SCI-ENGI-MEDCO SOLUTIONS, INC — Department of Health and Human Services SBIR Phase I: 102

Description

Project Summary Abstract Chronic cardiotoxicity is a clinically unresolved issue for cancer patients who are treated particularly with anthracycline based drugs Currently triple negative breast cancer TNBC patients have no option but to rely on these nonspecific chemotherapeutics New technologies are needed to reduce the off target toxicity including anthracycline related cardiotoxicity ARC and more importantly monitor the reduction of cardiotoxicity in vivo A priori activation of apoptosis of pathways of tumor AAAPT is a novel technology which sensitizes low responsive tumor cells and cancer stems cells CSCs in several types of cancers e g colon lung prostate breast brain and renal by multiple mechanisms including a activating cell death pathway CD b inhibiting survival pathway NF kB and c inhibiting poly ADP ribose polymerase PARP Most cancer cells circumvent exogenous and endogenous toxicity by deactivating cell death pathway activating inhibition pathway and hyperactivating PARP in heart leading to cardiotoxicity Current guidelines for predicting monitoring ARC include left ventricular ejection fraction LVEF LV volume and diastolic function which appear to be too late as compared to biological functions at molecular level such as cell death in heart Our collaborators from Johns Hopkins University have demonstrated the prediction of dose dependent cardiotoxicity for doxorubicin using mTc SPECT CT Hence we propose AAAPT leading candidates AMP to be neoadjuvant to chemotherapy e g doxorubicin in order to reduce ARC since combination of AAAPT and doxorubicin has reduced IC significantly in vitro compared to doxorubicin alone Our specific aims are Specific Aim To a synthesize leading AAAPT candidates AMP and b validate sensitization of TNBC MDA MB cells to front line therapeutics e g doxorubicin gemcitabine Herceptin and paclitaxel and c assess the cardiotoxicity of the combination of drugs in induced pluripotent stem cell derived cardiomyocytes iPSc during first months The objective will be accomplished at Sci Engi Medco Solutions associated laboratories under PI PD supervision Specific Aim To a determine the dose at which doxorubicin exhibit cardiotoxicity in orthotopic TNBC MDA MB tumor xenograft nude rat nu nu by quantifying cell death in myocardium correlated to cardiotoxicity The milestones include in vivo tumor cardiotoxicity data corroborated with transthoracic echocardiography and cell death in myocardium by tunnel assays respectively and further correlated to image density in mTc SPECT CT which will be carried out by Dr Pomper Gabrielson at Johns Hopkins University Specific Aim To assess the efficacy of AMP AMP and doxorubicin combination for tumor regression with low or no cardiotoxicity in vivo using two animal models namely TNBC MDA MB and BT tumor xenograft nude rat nu nu model The milestones include a tumor volume measurement correlated to tumor cell death using SPECT CT imaging histology of tumor ex vivo with tunnel assays and b quantification of cardiotoxicity Expected Outcome The foremost outcome is a potential use of AAAPT as a neoadjuvant to chemotherapy and SPECT CT as an imaging tool to risk stratify patients for CRC prior to develop cardiomyopathy The second outcome would be a potential extension of AAAPT synergy to other front line chemotherapeutics e g doxorubicin gemcitabine carboplatin PI K inhibitor Novartis and other cancers e g colon lung prostate breast brain and renal which are refractory to current treatments Project Narrative Cardiotoxicity is a chronic clinical issue for chemotherapy treated cancer patients particularly for triple negative breast cancer patients who would not respond to regular receptor based targeted therapy The goal of our proposal is to reduce cardiotoxicity by using novel targeted apoptosis activation technology as a neoadjuvant to chemotherapy We propose theranostics of reduction of cardiotoxicity by adding imaging component using mTc SPECT CT for a potential risk stratification of patients for chemotherapy related cardiotoxicity prior to the development of cardiomyopathy