A small molecule broad spectrum inhibitor of antiapoptotic genes to treat cancer

一种治疗癌症的小分子广谱抗凋亡基因抑制剂

• 批准号: 8647283
• 负责人: Fengzhi Li
• 金额: $ 22.5万
• 依托单位: CANGET BIOTEKPHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647283
• 关键词: ABCG2 gene; Accounting; Address; Affect; Age-Years; Animal Model; Antineoplastic Agents; Apoptosis Inhibitor; BCL2 gene; BIRC4 gene; Cancer Model; Cancer Patient; Cessation of life; Clinical; Clinical Research; Clinical Trials; Colon; Colon Carcinoma; Colonic Neoplasms; Colonoscopy; Colorectal Cancer; Cyclic GMP; Data; Dose; Drug Formulations; Drug Kinetics; FDA approved; Family; Funding; Genes; Goals; Half-Life; Head and Neck Cancer; Hour; Human; Inhibition of Apoptosis; Injection of therapeutic agent; Investigational Drugs; Investigational New Drug Application; Life; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Methods; Mutation; Pain; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Play; Process; Proteins; Published Comment; Resistance; Resistance development; Risk; Role; Small Business Innovation Research Grant; Staging; Study Section; Testing; Therapeutic Index; Time; Topoisomerase; Topotecan; Toxic effect; United States; United States National Institutes of Health; Up-Regulation; cancer cell; cancer type; cell growth; clinically relevant; design; drug development; fighting; improved; inhibitor/antagonist; intravenous injection; meetings; mutant; novel; overexpression; programs; public health relevance; radiation resistance; resistance factors; resistance mechanism; response; small molecule; success; survivin; tumor

Abstract The goal of this fast-track SBIR proposal is to file an investigational new drug (IND) application for testing a novel anticancer drug (FL118) that is designed to overcome inherent and acquired treatment resistance. Many types of cancers are not detected until they are very advanced and have already become resistant to FDA approved treatments. In addition, many non-advanced cancers respond well to initial treatments and then develop resistance. Therefore, overcoming resistance to treatment is a major goal in the field. We are focused first on treatment of colorectal cancer, as it accounts for 9% of all cancer deaths in the United States. Many colorectal cancers have developed resistance by the time they are detected and many develop resistance during treatment, even though the cancer was detected fairly early on. These treatment resistant cancers result in painful deaths. Upregulation of Survivin, XIAP, cIAP2, and Mcl-1 contributes the treatment (drug, radiation) resistance of colorectal cancer. FL118 reduces expression of these four gene products. In addition, FL118 overcomes topotecan resistance, resistance derived from Top1 mutations or from overexpression of ABCG2/BCRP or ABCC4/MRP4. Loss or mutation of p53 is also an important resistance factor in cancer; however, FL118 efficacy is not affected by p53 status. FL118 is rapidly accumulated in tumor (T1/2 > 6h). FL118 has a therapeutic index (TI) e5 against colon and head-&-neck cancers using a clinically relevant method for the calculation of TI. Finally, we have several backup compounds and have a medicinal chemistry program in parallel, in case FL118 fails at some point in the drug development process. All in all, FL118 has already passed several hurdles and appears to effectively overcome many known mechanisms of resistance. These features make FL118 not only be a very safe anticancer drug but also highly effective to overcome treatment resistance and advanced colon cancer. In Phase I, our Specific Aim is to test the feasibility of using FL118 as an anticancer agent for fighting resistant colon cancers. Test of Feasibility: We must observe 1) a TI of FL118 e 4, 2) a terminal half-life e6 hrs in tumor, 3) overcoming topotecan resistance in 3 human colon cancer models, and 4) FL118 has good efficacy in an immuno-competent cancer model. If our test of feasibility is met, we will apply for Phase II funding. Otherwise, we will not. Thus, the risk to the NIH is no more than a Phase I, but the fast-track approach can save our company up to 9-12 months, which is important for a start-up company. In Phase II, our Specific Aim is to file an IND. We will carry out all IND enabling studies, to this end. Criteria for Success: The FDA must accept our IND and allow for clinical Phase I/IIa studies to begin explicitly or implicitly, i.e. not say no within the standard 30-day waiting period. Many cancers share these common mechanisms of resistance, thus FL118 may be effective against different types of cancers. Such studies will follow later, as developing FL118 in all cancer types at once is not practical.

抽象的 这个快速轨道SBIR提案的目的是提交研究新药（IND）测试申请 旨在克服固有和获得的治疗耐药性的新型抗癌药（FL118）。许多 直到非常先进并且已经对FDA具有抵抗力，才检测到癌症的类型 批准的治疗方法。此外，许多非先进的癌症对初始治疗的反应很好，然后 产生阻力。因此，克服对治疗的抵抗是该领域的主要目标。我们集中精力 首先是结直肠癌的治疗，因为它占美国所有癌症死亡的9％。 许多结直肠癌在被发现时已经发展出抗药性 即使在早期发现癌症时，也可以在治疗过程中进行抗性。这些耐药性 癌症导致痛苦的死亡。 Survivin，XIAP，CIAP2和MCL-1的上调贡献了治疗 （药物，辐射）结直肠癌的抗性。 FL118降低了这四种基因产物的表达。在 另外，FL118克服了拓扑替康的抗性，源自TOP1突变或从 ABCG2/BCRP或ABCC4/MRP4的过表达。 p53的损失或突变也是重要的阻力 癌症的因素；但是，FL118疗效不受p53状态的影响。 FL118迅速积聚在肿瘤中 （T1/2> 6H）。 FL118使用临床上的结肠和头癌具有治疗指数（TI）E5 计算Ti的相关方法。最后，我们有几种备用化合物，并具有药用 化学计划并行，如果FL118在药物开发过程中的某个时候失败。总而言之， FL118已经通过了几个障碍，似乎有效地克服了许多已知机制 反抗。这些功能使FL118不仅是一种非常安全的抗癌药，而且还非常有效 克服耐药性和晚期结肠癌。 在第一阶段，我们的具体目的是测试使用FL118作为战斗剂的可行性 抵抗结肠癌。可行性测试：我们必须观察1）FL118 E 4，2）终端半衰期E6的Ti 肿瘤中的HRS，3）克服3种人类结肠癌模型中的拓扑替康抵抗力，而4）FL118良好 免疫能力癌症模型的功效。如果我们满足可行性的测试，我们将申请II阶段 资金。否则，我们不会。因此，NIH的风险不过是第一阶段，而是快速轨道的方法 可以节省我们的公司长达9-12个月，这对于一家初创公司很重要。 在第二阶段，我们的具体目的是提交IND。到此为止，我们将进行所有IND促进研究。 成功的标准：FDA必须接受我们的IND，并允许临床I/IIA研究明确开始 或隐式，即在标准的30天等待期内不拒绝。 许多癌症具有这些共同的抵抗机制，因此FL118可能对不同的不同 癌症类型。此类研究将在稍后进行，因为在所有癌症类型中开发FL118都是不切实际的。