Westover D.,Roswell Park Cancer Institute |
Ling X.,Roswell Park Cancer Institute |
Ling X.,Canget Biotekpharma, Llc |
Lam H.,Roswell Park Cancer Institute |
And 6 more authors.
Molecular Cancer | Year: 2015
Background: Irinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions. Methods: Colon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity. Results: Both pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance. Conclusions: Our results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug-refractory cancers resulting from high expression of ABCG2. © Westover et al.; licensee BioMed Central. Source
Ling X.,Roswell Park Cancer Institute |
Ling X.,Canget Biotekpharma, Llc |
Xu C.,Roswell Park Cancer Institute |
Fan C.,Roswell Park Cancer Institute |
And 3 more authors.
Cancer Research | Year: 2014
Anticancer agent FL118 was recently identified in screening of small-molecule inhibitors of human survivin expression. Although FL118 is a camptothecin analogue, its antitumor potency is much superior to other FDA-approved camptothecin analogues (irinotecan and topotecan). The mechanism of action (MOA) underlying the antitumor effects of FL118 remains to be fully elucidated. Here, we report that FL118 activates tumor suppressor p53 as a novel MOA in p53 wild-type cancer cells. Our studies show that this MOA involves an induction of proteasomal degradation of MdmX, a critical negative regulator of p53, in a manner largely independent of ATM-dependent DNA damage signaling pathway but dependent on E3-competent Mdm2. FL118 inhibits p53 polyubiquitination and monoubiquitination by Mdm2-MdmX E3 complex in cells and in cell-free systems. In contrast, FL118 stimulates Mdm2-mediated MdmX ubiquitination. Coimmunoprecipitation revealed that FL118 slightly decreases Mdm2-p53 interactions and moderately increases Mdm2-MdmX interactions, suggesting a change of targeting specificity of Mdm2-MdmX E3 complex from p53 to MdmX, resulting in accelerated MdmX degradation. As a result, p53 ubiquitination by Mdm2-MdmX E3 complex is reduced, which in turn activates p53 signaling. Activation of the p53 pathway by FL118 induces p53-dependent senescence in colorectal cancer cells. However, in the absence of p53 or in the presence of MdmX overexpression, FL118 promotes p53-independent apoptosis. These two distinct cellular consequences collectively contribute to the potent effects of FL118 to inhibit clonogenic potential of colon cancer cells. This study identifies a potential application of FL118 as an MdmX inhibitor for targeted therapies. ©2014 AACR. Source
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.99K | Year: 2014
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. FL1
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 903.05K | Year: 2015
DESCRIPTION provided by applicant The goal of this fast track SBIR proposal is to file an investigational new drug IND application for testing a novel anticancer drug FL 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 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 cIAP and Mcl contributes the treatment drug radiation resistance of colorectal cancer FL reduces expression of these four gene products In addition FL overcomes topotecan resistance resistance derived from Top mutations or from overexpression of ABCG BCRP or ABCC MRP Loss or mutation of p is also an important resistance factor in cancer however FL efficacy is not affected by p status FL is rapidly accumulated in tumor T andgt h FL has a therapeutic index TI e against colon and head andamp 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 FL fails at some point in the drug development process All in all FL has already passed several hurdles and appears to effectively overcome many known mechanisms of resistance These features make FL 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 FL as an anticancer agent for fighting resistant colon cancers Test of Feasibility We must observe a TI of FL e a terminal half life e hrs in tumor overcoming topotecan resistance in human colon cancer models and FL 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 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 day waiting period Many cancers share these common mechanisms of resistance thus FL may be effective against different types of cancers Such studies will follow later as developing FL in all cancer types at once is not practical PUBLIC HEALTH RELEVANCE There are about 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
Canget Biotekpharma, Llc | Entity website
Partnership: We welcome partners from pharmaceutical companies and/or other investors to develop anticancer drugs together with Canget BioTekpharma from its pipeline and share the benefits Contracts: Provide genetically engineered cancer cell-based drug screening model systems for other pharmaceutical companies to screen their own compound libraries (US Patent No.: US 7,569,221 B2) Canget BioTekpharma Company Copyright ...