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.

摘要 这一快速SBIR提案的目标是提交一份研究性新药（IND）申请，以测试一种 新型抗癌药物（FL 118），旨在克服固有和获得性治疗耐药性。许多 某些类型的癌症直到非常晚期才被发现，并且已经对FDA产生了抗药性。 批准的治疗。此外，许多非晚期癌症对初始治疗反应良好， 产生抵抗力。因此，克服对治疗的抗性是该领域的主要目标。我们专注 首先是治疗结直肠癌，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产生了耐药性， 尽管癌症在相当早的时候就被发现了，但在治疗过程中仍然存在耐药性。 癌症导致痛苦的死亡。Survivin、XIAP、cIAP 2和Mcl-1的上调有助于治疗 (drug、辐射）抵抗性。FL 118减少这四种基因产物的表达。在 此外，FL 118克服了拓扑替康耐药性、源自Top1突变或源自 ABCG 2/BCRP或ABCC 4/MRP 4过表达。p53的缺失或突变也是一种重要的耐药性 然而，FL 118的疗效不受p53状态的影响。FL 118在肿瘤中迅速积聚 (T1/2 > 6h）。FL 118具有针对结肠癌和头颈癌的治疗指数（TI）e5， 计算TI的相关方法。最后，我们有几种备用化合物， 化学程序并行，以防FL 118在药物开发过程中的某个点失败。总的来说， FL 118已经通过了几个障碍，并且似乎有效地克服了许多已知的免疫机制。 阻力这些特征使得FL 118不仅是一种非常安全的抗癌药物，而且对 克服治疗抵抗和晚期结肠癌。 在第一阶段，我们的具体目标是测试使用FL 118作为抗癌剂的可行性， 耐药性结肠癌。可行性测试：我们必须观察1）FL 118 e 4的TI，2）终末半衰期e 6 3）在3种人结肠癌模型中克服拓扑替康耐药性，和4）FL 118具有良好的抗肿瘤作用。 在免疫活性癌症模型中的功效。如果我们的可行性测试通过，我们将申请第二阶段 经费否则，我们不会。因此，对NIH的风险不超过第一阶段，但快速通道方法 可以为我们的公司节省9-12个月的时间，这对一家初创公司来说很重要。 在第二阶段，我们的具体目标是提交IND。我们将为此开展所有IND使能研究。 成功标准：FDA必须接受我们的IND，并明确允许临床I/IIa期研究开始 或含蓄地，即在标准的30天等待期内不说不。 许多癌症共享这些共同的耐药机制，因此FL 118可有效对抗不同的癌症。 癌症的类型。这些研究将随后进行，因为在所有癌症类型中同时开发FL 118是不切实际的。