15 Developmental Therapeutics

项目摘要/摘要 发展治疗计划(DTP)的中心主题是实践精确度原则 治疗，在恶性肿瘤的病理生理学中识别新的靶点，以开发阻断 它们的功能并将这些药物应用于恶性肿瘤患者的临床试验 标志着目标蛋白质或途径的存在或活性。该计划有47名成员(33名小学生 来自13个部门的14名助理)，由William Plunkett领导，他开发了多个反 实验室中的白血病药物；Funda Meric-Bernstam，领导第一阶段的内科科学家 朱利奥·德拉塔，一位在药物开发方面拥有丰富经验的内科科学家； 已经开发了多种靶向疗法的临床试验者詹姆斯·姚说。该计划围绕以下几个方面进行组织 4个主要主题：1)发现和确认新靶点，2)开发新疗法，3)实施 原则验证临床试验，以及4)罕见癌症治疗方法的开发。每个主题都是 通过一个特定的目标来解决。目标1：鉴定和验证与肿瘤分子生物学相关的新靶点 肿瘤；目标2：开发针对新靶点的药物；单独和联合治疗；目标3：至 用首例人类制剂或新的组合进行生物标记物驱动的试验；目标4：识别新的 罕见肿瘤的治疗方法。年度直接同行审查供资总额为10 284 482美元，其中2 839 686美元(28%) 来自NCI拨款，这是计划年度直接同行审查癌症相关资金的109% 自从上一次竞争性续签以来。自上次提交以来，DTP成员已撰写了1048份出版物： 454(43%)代表方案内协作，681(65%)代表方案间协作， 645个(62%)为机构间合作。59%的出版物出现在期刊上， IF&gt；5和23%出现在IF&gt；10的期刊上，包括血液，癌症细胞，癌症发现，细胞，JAMA，J Clin Invest、J Natl癌症研究所、J Clin Onol、柳叶刀、柳叶刀、摩尔细胞和自然。在最后一次拨款期间 期间，发现了几个新的靶点，包括肺癌中的miR-155，S阶段蛋白激酶相关的 蛋白2泛素连接酶，以及依赖氧化磷酸化生存的肿瘤的易感性。 重要的是，DTP成员已经发现了抑制这些靶标中每一个的新试剂，并且 目前正在开发中。新的代理商包括针对miR-155的那些，缺乏症，铂出口商在 卵巢癌、淋巴瘤中的Bly3、c-Kit、JAK2和STAT3。DTP成员已经确定了需要 氧化磷酸化促进了它们的生长，并创造了一种候选的抑制剂，目前正在进行临床试验。 与PI3K通路激活突变相匹配的药物将1期应答率从6%提高到27% 延长治疗失败前的时间。年首次化疗免疫治疗试验15年分析 以前未经治疗的慢性淋巴细胞性白血病显示了与首次治愈有关的预后因素(37%)， 指导单机构研究人员发起的纳入新靶向药物的试验的设计。

PROJECT SUMMARY/ABSTRACT The central theme of the Developmental Therapeutics Program (DTP) is to practice the principles of precision therapy, identifying new targets within the pathophysiology of a malignancy to develop novel agents that block their functions and apply these agents to clinical trials in patients whose malignancies exhibit the biomarkers signifying the presence or activity of the target protein or pathway. The program has 47 members (33 primary and 14 associate) from 13 departments and is led by William Plunkett, who has developed multiple anti- leukemic agents in the laboratory; Funda Meric-Bernstam, a physician-scientist who leads the phase 1 department; Giulio Draetta, a physician-scientist who has extensive experience in drug development; and James Yao, a clinical trialist who has developed multiple targeted therapies. The program is organized around 4 major themes: 1) Discovery and Validation of Novel Targets, 2) Development of Novel Therapies, 3) Conduct of Proof-of-Principle Clinical Trials, and 4) Development of Therapies for Rare Cancers. Each theme is addressed by a specific aim. Aim 1: To identify and validate novel targets relevant to the molecular biology of tumors; Aim 2: To develop agents against new targets individually and in combination therapies; Aim 3: To conduct biomarker-driven trials with first-in-human agents or novel combinations; and Aim 4: To identify novel therapies for rare tumors. Annual direct peer-reviewed funding totals $10,284,482, of which $2,839,686 (28%) is from NCI grants, which is an increase of 109% in program annual direct peer-reviewed cancer-related funding since the last competitive renewal. Since the last submission, DTP members have authored 1048 publications: 454 (43%) represent intra-programmatic collaborations, 681 (65%) represent inter-programmatic collaborations, and 645 (62%) were inter-institutional collaborations. Fifty-nine percent of publications appeared in journals with IF >5, and 23% appeared in journals with IF >10, including Blood, Cancer Cell, Cancer Discov, Cell, JAMA, J Clin Invest, J Natl Cancer Inst, J Clin Oncol, Lancet, Lancet Oncol, Mol Cell, and Nature. During the last grant period, several novel targets were identified, including miR-155 in lung cancer, S-phase kinase-associated protein 2 ubiquitin ligase, and the susceptibility of tumors that depend on oxidative phosphorylation for survival. Importantly, novel agents to inhibit each of these targets have been discovered by DTP members and are currently in development. New agents include those that target miR-155, deficiency, the platinum exporter in ovarian cancer, BLy3 in lymphoma, c-Kit, JAK2, and STAT3. DTP members have identified tumors that require oxidative phosphorylation for their growth and have created a candidate inhibitor that is presently in clinical trials. Drugs matched with activating mutations in the PI3K pathway increased phase 1 response rates from 6% to 27% and increased the time before treatment failure. The 15-year analysis of the first chemoimmunotherapy trial in previously untreated CLL revealed prognostic factors associated with the first cures of this disease (37%), guiding the design of single-institution investigator-initiated trials that incorporate new targeted agents.