cancer; human disease; immunogenic; improved; men; mortality; mouse model; multidisciplinary; novel diagnostics; novel therapeutics; outcome forecast; pre-clinical; preclinical study; predictive modeling; prevent; programs; response; tumor; tumor progression

DESCRIPTION (provided by applicant): The MSKCC SPORE in Prostate Cancer, initially funded in 2001, focused on four broad translational research goals: (1) to develop better predictive models of prognosis for localized prostate cancer incorporating validated molecular markers to improve treatment selection; (2) to identify critical molecular and genetic mechanisms of prostate carcinogenesis, progression, and metastasis; (3) to develop PSMA- targeted DMA vaccines for men with rising PSA after local therapy; and (4) to develop new mechanism- based drugs for castrate-resistant metastatic cancers. With strong support from the SPORE and our institution, we have made considerable progress. We have completed a long-term study of watchful waiting in a large British cohort and have collected diagnostic biopsy specimens as tissue microarrays for marker analyses. We have created more than a dozen new animal models of prostate cancer that mimic the human disease, and identified and validated predictive molecular markers. We have documented the efficacy of a PSMA DNA vaccine in a phase 1 clinical trial. And we have demonstrated that Hsp90 targeted therapy with ansamycin degrades the androgen receptor and is active against castrate metastatic prostate cancer. We now have in place an experienced, productive multidisciplinary team of investigators committed to translational research in prostate cancer, a large patient population amenable to participation in clinical trials, and superb infrastructure to support such trials. With a large cadre of scientists exploring the biology of prostate cancer and developing new therapeutic strategies, we have a healthy pipeline of new ideas ripe for investigation as diagnostic and therapeutic interventions. In preparing our SPORE for the next cycle, we have retained the overall objectives and the four major research projects, which function as flexible, multidisciplinary programs where we are able to shift emphasis to the most promising areas of research within the framework of original goals as new information emerges. We have added one new project, Checkpoint Blockade in Immunotherapy of Prostate Cancer, by James Allison, recently recruited here as Chair of Immunology. We will retain five cores (Biospecimen, Biostatistics, Animal Models, Animal Imaging, and Administration) and discontinue the DNA Array Core, replaced by the MSKCC core facility. Career Development has successfully recruited four new translational investigators to our SPORE, and Developmental Research has funded ten pilots with over $1.8 million in additional institutional support, several of which have achieved independent funding. Our investigators collaborate successfully with other SPOREs in Prostate Cancer and institutions and they have been among the leaders in inter-SPORE clinical trials and the pilot National Biorepository Network. With continued support the MSKCC SPORE is well positioned to move novel diagnostic and therapeutic interventions rapidly from the laboratory to the human disease with the goal of reducing morbidity and mortality from prostate cancer.

描述（由申请人提供）：前列腺癌 MSKCC SPORE 最初于 2001 年资助，重点关注四个广泛的转化研究目标：(1) 开发更好的局限性前列腺癌预后预测模型，结合经过验证的分子标志物以改善治疗选择； (2) 确定前列腺癌发生、进展和转移的关键分子和遗传机制； (3) 为局部治疗后 PSA 升高的男性开发 PSMA 靶向 DMA 疫苗； (4)开发针对去势抵抗性转移癌的新机制药物。在SPORE和我们机构的大力支持下，我们取得了长足的进步。我们已经在英国大型队列中完成了一项观察等待的长期研究，并收集了诊断活检标本作为组织微阵列用于标记分析。我们创建了十多种模拟人类疾病的新前列腺癌动物模型，并鉴定和验证了预测分子标记。我们已经在一期临床试验中记录了 PSMA DNA 疫苗的功效。我们已经证明，安莎霉素 Hsp90 靶向治疗可降解雄激素受体，并且对去势转移性前列腺癌具有活性。我们现在拥有一支经验丰富、富有成效的多学科研究团队，致力于前列腺癌的转化研究，有大量愿意参与临床试验的患者群体，以及支持此类试验的一流基础设施。随着一大批科学家探索前列腺癌的生物学并开发新的治疗策略，我们拥有了一系列健康的新想法，可供研究作为诊断和治疗干预措施。在为下一个周期准备 SPORE 时，我们保留了总体目标和四个主要研究项目，这些项目作为灵活的多学科计划，随着新信息的出现，我们能够将重点转移到原始目标框架内最有前途的研究领域。我们增加了一个新项目，即前列腺癌免疫治疗中的检查点封锁，由 James Allison 负责，他最近被任命为免疫学系主任。我们将保留五个核心设施（生物样本、生物统计学、动物模型、动物成像和管理），并停止使用 DNA 阵列核心设施，并由 MSKCC 核心设施取代。职业发展已成功为我们的 SPORE 招募了四名新的转化研究者，发展研究已为 10 名试点项目提供了超过 180 万美元的额外机构支持，其中一些项目已获得独立资助。我们的研究人员与前列腺癌和机构中的其他 SPORE 成功合作，他们一直是 SPORE 间临床试验和国家生物样本库网络试点的领导者之一。在持续的支持下，MSKCC SPORE 完全有能力将新型诊断和治疗干预措施从实验室快速转移到人类疾病，以降低前列腺癌的发病率和死亡率。