Developmental Therapeutics Research Program

发育治疗研究计划

• 批准号: 10380717
• 负责人: John James Letterio
• 金额: $ 5.51万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380717
• 关键词: AML/MDS; ATP phosphohydrolase; Address; Advanced Malignant Neoplasm; Apoptosis; Azacitidine; BCL2 gene; BH4 Domain; Back; Base Excision Repairs; Biological Markers; Biotechnology; Brain; Breast; Cancer Biology; Cancer Center; Cancer Center Support Grant; Cancer Patient; Cancer Therapy Evaluation Program; Catchment Area; Clinical; Clinical Research; Clinical Trials; Collaborations; Colon; Comprehensive Cancer Center; Creativeness; Cytometry; DNA Repair; DNA Repair Inhibition; Decitabine; Development; Developmental Therapeutics Program; Differentiation Therapy; Direct Costs; Disease; Drug Kinetics; Drug resistance; Drug resistance pathway; Drug usage; Effectiveness; Epidermal Growth Factor Receptor; Epigenetic Process; Funding; Gene Mutation; Genetic; Genetic Markers; Genomics; Goals; Grant; Growth; Hand; Hematopoietic; Image; Immune; Laboratories; Leadership; Link; Malate Dehydrogenase; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mentors; Mutation; New Agents; Non-Small-Cell Lung Carcinoma; Oral; Outcome; Ovary; Oxidoreductase; Pancreas; Pathway interactions; Peer Review; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Program Research Project Grants; Protein Phosphatase 2A Regulatory Subunit PR53; Proteomics; Protocols documentation; Publications; Publishing; RNA Splicing; Radiation; Relapse; Research Personnel; Research Project Grants; Resistance; Resource Sharing; Role; SMARCA5 gene; Sampling; Scientist; Series; Solid Neoplasm; System; TP53 gene; TP53-mutant acute myeloid leukemia; Tetrahydrouridine; Therapeutic; Therapeutic Human Experimentation; Training; Transforming Growth Factor beta; Uracil; Validation; Work; advanced breast cancer; analog; anticancer activity; cancer cell; cancer drug resistance; cancer genetics; cancer immunotherapy; clinical development; combinatorial; drug development; drug discovery; early phase clinical trial; early phase trial; first-in-human; glycogen synthase kinase 3 beta inhibitor; immune checkpoint; improved; inhibitor; lung small cell carcinoma; member; methoxyamine; molecular marker; molecular targeted therapies; new therapeutic target; novel; novel strategies; novel therapeutics; nucleoside analog; nucleotide metabolism; patient derived xenograft model; phase II trial; pre-clinical; pre-clinical assessment; pre-clinical research; preclinical development; preclinical study; programs; pyrimidine metabolism; response; tumor; working group

DEVELOPMENTAL THERAPEUTICS (DT) RESEARCH PROGRAM PROJECT SUMMARY/ABSTRACT The Developmental Therapeutics (DT) Research Program develops and evaluates novel therapeutics and combinations that: 1) overcome drug resistance of cancer cells mediated by a spectrum of genetic and epigenetic mechanisms; 2) inhibit growth and drug-resistant pathways of cancer; and 3) utilize novel immune checkpoint therapeutics to increase the proportion of cancer patients who benefit. The overall approach of the DT Program is to leverage the creativity and expertise of basic scientists in the Case Comprehensive Cancer Center (Case CCC) Programs by analyzing new agents for specific validated molecular targets and new therapeutic compounds for preclinical and clinical validation in early-phase clinical trials. DT members guide their development, and convey clinical samples back to laboratory investigators to drive further discovery. This bidirectional interchange enables DT's continued role as a major convener of new therapeutic concepts for the Center’s Programs. The program is organized around 3 scientific aims: (1) Interrogate cancer pathways to develop new efficacious therapeutics; (2) Implement early-phase clinical trials around novel pathway targets, new agents and combinatorial approaches; and (3) Implement early-phase trials around novel approaches to cancer immunotherapies, to widen their activity spectra. These aims reflect major working groups and initiatives that coalesces program members with other cancer center investigators through inter-programmatic collaborations that result in preclinical and clinical research efforts, grants, and trial protocols. Extensive use of an array of shared resources, in particular Translational, Cytometry, Imaging, Proteomics, and Drug Discovery facilitate all aspects of member discoveries. Under the leadership of Yogen Saunthararajah (Co-Leader) and John Letterio (Co-Leader) the DT Program has 52 members including 18 full, 5 associate and 29 clinical members representing 21 different departments across the consortium. Members are funded by a total of $12.5M in research grant funding (annual direct costs), of which $5.1M is peer-reviewed and $2.9M is NCI-funded. Between 2012 and 2016, DT program members published 1,012 publications. Cancer and program related publications included 35% inter- programmatic, 25% intra-programmatic, 14% inter- and intra-programmatic and 10% that involved collaborations with another Cancer Center. This highly effective Program has made major practice-changing contributions benefiting cancer patients. Examples include: discoveries of first-in-class compounds (SMARCA5 inhibitor, PP2A activator, malate dehydrogenase inhibitor, base excision repair target with methoxyamine); discoveries targeting EGFR resistance, inhibition of uracil glycosylase and the inhibition of the BH4 domain of Bcl-2; analysis into the genetic markers of resistance to radiation; and identification of several small cell lung cancer genetic subsets. !

药物治疗（DT）研究 项目总结/摘要 发展治疗学（DT）研究计划开发和评估新的治疗方法， 组合物，其：1）克服由一系列遗传和免疫调节因子介导的癌细胞的耐药性， 表观遗传机制; 2）抑制癌症的生长和耐药途径;和3）利用新的免疫 检查点疗法，以增加受益的癌症患者的比例。而采取的总体做法 DT计划是利用基础科学家的创造力和专业知识， 中心（案例CCC）通过分析新药物的特定验证分子靶点和新的 在早期临床试验中进行临床前和临床验证的治疗化合物。DT会员指南 他们的发展，并传达临床样本回到实验室研究人员推动进一步的发现。这 双向交换使DT能够继续作为新治疗概念的主要召集人， 中心的方案。该计划围绕3个科学目标组织：（1）询问癌症途径， 开发新的有效疗法;（2）围绕新的途径靶点开展早期临床试验， 新药物和组合方法;（3）围绕新方法进行早期试验， 癌症免疫疗法，以扩大其活性谱。这些目标反映了各主要工作组和 通过跨项目将项目成员与其他癌症中心研究人员联合起来的举措 合作，导致临床前和临床研究工作，赠款和试验方案。广泛使用 一系列共享资源，特别是翻译，细胞测量，成像，蛋白质组学和药物发现 促进成员发现的各个方面。 在Yogen Saunthararajah（联合领导人）和John Letterio（联合领导人）的领导下，DT计划 有52名会员，包括18名正式会员、5名副会员及29名临床会员，分别代表21个不同部门 整个财团。成员由总计1250万美元的研究补助金资助（每年直接 成本），其中510万美元是同行评审，290万美元是NCI资助。在2012年至2016年期间，DT计划 会员出版了1，012份出版物。癌症和计划相关的出版物包括35%的跨- 方案内25%，方案间和方案内14%， 与其他癌症中心合作。这一卓有成效的方案使实践发生了重大变化， 帮助癌症患者。例子包括：发现一流的化合物 （SMARCA 5抑制剂、PP 2A激活剂、苹果酸脱氢酶抑制剂、碱基切除修复靶标， 甲氧胺）;靶向EGFR抗性、抑制尿嘧啶糖基化酶和抑制尿嘧啶糖基化酶的发现。 Bcl-2的BH 4结构域;辐射抗性遗传标记的分析;几种辐射抗性基因的鉴定 小细胞肺癌基因亚型。 !