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

Abstract The goal of this fast track SBIR proposal is to file an investigational new drugINDapplication for testing a novel anticancer drugFLthat is designed to overcome inherent and acquired treatment resistanceMany types of cancers are not detected until they are very advanced and have already become resistant to FDA approved treatmentsIn additionmany non advanced cancers respond well to initial treatments and then develop resistanceThereforeovercoming resistance to treatment is a major goal in the fieldWe are focused first on treatment of colorectal canceras it accounts forof all cancer deaths in the United StatesMany colorectal cancers have developed resistance by the time they are detected and many develop resistance during treatmenteven though the cancer was detected fairly early onThese treatment resistant cancers result in painful deathsUpregulation of SurvivinXIAPcIAPand Mclcontributes the treatmentdrugradiationresistance of colorectal cancerFLreduces expression of these four gene productsIn additionFLovercomes topotecan resistanceresistance derived from Topmutations or from overexpression of ABCGBCRP or ABCCMRPLoss or mutation of pis also an important resistance factor in cancerhoweverFLefficacy is not affected by pstatusFLis rapidly accumulated in tumorTandgthFLhas a therapeutic indexTIagainst colon and head andampneck cancers using a clinically relevant method for the calculation of TIFinallywe have several backup compounds and have a medicinal chemistry program in parallelin case FLfails at some point in the drug development processAll in allFLhas already passed several hurdles and appears to effectively overcome many known mechanisms of resistanceThese features make FLnot only be a very safe anticancer drug but also highly effective to overcome treatment resistance and advanced colon cancerIn Phase Iour Specific Aim is to test the feasibility of using FLas an anticancer agent for fighting resistant colon cancersTest of FeasibilityWe must observea TI of FLa terminal half lifehrs in tumorovercoming topotecan resistance inhuman colon cancer modelsandFLhas good efficacy in an immuno competent cancer modelIf our test of feasibility is metwe will apply for Phase II fundingOtherwisewe will notThusthe risk to the NIH is no more than a Phase Ibut the fast track approach can save our company up tomonthswhich is important for a start up companyIn Phase IIour Specific Aim is to file an INDWe will carry out all IND enabling studiesto this endCriteria for SuccessThe FDA must accept our IND and allow for clinical Phase I IIa studies to begin explicitly or implicitlyi enot say no within the standardday waiting periodMany cancers share these common mechanisms of resistancethus FLmay be effective against different types of cancersSuch studies will follow lateras developing FLin all cancer types at once is not practical Narrative There are aboutcancer deaths in the US each yearThese deaths are primarily due to the fact that cancers become resistant to FDA approved treatmentsThereforeovercoming resistance to treatment is a major goal in the fieldThis 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