PET imaging of Chemotherapy-Induced Cardiotoxicity - Title: PET Imaging of Chemotherapy-Induced Cardiotoxicity Abstract. Cardiovascular disease is now the second leading cause of long‐term morbidity and mortality among cancer survivors. Both conventional chemotherapy and targeted therapies are associated with an increased risk of myocardial damage, resulting in left ventricular dysfunction and heart failure. Overall, cardiotoxicity from chemotherapeutic agents have been observed with drugs encompassing wide range of structural domains, including anthracyclines (Doxorubicin), alkylating agents (Cisplatin), taxanes (Paclitaxel), and monoclonal antibodies (Herceptin etc). Therefore, noninvasive detection strategies capable of providing a very early and specific readout prior to development of decreased cardiac function could significantly impact patient care, allowing for early treatments of cardioprotective therapies and modification of chemotherapeutic regimens. To accomplish this objective, our team has developed 68Ga-Galmydar, a novel PET tracer which gives a highly sensitive and specific functional readout of mitochondria status within the myocardium. Deploying the fluorescent traits of this molecular imaging probe, we have performed live-cell fluorescence imaging which has shown a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment. Data show uptake profiles that are both dose- and time-dependent. 68Ga-Galmydar micro-PET/CT imaging demonstrates a 1.91-fold lower uptake and retention in hearts of DOX-treated rats compared to their vehicle treated control counterparts. Biodistribution studies performed post-imaging also confirm these imaging derived- SUV data. These data strongly indicate that 68Ga-Galmydar PET imaging has the potential to serve as a noninvasive strategy for the detection of DOX-induced cardiotoxicity at earliest stages. Armed with this provocative preliminary data, the specific aims of this RO1 proposal are: 1) A. Assess the potential of 68Ga- Galmydar to monitor chemotherapy (DOX, Paclitaxel, Herceptin)-induced cardiotoxicity with or without cardio- protectants and perform comparative analysis with 2 reference standards (13N-Ammonia; perfusion and cell viability marker) and fasting 18F-FDG (inflammation marker) in rabbit models in vivo. B. Validate the potential of 68Ga-Galmydar PET imaging to provide early detection of cardiotoxicity prior to other imaging-demonstrable functional and structural myocardial abnormalities. Specifically, PET findings will be compared to MRI-determined myocardial strain, and native myocardial T1 values, T2 values, extracellular volume (ECV), and late gadolinium enhanced (LGE) imaging, under identical conditions. Rabbit models will be imaged with PET/MRI. 2) Evaluate 68Ga-Galmydar potential for noninvasive detection of chemotherapy-induced cardiotoxicity in breast cancer (n=10) and lymphoma patients (n=20, 15 males and 5 females) and perform comparative analysis with 18F-FDG to evaluate concurrent myocardial inflammation (as positive contrast to expected 68Ga-Galmydar signal decrease) in same participants. Successful completion of the proposed aims will deliver a versatile molecular PET imaging tracer for monitoring earliest stages of myocyte impairment in patients undergoing chemotherapy, thus steering the field towards imaging-guided stratification of treatment plans within medical oncology and benefiting the management of cancer patients.
