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

摘要 这一快速通道SBIR提案的目标是提交研究新药(IND)申请，以测试 一种新型抗癌药物(FL118)，旨在克服固有和获得性治疗耐药性。许多 癌症类型直到非常晚期才能被检测出来，并且已经对FDA产生了抗药性 批准的治疗方法。此外，许多非晚期癌症对最初的治疗反应良好，然后 产生抵抗力。因此，克服治疗耐药性是该领域的主要目标。我们专注于 首先是结直肠癌的治疗，因为它占美国所有癌症死亡人数的9%。 许多结直肠癌在被发现时已经产生了耐药性，而且许多已经发展成 在治疗过程中产生耐药性，尽管癌症在相当早的时候就被发现了。这些治疗具有抗药性 癌症会导致痛苦的死亡。Survivin、XIAP、cIAP2和Mcl-1的上调有助于治疗 (药物、辐射)对结直肠癌的耐药性。FL118可降低这四种基因产物的表达。在……里面 此外，FL118还克服了拓扑替康耐药性，即Top1突变或 ABCG2/BCRP或ABCC4/MRP4过表达。P53的丢失或突变也是一种重要的耐药性 在癌症中的因素；然而，FL118的疗效不受P53状态的影响。FL118在肿瘤组织中迅速蓄积 (T1/2&gt；6h)。FL118对结肠癌和头颈癌的治疗指数(TI)e5在临床上使用 有关TI的计算方法。最后，我们有几种备用化合物，还有一种药用 并行的化学程序，以防FL118在药物开发过程中的某个点失败。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的机制 抵抗。这些特点使FL118不仅是一种非常安全的抗癌药物，而且对 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FL118作为抗癌剂用于抗癌的可行性 耐药结肠癌。可行性检验：我们必须观察到1)f118e4的tI，2)末端半衰期e6 HRS在肿瘤中的作用，3)在3种人结肠癌模型中克服拓扑替康耐药，以及4)FL118具有良好的 在免疫活性癌症模型中的疗效。如果我们的可行性测试合格，我们将申请二期工程 资金问题。否则，我们将不会这样做。因此，NIH面临的风险只不过是第一阶段，而是快速通道方法 可以为我们的公司节省长达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。为此，我们将开展所有支持IND的研究。 成功标准：FDA必须接受我们的IND，并允许临床I/IIa期研究明确开始 或含蓄的，即在标准的30天等待期内不说不。 许多肿瘤都有这些共同的耐药机制，因此FL118可能对不同的肿瘤有效 癌症的类型。这样的研究将在以后进行，因为同时在所有类型的癌症中开发FL118是不现实的。

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.