Molecular Cardiology Research Institute (MCRI)

Human Clinical: Tufts Medical Center

Cardiology:
Iris Jaffe, MD, PhD
Gordon Huggins, MD

Cardio-Oncology
Jenica Upshaw, MD

Oncology
Rachel Buchsbaum, MD
Susan Parsons, MD

Veterinary:Cummings School

Vet Cardiology, Exosomal MicroRNAs
Vicky Yang, DVM, PhD

Comparative Oncology
Cheryl London, DVM, PhD

Basic Cardiovascular Science: Molecular Cardiology Research Institute

Vascular Biology, Hypertension:
Iris Jaffe, MD, PhD

Cardiovascular Biology, Pharmacology:
Lakshmi Pulakat, PhD

Cardiac Biology, Heart Failure, Genetics
Gordon Huggins, MD

Cardiomyocyte, Death Imaging
Howard Chen, MD

Statistical Methods: BERD, IRCHPS, Tufts CTSI

BERD Director,
Norma Terrin, PhD

Statistician
Lori Lyn Price, MAS

Iris Jaffe, MD, PhD

My lab explores molecular mechanisms of cardiovascular disorders including hypertension, atherosclerosis, vascular remodeling after injury, vein graft failure, pulmonary hypertension and pre-eclampsia. We use in vitro molecular techniques in human vascular cells, whole vessels studies of vascular contractile and relaxation function, global genomic, gene expression and proteomic techniques, and in vivo mouse models with state-of-the-art transgenic and tissue-specific knockouts. The long-term goal is to identify novel and improved therapies to prevent and treat cardiovascular disease. More recently we have begun to explore the vascular complications of cancer therapies as they pose a conundrum in cardiology care with limited mechanistic understanding. To begin to systematically understand the direct effects of cancer drugs on the endothelium, we collaborated with J. Jaffe at the Broad Institute to perform proteomic studies on ECs treated with cancer drugs. We identified a phospho-proteomic profile associated with endothelial toxicity of ABL-kinase targeted CML therapies. The proteomic strategy predicted that the new CML drug bosutinib would be non-toxic and this was confirmed in vitro in human ECs and recent clinical data supports the conclusion. A similar approach used phospho-proteomics to determine a signature of VEGFRI-induced responses in ECs that we are using to understand the mechanism of VEGFRI-induced hypertension and to predict better ways to control blood pressure in cancer patients treated with these agents.

Gordon Huggins, MD

My research lab is interested in uncovering the genetic regulators contributing to cardiomyopathy and heart failure. Specifically, on a clinical and basic research basis we contribute to genetic analysis of patients with cardiomyopathy and investigate the molecular mechanism(s) responsible for the heart failure. In collaboration with MCRI and CVC investigators studying heart failure, we are interested in understanding how the heart responds to chemotherapy and how genetic factors may interact with treatment in a way that causes heart failure. We continue exploring the underlying mechanisms with the ultimate goal of developing personalized therapies that will prevent or reverse cardiomyopathy that is so devastating in heart failure patients.

Jenica Upshaw, MD

The goal of my research is to improve outcomes of patients with cancer who are receiving potentially cardiotoxic cancer treatment. Recent work in cardio-oncology has included a systematic review of the cardiac complications of patients treated for Hodgkin’s Lymphoma, longitudinal assessment of echocardiographic changes with breast cancer therapy, analysis of fluoropyrimidine cardiotoxicity trial reporting and the development of a clinical prediction model for anthracycline cardiotoxicity. I am an active member of the ECOG-ACRIN Cardiotoxicity Subcommittee, the American College of Cardiology Cardio-Oncology section and an Assistant Editor of JACC: CardioOncology. Clinically, I care for patients with cardiovascular disease and cancer and have expertise in the clinical manifestations of cancer-therapy associated cardiovascular toxicity.

Rachel Buchsbaum, MD

I am interested in breast cancer therapy, risk assessment and prevention. My lab is exploring the role of the tumor microenvironment in breast cancer biology, with a specific focus on how intra-cellular and inter-cellular signaling pathways are affected in the co-evolution of breast cancer and the breast cancer microenvironment. A major aim is translating our findings in the laboratory to the development of prognostic, predictive, and therapeutic tools for the treatment of patients with breast cancer.

Susan Parsons, MD

My primary research interests include the assessment of quality of life, functional impact, and fiscal impact of chronic illness on children and their families with a focus on childhood cancer and HSCT. I am also actively involved in survey instrument and methodological design and interpretation and actively mentors health professionals in this field. I am the Director of the program on Measurement, Outcomes, and Statistics, of the Tufts Cancer Center.

Vicky Yang, DVM, PhD

My main research interest includes non-ischemic cardiac diseases in veterinary patients, including myxomatous mitral valve disease (MVP) and cardiotoxicity secondary to anti-cancer therapy. Because of the similarities between many veterinary and human cardiac disorders, I am particularly interested in the translational and comparative utility of veterinary patients for human diseases. For example, dogs develop nearly identical cardiac responses to the most common anti-cancer agents, including doxorubicin. My laboratory is specifically interested in understanding how extracellular vesicle-associated non-coding RNAs contribute to cardiovascular injury secondary to anti-cancer therapy. We are also interested in evaluating their potential as novel biomarkers and therapeutic targets in.

Cheryl London, DVM, PhD

My work bridges clinical and laboratory studies in comparative oncology, a field that brings together researchers from veterinary and human medicine to advance our understanding of cancer biology, as well as improve cancer treatment in both pets and people. I oversee studies of novel therapies and diagnostics in animals with naturally occurring cancer and other diseases, aiming to optimize cutting-edge approaches for pets before moving them into human trials. My research centers on the identification, validation, and improvement of small molecule and immune modulatory treatment strategies.

Lakshmi Pulakat, PhD 

Research in our lab is focused on characterizing cardiovascular reparative signaling pathways that have the potential to repair cardiovascular damage arising either from chronic diseases (diabetes, obesity), or drug treatments (such as chemotherapy). We reported that Angiotensin II type 2 receptor (AT2R), that promotes anti-inflammatory signaling is part of the cardiac signature that defines cardiac structural and functional integrity in female diabetic rats. We also showed that AT2R directly interacts with ErbB2 (a molecule implicated in cardiovascular and neural protection as well as in promoting aggressive breast cancer and many other cancer types, including ovarian, stomach, bladder, salivary, and lung carcinomas), indicating the potential of AT2R to regulate ErbB2 signaling. Moreover, we found that AT2R increased the expression of neuro-protective and proliferative marker MCL-1, yet suppressed human breast cancer cell growth. Based on our observations (both published and preliminary), we think that increasing AT2R expression and activation can be cardiovascular and neural protective and will attenuate cardiac and brain damage caused by diabetes and/or chemotherapy. In collaboration with industry, we study protective effects of new AT2R agonists that increase AT2R expression and signaling in human and murine cardiovascular cells, and inhibitory effects of these drugs on human cancer cell growth. We use cell culturing and animal models for diabetes, cancer, and chemotherapy-induced cardiotoxicity, combined with genomics, proteomics and bioinformatics approaches to define changes in cardio-protective molecular signature in response to diabetes and drug treatments. Our ultimate goal is to develop new treatment paradigms to mitigate myocardial structural damage (fibrosis, scarring) resulting from metabolic diseases and cardiotoxic drug treatments, and determine whether AT2R peptide agonists are effective in the treatment of diabetes- and chemotherapy-associated cardiac damage in children and adults.

Howard Chen, MD

I am interested in breast cancer therapy, risk assessment and prevention. My lab is exploring the role of the tumor microenvironment in breast cancer biology, with a specific focus on how intra-cellular and inter-cellular signaling pathways are affected in the co-evolution of breast cancer and the breast cancer microenvironment. A major aim is translating our findings in the laboratory to the development of prognostic, predictive, and therapeutic tools for the treatmentMy research lab aims to develop molecular imaging technology to investigate the molecular mechanisms of cardiotoxicity after cancer therapy, specifically by directly image the crosstalk among cell death and survival processes. My lab showed that a targeted nanoprobe sensitive to autophagy, a cellular response to stress conditions, can be multiplexed with apoptosis (programmed cell death) imaging to allow simultaneous detection and quantification in vivo. We discovered that impairment in cardiomyocyte autophagy after chemotherapy leads to increased cell death. Interestingly, autophagy stimulation by pharmacological means or by fasting restores basal autophagic activities, reduces cardiomyocyte death, and enhances cardiac function. We continue to explore the underlying molecular mechanisms to better predict the risk for cardiotoxicity, and to evaluate therapeutic interventions that will impact the millions of cancer patients undergoing chemotherapy of patients with breast cancer.

Norma Terrin, PhD

Research Interest and Expertise Relevant to Cardio-Oncology: I am interested in research on statistical methods and in their application for addressing clinical and translational research questions. I served on the faculty of the Department of Statistics at Carnegie Mellon University, where I taught and conducted research in stochastic processes and statistical methodology. Since coming to Tufts Medical Center in 1996, my methodological research has included longitudinal analysis, joint models for longitudinal and survival outcomes, meta-analysis, publication bias, predictive modeling, and model performance. My funding as Principal Investigator has come from the National Science Foundation (NSF), the Agency for Healthcare Research and Quality (AHRQ), and the National Cancer Institute (NCI). I collaborate with clinical, translational, and health services researchers in many departments across the Tufts CTSI affiliates, including Hematology-Oncology and Cardiology. I have experience with hierarchical models, which will be especially relevant for the 3-species research we plan to pursue in the cardio-oncology project.

Lori Lyn Price, MAS

The statistical and data management expertise I bring to the project are not specific to cardiooncology research, but based on almost 20 years of experience working as a collaborative statistician for both NIH-funded projects and smaller projects funded by other means.

Trainees:

Kimberly Majoy, CVT, VTS, MPH

I am dedicated to promoting animal health and advancing the science of diagnosing, treating, and preventing animal diseases. I am involved in clinical and laboratory studies in comparative oncology, a field that brings together researchers from veterinary and human medicine to advance our understanding of cancer biology, as well as improve cancer treatment in both pets and people.

Sally Robinson, DVM, PhD

Canine cancer patients are susceptible to cardiovascular toxicity arising from cancer therapy. A major focus of the Yang Lab is to improve our ability to detect and manage negative effects of cancer therapy on the cardiovascular system. Doxorubicin is commonly used in veterinary oncology to treat many types of cancer but can result in cardiotoxicity. Earlier detection of cardiac damage is needed during therapy so cardioprotective measures can be implemented before irreversible damage occurs. We study extracellular vesicles that are secreted by cells of the body into the circulation and the microRNA they contain (EV-miRNA) in canine cancer patients undergoing therapy with doxorubicin. Our preliminary studies have shown that EV-miRNA may serve as biomarkers of early cardiotoxicity. My primary focus is to investigate the role of autophagy in preventing apoptosis during doxorubicin induced cardiotoxicity and have optimized culture of myocardial tissue slices to investigate these processes. I plan to explore the role of EV-miRNA secreted from cardiac tissue in regulating genes that control the balance between autophagy and apoptosis. From these studies, we can determine if modulating autophagy through genetic or pharmacologic approaches is a rational cardioprotective strategy in the setting of cancer therapy-associated cardiotoxicity.

Joshua Man, BA

I am studying the mechanisms of vascular toxicity associated with targeted cancer therapies. Using cellular and mouse models, we are particularly interested in understanding the mechanisms by which 1) tyrosine kinase inhibitors (TKI) used to treat chronic myeloid leukemia increase the risk of heart attack and stroke; and 2) vascular endothelial growth factor receptor inhibitors used to treat multiple cancers cause elevated blood pressure. In collaboration with the Broad Institute, we have previously composed a phosphoproteomic signature of TKI-associated toxicity in human endothelial cells by mass spectrometry that was able to accurately predict the toxicity of a relatively unknown TKI. Based on this proof-on-concept, we hypothesize that this approach enables us to predict the vascular toxicity profile of other cancer therapies in development and nominate “antidotes” with opposing signatures that can mitigate these toxicities and improve outcomes in cancer patients and survivors.