PARP Inhibition To Enhance Induction for Head and Neck Cancer

描述（由申请方提供）：局部晚期头颈癌（LAHNC）的诱导（新辅助）化疗由紫杉烷、铂和5-氟尿嘧啶（TPF）组成的三种药物方案组成。TPF诱导化疗是有效的，但与显着的毒性，特别是骨髓抑制和粘膜炎。据报道，总体缓解率超过80%，完全缓解（CR）率范围为20%至54%。达到CR与良好的预后相关，而诱导化疗失败预示着对后续放疗的抵抗。为了提高LAHNC诱导治疗后的CR率，我们启动了一项联合聚（ADP-核糖）聚合酶抑制剂维利帕尼与顺铂、5 FU和多西他赛治疗的试验。先前，我们已经表明，维利帕尼增强了用放射或遗传毒性疗法治疗的细胞和肿瘤的加速衰老。在此，我们打算进行构成本试验相关研究的平行临床前研究。因此，我们打算检查来自治疗的患者肿瘤的组织培养物、动物模型和活组织检查，以了解加速衰老是否是在有或没有维利帕尼的诱导治疗中成功的潜在介体。我们还希望鉴定指示对维利帕尼和/或诱导疗法的敏感性并且指示这些治疗的成功的生物标志物。

DESCRIPTION (provided by applicant): Induction (neoadjuvant) chemotherapy for locally advanced head and neck cancer (LAHNC) constitutes a three drug regimen consisting of a taxane, a platin, and 5-fluorouracil (TPF). TPF induction chemotherapy is effective but is associated with significant toxicity especially myelosuppression and mucositis. Overall response rates exceeding 80% and complete response (CR) rates ranging from 20 to 54% have been reported. Achieving CR correlates with good prognosis while failure to respond to induction chemotherapy predicts resistance to subsequent radiotherapy. Toward enhancing CR rates after induction therapy in LAHNC, we have initiated a trial combining the poly(ADP-ribose) polymerase inhibitor veliparib with cisplatin, 5FU and docetaxel therapy. Previously, we have shown that veliparib enhances accelerated senescence in cells and tumors treated with radiation or genotoxic therapy. Here, we intend to pursue parallel preclinical research constituting correlative studies for this trial. Thus, we intend to examine tissue culture, animal models and biopsies from treated patient tumors to understand whether accelerated senescence is a potential mediator of success in induction therapy, with or without veliparib. We also hope to identify biomarkers that indicate sensitivity to veliparib and/or induction therapy, and that indicate success of these treatments.