(PQ9) Mitigation of chemotherapy induced peripheral neuropathy

 描述（由申请人提供）：肺癌目前是死亡的主要原因。在接受化疗剂的肺癌患者中发生的这些严重神经毒性副作用之一是化疗诱导的周围神经病变（CIPN）。我们的建议将集中在由顺铂和紫杉醇诱导的CIPN上，因为这是治疗常见癌症（包括非小细胞肺癌）中最有效和广泛使用的两种化疗药物。CIPN可能是化疗的剂量限制因素或导致治疗提前终止，从而影响生存和生活质量。目前，还没有有效的治疗方法来处理潜在的致病机制，如神经变性。此外，目前处理CIPN疼痛症状的对症治疗通常无效。因此，确定替代形式的治疗是一个至关重要的医疗需求。在本申请中，我们将重点关注烟碱乙酰胆碱受体（nAChR）调节剂，特别是α7亚型，作为治疗CIPN的潜在靶点。这些受体由参与疼痛传递的中枢和外周神经元细胞（背根神经节）以及参与炎症反应的巨噬细胞和其他细胞表达。在目标1中，我们将测试α7 nAChR沉默激动剂预防或改善顺铂和紫杉醇诱导的周围神经病变发展的能力，包括伴随CIPN的明确的神经病变。在目标2中，我们将在培养的非小细胞肺癌细胞系和患者源性肿瘤细胞以及荷瘤小鼠中检测α7 nAChR沉默激动剂，以消除这些药物刺激肿瘤生长或损害化疗（顺铂和紫杉醇）效力的可能性。此外，将在荷瘤小鼠中证实α7 nAChR沉默激动剂对CIPN的抑制。如果可以确定有效的治疗/预防，则应该可以治疗患者或延长治疗时间，因为剂量依赖性神经病不会成为限制性毒性，并且依从性和生活质量将得到改善。

 DESCRIPTION (provided by applicant): Lung cancer is currently a leading cause of mortality. One of these serious neurotoxic side effects that develop in lung cancer patients receiving chemotherapeutic agents is chemotherapy-induced peripheral neuropathy (CIPN). Our proposal will be focused on CIPN induced by cisplatin and paclitaxel since these are two of the most effective and widely used chemotherapy drugs in the treatment of common cancers, including non- small cell lung cancer. CIPN can be a dose-limiting factor for chemotherapy or result in premature termination of treatment, thereby influencing survival and quality of life. Currently, there are no effective therapies that deal with the underlying pathogenic mechanisms such as neurodegeneration. In addition, the current symptomatic therapies that deal with painful symptoms of CIPN are generally ineffective. Therefore, the identification of alternative forms of therapy is a crucial medical need. In this application we will focus on nicotinic acetylcholine receptors (nAChRs) modulators, in particular α7 subtypes, as potential targets for treatment of CIPN. These receptors are expressed by central and peripheral neuronal cells (dorsal root ganglia) involved in pain transmission and by macrophages and other cells involved in the inflammatory responses. In Aim 1, we will test the ability of α7 nAChR silent agonists to prevent or ameliorate the development of peripheral neuropathy induced by cisplatin and paclitaxel, including well- defined neuropathologies that accompany CIPN. In Aim 2, we will test the α7 nAChR silent agonists in non-small cell lung cancer cell lines and patient derived tumor cells in culture as well as in tumor bearing mice to eliminate the possibility that these agents stimulate tumor growth or compromise the potency of chemotherapy (cisplatin and paclitaxel). In addition, suppression of CIPN by the α7 nAChR silent agonists will be confirmed in the tumor bearing mice. If effective treatment/prevention can be identified, it should be possible to treat patients or prolonged periods as dose-dependent neuropathy will not be a limiting toxicity and compliance as well as quality of life will be improved.