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 95), 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 99mTc- SPECT-CT. Hence, we propose AAAPT leading candidates AMP-001/002 to be neoadjuvant to chemotherapy (e.g. doxorubicin) in order to reduce ARC since combination of AAAPT and doxorubicin has reduced IC50 significantly in vitro compared to doxorubicin alone.
Our specific aims are;
Specific Aim 1 : To a) synthesize leading AAAPT candidates AMP-001-002 and b) validate sensitization of TNBC MDA-MB-231 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 6 months. The objective will be accomplished at Sci-Engi-Medco Solutions associated laboratories under PI/PD supervision.
Specific Aim 2 : To a) determine the dose at which doxorubicin exhibit cardiotoxicity in orthotopic TNBC MDA-MB- 231 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 99mTc-SPECT-CT, which will be carried out by Dr. Pomper/Gabrielson at Johns Hopkins University.
Specific Aim 3 : To assess the efficacy of AMP-001/AMP-002 and doxorubicin combination for tumor regression with low or no cardiotoxicity in vivo using two animal models namely, TNBC MDA-MB-231 and BT4 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, PI3K inhibitor Novartis) and other cancers (e.g. colon, lung, prostate, breast, brain and renal) which are refractory to current treatments.
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 99mTc-SPECT-CT for a potential risk stratification of patients for chemotherapy related cardiotoxicity prior to the development of cardiomyopathy.
