NEW INVESTIGATOR TRAINING IN DRUG DEVELOPMENT

描述：(申请人的描述)本申请的主要目的 提案是为斯普里格斯博士和他的职业生涯提供工资支持 以病人为中心的研究领域的发展活动。斯普里格斯博士 目前指导四名年轻教员和三名内科肿瘤学 伙计。他还直接负责每年一名妇科研究员的工作。这个 斯普里格斯博士自己的研究计划的实验假设是 耐药性是由基因表达调控控制的。这个 对抗性的横向调节是基于数据显示的 激活核因子-kB DNA结合是获得性顺铂的共同特征 卵巢癌中的耐药性。这种抵抗力可以通过特定的 治疗性干预。我们正在检测核因子-kB的激活及其 体外和体内的药理抑制，链接实验室 研究与临床研究与实验室的相关性。核因子-kB的作用 将检测CDDP对细胞毒性的抗性的激活情况。我们 将描述与获得的CDDP相关的生物事件 对核因子-kB激活的抵抗力、敏感性和关联性。穿过 转基因实验，我们将检测转录激活物，核因子-kB 及其对化疗药物敏感性的影响(积极和消极)和 抵抗。这些观察结果将推广到新药开发中。 通过对包括阿萨霉素抗生素在内的新制剂的研究，一种 MSKCC和蛋白质小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理研究 提出了对药物反应的影响，这些影响将与 研究药物治疗后患者来源的组织。这项建议 代表着一个独特的机会，可以培训研究员在 获得性耐药的初步临床实验室研究 研究可能克服这种抗药性机制的新药物。 与转录后调控相关的其他实验室研究 肿瘤坏死因子-α，一种重要的卵巢癌自分泌生长因子，也 描述。这一机制显然与CDDP的急性损伤有关。 回应也是如此。这些试点研究是与以下其中一项联合进行的 受训人员预计将支持卵巢癌的进一步研究。

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.