PARP Inhibition To Enhance Induction for Head and Neck Cancer

描述(申请人提供)：局部晚期头颈癌的诱导(新辅助)化疗(LAHNC)由三种药物方案组成，包括紫杉烷、铂和5-氟尿嘧啶(TPF)。TPF诱导化疗是有效的，但存在明显的毒性反应，尤其是骨髓抑制和粘膜炎。据报告，总应答率超过80%，完全应答率从20%到54%不等。获得完全缓解与良好的预后相关，而对诱导化疗无效则预示着对后续放射治疗的抵抗。为了提高LAHNC诱导治疗后的CR率，我们启动了一项试验，将聚(ADP-核糖)聚合酶抑制剂veliparib与顺铂、5FU和多西紫杉醇联合治疗。此前，我们已经证明，维利帕利可促进放射或基因毒性治疗治疗的细胞和肿瘤的加速衰老。在这里，我们打算进行平行的临床前研究，构成这项试验的相关研究。因此，我们打算检查组织培养、动物模型和经治疗的患者肿瘤的活检，以了解加速衰老是否是诱导治疗成功的潜在中介，无论是否使用维利帕利。我们还希望找出对维拉帕利和/或诱导治疗敏感的生物标志物，并指出这些治疗的成功。

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.