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.
There are about 500,000 cancer deaths in the US each year. These deaths are primarily due to the fact that cancers become resistant to FDA approved treatments. Therefore, overcoming resistance to treatment is a major goal in the field. This is a proposal to overcome acquired and inherent resistance to treatment and thus prolong and save the lives of cancer patients by focusing on colon cancer.
|Ling, Xiang; Wu, Wenjie; Fan, Chuandong et al. (2018) An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer. J Exp Clin Cancer Res 37:240|
|Li, Fengzhi; Jiang, Tao; Li, Qingyong et al. (2017) Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer? Am J Cancer Res 7:2350-2394|
|Li, Fengzhi; Ling, Xiang; Harris, Danni L et al. (2017) Topoisomerase I (Top1): a major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity? Am J Cancer Res 7:370-382|
|Westover, David; Ling, Xiang; Lam, Hong et al. (2015) FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance. Mol Cancer 14:92|
|Ling, Xiang; Liu, Xiaojun; Zhong, Kai et al. (2015) FL118, a novel camptothecin analogue, overcomes irinotecan and topotecan resistance in human tumor xenograft models. Am J Transl Res 7:1765-81|