NEW INVESTIGATOR TRAINING IN DRUG DEVELOPMENT

药物开发新研究者培训

• 批准号: 6378109
• 负责人: DAVID R SPRIGGS
• 金额: $ 10.33万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378109
• 关键词: arsenic; carboplatin; cis platinum compound; clinical research; drug design /synthesis /production; drug resistance; gemcitabine; human subject; human therapy evaluation; irinotecan; neoplasm /cancer chemotherapy; nuclear factor kappa beta; ovary neoplasms; paclitaxel; tirapazamine; topotecan; trimetrexate

DESCRIPTION: (Applicant's Description) The principal purpose of this proposal is to provide salary support for Dr. Spriggs and his career development activities in the area of patient oriented research. Dr. Spriggs currently mentors four young faculty members as well as three medical oncology fellow. He also has direct responsibility for one Gyn Fellow annually. The experimental hypothesis of Dr. Spriggs' own research research program is that drug resistance is controlled by regulation of gene expression. The transciptional regulation of resistance is based on data demonstrating the activation of NF-kB DNA binding is a common feature of acquired CDDP resistance in ovarian cancer. This resistance can be abrogated by specific therapeutic interventions. We are examining NF-kB activation and its pharmacologic inhibition, both in vitro and in vivo, linking laboratory studies to clinical studies with laboratory correlates. The effect of NF-kB activation on resistance to the cytotoxicity of CDDP will be examined. We will delineate the related biologic events associated with acquired CDDP resistance, sensitivity and the association to NF-kB activation. Through transfection experiments, we will examine the transcriptional activator, NF-kB and its effects (positive and negative) on chemotherapy drug sensitivity and resistance. These observations will be extended into new drug development through investigations of new agents including the ansamycin antibiotics, a novel class of agents under development at the MSKCC and the proteosome inhibitor PS-341. Mechanistic studies relating the effect of the inhibitors to drug response are proposed and these effects will be linked to studies of patient derived tissues after investigational drug treatment. This proposal represents a unique opportunity to train fellows in the integration of laboratory studies of acquired drug resistance with the initial clinical studies of new agents which may overcome this mechanism of resistance. Additional laboratory studies related to post transcriptional regulation of TNF-alpha, an important autocrine growth factor for ovarian cancer, are also described. This mechanism is apparently involved in acute CDDP damage response as well. These pilot studies, performed in conjunction with one of the trainees is expected to support additional research in ovarian cancer.

描述：（申请人的描述）此的主要目的 提案是为 Spriggs 博士及其职业生涯提供薪资支持 以患者为导向的研究领域的开发活动。 斯普里格斯博士 目前指导四名年轻教师以及三名肿瘤内科人员 伙计。 他每年还直接负责一名妇科研究员。 这 Spriggs 博士自己的研究计划的实验假设是 耐药性是通过基因表达的调节来控制的。 这 耐药性的转录调节基于数据证明 NF-kB DNA 结合的激活是获得性 CDDP 的共同特征 卵巢癌的抵抗力。 这种阻力可以通过特定的方法消除 治疗干预。 我们正在研究 NF-kB 激活及其 体外和体内药理抑制，连接实验室 研究到与实验室相关的临床研究。 NF-kB的作用 将检查对 CDDP 细胞毒性的抵抗的激活。 我们 将描述与获得性 CDDP 相关的相关生物学事件 耐药性、敏感性以及与 NF-kB 激活的关联。 通过 转染实验，我们将检查转录激活因子，NF-kB 及其对化疗药物敏感性的影响（积极和消极） 反抗。 这些观察结果将延伸到新药开发中 通过对包括安沙霉素抗生素在内的新药物的研究， MSKCC 和蛋白酶体正在开发的新型药物 抑制剂PS-341。 与抑制剂作用相关的机制研究 提出了对药物反应的影响，这些影响将与以下研究联系起来： 研究药物治疗后的患者来源组织。 这个提议 提供了一个独特的机会来培训研究员融入 获得性耐药性与初始临床的实验室研究 研究可能克服这种耐药机制的新药物。 与转录后调控相关的其他实验室研究 TNF-α 是卵巢癌重要的自分泌生长因子， 描述的。 该机制显然与急性 CDDP 损伤有关 回应也是如此。 这些试点研究是与其中一项研究联合进行的 学员预计将支持卵巢癌的更多研究。