Gemcitabine-Radiation for Advanced Pancreatic Cancer

描述（由申请人提供）：在我们之前的申请中，我们在临床前研究的基础上设计了新颖合理的临床试验，将吉西他滨与放疗结合治疗晚期头颈癌和胰腺癌患者，并取得了良好的临床结果。该提案的长期目标是通过添加改进的放射治疗技术和添加以EGFR拮抗剂形式的分子靶向治疗的机制和临床研究来改善使用吉西他滨和放疗治疗胰腺癌的结果。这一目标将通过4个具体目标来实现。具体目标1是基于我们的实验室和临床经验开展新的临床试验，使用吉西他滨和放疗联合奥沙利铂。在Aim 1A中，我们建议通过用奥沙利铂代替顺铂（基于临床和临床前研究）来改进我们早期的结果，目标是在保持疗效的同时降低全身毒性。在Aim 1B中，我们建议提高辐射剂量，从而增加可切除性和局部控制。我们假设这可以通过主动呼吸控制（ABC）的应用来安全地完成，以减少器官运动，以及强度调节放射治疗（IMRT），以减少目标体积。目的2是阐明吉西他滨和EGFR抑制剂对细胞周期进展（目的2A）和EGFR信号传导（目的2B）的相互作用机制。目的3：优化EGFR靶向治疗联合吉西他滨和放疗对移植人胰腺肿瘤裸鼠的治疗效果。目标4是基于我们的实验室和临床经验开展新的临床试验，使用吉西他滨、奥沙利铂和剂量递增放疗联合EGFR靶向治疗局部晚期胰腺癌。虽然该应用主要针对局部晚期疾病，但其结果应直接适用于可切除疾病的患者；事实上，我们期望增加被认为是不可切除的病人的切除率。我们认为，我们的临床前和临床团队在这一领域拥有10年的领先临床试验记录，这可能会使这些研究改善患者的预后。

DESCRIPTION (provided by applicant): In our previous application, we designed novel and rational clinical trials, based on our preclinical studies, combining gemcitabine with radiation for the treatment of patients with advanced head and neck cancers and pancreatic cancer that have produced promising clinical results. The long-term goal of this proposal is to improve upon the results of treatment of pancreatic cancer using gemcitabine and radiation through mechanistic and clinical studies of the addition of improved radiation therapy techniques and the addition of molecularly targeted therapy, in the form of EGFR antagonists. This goal will be addressed through 4 specific aims. Specific Aim 1 is to carry out new clinical trials based on our laboratory and clinical experience using gemcitabine and radiation combined with oxaliplatin. In Aim 1A, we propose to improve upon our earlier results by substituting oxaliplatin for cisplatin (based on clinical and preclinical studies), with the goal of decreasing systemic toxicity while maintaining efficacy. In Aim 1B we propose to escalate the dose of radiation, thereby increasing resectability and local control. We hypothesize that this can be accomplished safely through the application of active breathing control (ABC), to minimize organ motion, and intensity modulated radiation therapy (IMRT), to minimize the target volume. Aim 2 is to elucidate the mechanism of interaction of gemcitabine and EGFR inhibitors on cell cycle progression (Aim 2A) and on EGFR signaling (Aim 2B). Aim 3 is to optimize the combination of EGFR targeted therapy with gemcitabine and radiation in nude mice bearing human pancreatic tumors as xenografts. Aim 4 is to carry out new clinical trials based on our laboratory and clinical experience using gemcitabine, oxaliplatin and dose escalated radiation combined with EGFR targeted therapy in the treatment of locally advanced pancreatic cancer. Although this application is focused on locally advanced disease, the results should be directly applicable to patients with resectable disease; indeed we expect to increase the rate of resection for patients considered to be unresectable. We feel our preclinical and clinical team with a track record of 10 years of carrying out leading clinical trials in this area makes it likely that these studies will improve patient outcome.