11 Prostate Cancer

项目总结/摘要 前列腺癌计划（PCaP）由来自16个国家的50名成员（30名主要成员，18名副成员，2名辅助成员）组成。 部门该计划由国际公认的医学博士Christopher J. Logothetis领导 肿瘤学家，并由蒂莫西·C.汤普森，一个实验室科学家，和菲利普詹科蒂，一个 有成就的物理学家兼科学家PCaP的主要科学目标是建立在我们对 前列腺癌，以开发更有效的治疗和提高护理标准。该计划是有组织的 围绕3个主题：1）进展和预测的生物标志物; 2）靶向免疫和非免疫 微环境的成分，包括免疫成分;和3）靶向癌细胞信号传导。 每个主题都有一个具体的目标。目的1：开发血液、尿液和肿瘤组织的新检测方法 预测肿瘤复发、进展以及对现有和新疗法的敏感性或抗性。目标二： 了解肿瘤细胞与宿主的相互作用，并将这些知识转化为新的 针对微环境的治疗方法。目的3：用靶向前列腺癌细胞信号转导 新的单一药剂和顺序或同时使用的药剂组合。一年一度的Peer- 审查的资金总额为3，693，347美元，包括前列腺癌孢子，2，204，086美元（60%）来自NCI 赠款。自上次提交以来，该计划已撰写了350篇发表的论文，其中183篇（52%）是内部的。 其中112项（32%）是方案间合作，245项（70%）是外部合作。百分之四十九 的出版物出现在IF >5的期刊上，23%出现在IF >10的期刊上，包括Cancer Cell， Lancet Oncol，Proc Natl Acad Sci USA，Nature，N Engl J Med，Cell，Nat Genet，J Natl Cancer Inst，Sci Transl Med和J Clin Oncol.计划成员使用所有14个共享资源。在过去六年，《行动纲领》已： 发现了预测对第二代的反应性或初始/获得性抗性的生物标志物 雄激素受体信号传导抑制剂; 2）确定与“侵袭性变异”前列腺相关的生物标志物 在临床和协同临床模型中预测对基于铂的组合的响应的癌症表型; 3） 发现了前列腺癌中的免疫治疗靶点（例如，VISTA），其在T细胞和抗原- 递呈细胞，包括巨噬细胞; 4）与免疫检查点相关的髓源性抑制细胞 前列腺癌中的阻断抗性; 5）将FGF鉴定为前列腺癌中的靶点，提供了一种机制， VEGFR和c-met抑制剂卡博替尼的作用; 6）阐明了VEGFR和c-met抑制剂卡博替尼之间的串扰的影响。 PI 3 K/AKT/mTOR信号在调节前列腺癌靶向治疗效果中的作用; 7）鉴定的前列腺 通过雄激素受体介导的BRCAness调节PARP抑制剂的癌症易感性;和8）鉴定 癌症诱导的内皮细胞向具有成骨细胞功能的细胞的转变，并将其与骨相关联 转移

PROJECT SUMMARY/ABSTRACT The Prostate Cancer Program (PCaP) consists of 50 members (30 primary, 18 associate, 2 adjunct) from 16 departments. The program is led by Dr. Christopher J. Logothetis, an internationally recognized medical oncologist, and co-led by Drs. Timothy C. Thompson, a laboratory scientist, and Filippo Giancotti, an accomplished physician-scientist. The major scientific goal of the PCaP is to build on our understanding of prostate cancer to develop more effective treatment and improve standard of care. The program is organized around 3 themes: 1) Biomarkers for Progression and Prediction; 2) Targeting the Immune and Non-immune Components of the Microenvironment, including the immune component; and 3) Targeting Cancer Cell Signaling. Each theme is addressed by a specific aim. Aim 1: To develop new tests from blood, urine, and tumor tissues that predict tumor recurrence, progression, and sensitivity or resistance to existing and novel therapies. Aim 2: To understand tumor cell-host interactions and translate this knowledge into the development of novel therapeutic approaches targeting the microenvironment. Aim 3: To target prostate cancer cell signaling with novel single agents and with combinations of agents used sequentially or concurrently. The annual direct peer- reviewed funding totals $3,693,347, including a Prostate Cancer SPORE, and $2,204,086 (60%) is from NCI grants. Since the last submission, the program has authored 350 published papers, of which 183 (52%) are intra- programmatic, 112 (32%) are inter-programmatic, and 245 (70%) are external collaborations. Forty-nine percent of publications appeared in journals with IF >5 and 23% appeared in journals with IF >10, including Cancer Cell, Lancet Oncol, Proc Natl Acad Sci USA, Nature, N Engl J Med, Cell, Nat Genet, J Natl Cancer Inst, Sci Transl Med, and J Clin Oncol. Program members use all 14 shared resources. Over the past 6 years, the PCaP has 1) discovered biomarkers that predict responsiveness or initial/acquired resistance to the second-generation androgen receptor signaling inhibitors; 2) identified biomarkers associated with the “aggressive variant” prostate cancer phenotype that predict response to platinum-based combinations in clinical and co-clinical models; 3) discovered immunotherapy targets in prostate cancer (e.g., VISTA) that are expressed on T cells and antigen- presenting cells, including macrophages; 4) linked myeloid-derived suppressor cells with immune checkpoint blockade resistance in prostate cancer; 5) identified FGF as a target in prostate cancer, providing a mechanism of action for the VEGFR and c-met inhibitor cabozantinib; 6) elucidated the impact of cross-talk between PI3K/AKT/mTOR signaling in regulating efficacy of targeted therapy for prostate cancer; 7) identified prostate cancer vulnerability to PARP inhibitors regulated by androgen inhibitor-mediated BRCAness; and 8) identified cancer-induced transition of endothelial cells to cells with osteoblastic function and associated them with bone metastases.