MODULATION OF CLINICAL SENSITIVITY TO CHEMOTHERAPY

这项研究的中心假设是，可以在患者中识别和调节抗癌药物临床敏感性的关键决定因素。 据估计，大约90%的癌症死亡与化疗耐药性有关。 因此，开发改进的新型治疗方法对当前和未来的肿瘤学实践至关重要。 拟议的研究计划有可能确定具有临床意义的耐药机制，并促进新型治疗方法快速转化为早期临床试验。 这些试验的目标是使用生物化学和/或分子中间终点在人类受试者中建立调节的可行性-“原理证明”。 还建议指导下一代临床研究者进行转化治疗研究，因为耐药性方面的进展可能需要当前和未来研究者的共同努力。 拟议的研究包括三个具体目标：（1）量化编码生存因子的基因表达与晚期卵巢癌患者化疗后结局之间的关系;（2）进行旨在规避化疗耐药的新型治疗策略的初步临床试验;（3）指导临床研究人员设计和进行转化治疗试验。 这个中期职业研究者奖支持这些以患者为导向的研究和指导活动的候选人，同时促进他的直接和长期的职业发展。 候选人的近期职业目标是：（1）继续目前在卵巢癌和黑色素瘤的临床相关项目，（2）进行机械早期试验，（3）并促进重视和支持此类活动的临床文化。 他的长期职业目标是：（1）开发和维持转化治疗学的杰出计划，（2）在该计划中，开发基于调节决定化疗敏感性的关键机制的改进治疗策略。

The central hypothesis of the proposed research is that critical determinants of clinical sensitivity to anticancer drugs can be identified and modulated in patients. It is estimated that approximately 90 percent of cancer deaths are related to resistance to chemotherapy. Development of improved, novel treatments is therefore critical to the current and future practice of oncology. The proposed research program has the potential to identify clinically significant resistance mechanisms and promote rapid translation of novel treatments into early-phase clinical trials. The goal of these trials will be to establish feasibility of modulation-"proof-of-principle"-in human subjects, using biochemical and/or molecular intermediate endpoints. Mentoring of next-generation clinical investigators in the conduct of translational therapeutic investigations is also proposed, as progress against drug resistance will likely require the concerted efforts of current and future investigators. The proposed research includes three specific aims: (1) To quantitate relationships between expression of genes encoding survival factors and post-chemotherapy outcomes of patients with advanced ovarian carcinoma; (2) To perform initial clinical trials of novel treatment strategies designed to circumvent resistance to chemotherapy; and (3) To mentor beginning clinical investigators in the design and conduct of translational therapeutic trials. This Midcareer Investigator Award supports these patient-oriented research and mentoring activities of the candidate while promoting his immediate and long-term career development. The candidate's immediate career objectives are: (1) to continue current clinical correlative projects in ovarian carcinoma and melanoma, (2) to conduct mechanistic early-phase trials, (3) and to promote a clinical culture that values and supports such activities. His long-term career objectives are: (1) to develop and sustain an outstanding program in translational therapeutics and (2) within this program, to develop improved treatment strategies based on modulation of critical mechanisms that determine sensitivity to chemotherapy.