Development of a novel small molecule, UTL-5g, to treat oxaliplatin-induced throm

描述(申请人提供)：虽然奥沙利铂是第三代铂类药物，但它已超过其前身顺铂和卡铂，成为所有铂类药物中处方最多的。到目前为止，奥沙利铂已经成为各种化疗方案中不可或缺的一部分，特别是在晚期结直肠癌中。对于结直肠癌，奥沙利铂已经与亚叶酸(亚叶酸钙)和5-氟尿嘧啶(5-FU)一起使用；这种组合被称为FOLFOX，现在是结直肠癌的治疗标准。不幸的是，像许多其他抗癌药物一样，奥沙利铂有几个显著的副作用，最明显的是血小板减少。FOLFOX的使用是公认的，并被广泛用于结直肠癌。然而，在接受FOLFOX治疗的患者中，超过70%的患者出现了血小板减少症。到目前为止，还没有FDA批准的药物专门用于治疗奥沙利铂引起的血小板减少症。因此，开发一种针对奥沙利铂所致的血小板减少症的新药具有重要意义。该项目的最终目标是开发一种新型的小分子肿瘤坏死因子调节剂UTL-5G，与奥沙利铂联合用于结肠癌的治疗，以显著降低奥沙利铂引起的血小板减少症。在这项SBIR I期研究中，将进行几项临床前研究，以实现以下具体目标：目的1.为了证明UTL-5g以剂量依赖的方式增加奥沙利铂在体内降低的血小板数量(A)以确定血小板的最低点 奥沙利铂治疗后的MTD计数(即奥沙利铂治疗后多少天 血小板水平最低？)。(B)明确UTL-5g的剂量/程序与血小板计数的关系。(C)混合从(A)和(B)获得的时间表和剂量，以显示UTL-5G在改善奥沙利铂引起的血小板抑制方面的有效性。对于所有这些研究，在适用的情况下，我们将对血小板、白细胞、骨髓和CD41+巨核细胞进行计数/分析。通过分析AST、ALT、BUN、肌酸等指标，监测肝、肾的损伤情况。此外，还将检测细胞因子，包括肿瘤坏死因子-10和白介素10-10(均被奥沙利铂显著降低)。目的2.在目标1的基础上，选择剂量范围并进行疗效评估，以表明UTL-5G不影响奥沙利铂的抗癌活性(使用人结直肠癌细胞系HCT-15)。一旦这项SBIR第一阶段研究成功完成，我们将证明UTL-5G与奥沙利铂联合用于缓解奥沙利铂引起的血小板减少的可行性，UTL-5G是一种值得继续进行临床前开发的有前景的佐剂。

DESCRIPTION (provided by applicant): Although oxaliplatin is a third-generation platinum drug, it has become the most prescribed amongst all platinum drugs overtaking its predecessors, cisplatin and carboplatin. To date, oxaliplatin has become an integral part of various chemotherapy protocols, especially in advanced colorectal cancer. For colorectal cancer, oxaliplatin has been used with folinic acid (leucovorin) and 5-flurouracil (5-FU); this combination, referred to as FOLFOX, is now a treatment standard for colorectal cancer. Unfortunately, like many other anticancer drugs, oxaliplatin has several significant side effects, most notably, thrombocytopenia. The use FOLFOX is well established and widely used for colorectal cancer. However, thrombocytopenia has been noted in more than 70% of patients receiving FOLFOX. As of today, there is no FDA approved drug indicated specifically for treating oxaliplatin-induced thrombocytopenia. Therefore, it is of great importance to develop a new agent specifically for oxaliplatin-induced thrombocytopenia. The ultimate goal of this project is t develop a novel small-molecule TNF- modulator, UTL-5g, to be used in conjunction with oxaliplatin for the treatment of colon cancer to significantly reduce oxaliplatin-induced thrombocytopenia. In this SBIR phase I study, several preclinical studies will be conducted to achieve the following specific aims: Aim 1. To show that, in a dose dependent manner, UTL-5g increases number of platelets lowered by oxaliplatin in vivo (a) To determine the nadir of platelet count after oxaliplatin treatment at the MTD (i.e., how many days after oxaliplatin treatment will platelet level be the lowest?). (b) To define the relationship of dose/schedule of UTL-5g and blood platelet counts. (c) To blend the schedule and doses obtained from (a) and (b) to show the effectiveness of UTL-5g in ameliorating the platelet suppression induced by oxaliplatin. For all these studies, when applicable, we will conduct counts/analyses on platelets, WBC, bone marrow and CD41+ megakaryocytes. We will also monitor the injuries on liver and kidney by analyzing AST, ALT, BUN, and creatine. In addition, cytokines, including TNF- and IL-10 (both are significantly reduced by oxaliplatin) will be assayed. Aim 2. Based on aim 1, to select a dose range and conduct a therapeutic assessment to show that UTL-5g does not affect the anticancer activity of oxaliplatin (using a human colorectal cell line, HCT-15). Once this SBIR Phase I study is successfully completed, we will have shown the feasibility that UTL-5g can be used in conjunction with oxaliplatin to relieve oxaliplatin-induced thrombocytopenia and UTL-5g is a promising adjuvant agent worthy of continued preclinical development.