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

开发一种新型小分子 UTL-5g，用于治疗奥沙利铂诱导的血栓

• 批准号: 8454834
• 负责人: Jiajiu Shaw
• 金额: $ 27.64万
• 依托单位: 21ST CENTURY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2014-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454834
• 关键词: Acute; Adjuvant; Adverse effects; Affect; Antineoplastic Agents; Biological Assay; Blood Platelets; Bone Marrow; Carboplatin; Cell Line; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical Trials; Colon Carcinoma; Colorectal; Colorectal Cancer; Conduct Clinical Trials; Creatine; Development; Dosage Forms; Dose; Drug Formulations; Drug Kinetics; Effectiveness; FDA approved; Generations; Goals; Human; Immune; Injection of therapeutic agent; Injury; Interleukin-10; Kidney; Lethal Dose 50; Leucovorin; Liver; Mediating; Megakaryocytes; Modeling; Monitor; Neuropathy; New Agents; Patients; Pharmaceutical Preparations; Platelet Count measurement; Platinum; Preparation; Process; Protocols documentation; Purpura; Schedule; Small Business Innovation Research Grant; TNF gene; Therapeutic; Thrombocytopenia; Toxic effect; Wistar Rats; Work; anticancer activity; base; cytokine; in vivo; meetings; microbial alkaline proteinase inhibitor; neurotoxic; novel; oxaliplatin; phase 1 study; phase 2 study; pre-clinical; preclinical study; public health relevance; small molecule; standard care

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.

描述（由申请人提供）：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药物。迄今为止，奥沙利铂已成为各种化疗方案的组成部分，特别是在晚期结直肠癌中。对于结直肠癌，奥沙利铂已与亚叶酸（leucovorin）和5-氟尿嘧啶（5-FU）联合使用;这种组合，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症。FOLFOX已被广泛用于结直肠癌。然而，在超过70%接受FOLFOX治疗的患者中观察到血小板减少。截至目前，尚无FDA批准的药物专门用于治疗奥沙利铂诱导的血小板减少症。因此，开发新的抗奥沙利铂诱导的血小板减少症药物具有重要意义。本项目的最终目标是开发一种新型小分子TNF-α调节剂UTL-5g，与奥沙利铂联合治疗结肠癌，以显著降低奥沙利铂诱导的血小板减少症。在这项SBIR I期研究中，将进行几项临床前研究，以实现以下特定目标：目标1。为了显示UTL-5g以剂量依赖性方式增加体内奥沙利铂降低的血小板数量， 在MTD下奥沙利铂治疗后的计数（即，奥沙利铂治疗后多少天 血小板水平最低？）。(b)确定UTL-5g剂量/方案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在改善奥沙利铂诱导的血小板抑制中的有效性。对于所有这些研究，如适用，我们将对血小板、WBC、骨髓和CD 41+巨核细胞进行计数/分析。我们还将通过分析AST、ALT、BUN和肌酸来监测肝脏和肾脏的损伤。此外，还将测定细胞因子，包括TNF-α和IL-10（两者均被奥沙利铂显著降低）。目标2.基于目的1，选择剂量范围并进行治疗评估，以证明UTL-5g不会影响奥沙利铂的抗癌活性（使用人结直肠细胞系HCT-15）。一旦这项SBIR I期研究成功完成，我们将证明UTL-5g可与奥沙利铂联合用于缓解奥沙利铂诱导的血小板减少症的可行性，UTL-5g是一种值得继续临床前开发的有前景的辅助药物。