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 此快速通道 SBIR 提案的目标是提交研究性新药 (IND) 申请以测试 新型抗癌药物（FL118）旨在克服固有的和获得性的治疗耐药性。许多 癌症类型只有在非常晚期并且已经对 FDA 产生耐药性时才会被检测到 批准的治疗方法。此外，许多非晚期癌症对初始治疗反应良好，然后 产生抵抗力。因此，克服治疗耐药性是该领域的一个主要目标。我们专注 首先是结直肠癌的治疗，因为结直肠癌占美国所有癌症死亡的 9%。 许多结直肠癌在被发现时已经产生了耐药性，并且许多人发展为耐药性。 尽管癌症很早就被发现，但治疗期间仍存在耐药性。这些治疗耐药 癌症导致痛苦的死亡。 Survivin、XIAP、cIAP2 和 Mcl-1 的上调有助于治疗 结直肠癌的（药物、辐射）抵抗力。 FL118 降低这四种基因产物的表达。在 此外，FL118 还克服了拓扑替康耐药性、Top1 突变或源自拓扑替康的耐药性。 ABCG2/BCRP 或 ABCC4/MRP4 的过度表达。 p53的丢失或突变也是一个重要的抵抗力 癌症的因素；然而，FL118 的功效不受 p53 状态的影响。 FL118在肿瘤中快速积累 （T1/2 > 6 小时）。 FL118 对结肠癌和头颈癌的治疗指数 (TI) e5 TI计算的相关方法。最后，我们有几种备用化合物和一种药用药物 化学项目同时进行，以防 FL118 在药物开发过程中的某个时刻失败。总而言之， FL118 已经克服了几个障碍，并且似乎有效地克服了许多已知的机制 反抗。这些特性使得FL118不仅是一种非常安全的抗癌药物，而且对于癌症治疗也非常有效。 克服治疗耐药性和晚期结肠癌。 在第一阶段，我们的具体目标是测试使用 FL118 作为抗癌药物对抗癌症的可行性 耐药结肠癌。可行性测试：我们必须观察 1) FL118 e 4 的 TI，2) 终末半衰期 e6 肿瘤中的小时数，3) 克服了 3 种人类结肠癌模型中的拓扑替康耐药性，4) FL118 具有良好的 在免疫功能正常的癌症模型中的功效。如果我们的可行性测试通过，我们将申请第二阶段 资金。否则，我们不会。因此，NIH 面临的风险只不过是第一阶段，而是快速通道方法 可以为我们公司节省长达9-12个月的时间，这对于初创公司来说非常重要。 在第二阶段，我们的具体目标是提交 IND。为此，我们将开展所有 IND 授权研究。 成功标准： FDA 必须接受我们的 IND 并允许明确开始临床 I/IIa 期研究 或含蓄地，即在标准的 30 天等待期内不说不。 许多癌症具有这些共同的耐药机制，因此 FL118 可能对不同的癌症有效 癌症的类型。此类研究将在稍后进行，因为同时在所有癌症类型中开发 FL118 是不切实际的。