Faculty Spotlight: Javid Moslehi, MD

Cancer and Heart Disease

Thanks to novel cancer drugs and other advances, more than 18 million Americans are now cancer survivors. But these lifesaving therapies can cause cardiovascular side effects, both during treatment and years after. In response, a new discipline called “cardio-oncology” has emerged, which focuses on the cardiovascular health of cancer patients and survivors.

To improve care for cancer patients from diagnosis through survivorship, in 2021 the UCSF Division of Cardiology recruited Javid Moslehi, MD, founding chief of the Section of Cardio-Oncology and Immunology and the William Grossman, MD Distinguished Professor in Cardiology. And with his interdisciplinary approach and outstanding experience as a physician-scientist, Dr. Moslehi and his colleagues are leveraging discoveries about the heart health of cancer patients to better understand the underpinnings of all types of heart disease, far beyond those caused by cancer or cancer therapies.

In his first year, Dr. Moslehi has grown the Section of Cardio-Oncology and Immunology to include five faculty members, launched a cardio-oncology fellowship program, and increased patient volume, attracting up to 12 new patients each week. He has also continued his innovative cardio-oncology research in collaboration with an international team of colleagues, making fundamental discoveries about many aspects of this emerging subspecialty.

Thriving at the Intersections of Discovery

Dr. Moslehi’s journey to becoming a world expert in the burgeoning field of cardio-oncology included a few serendipitous turns. Born in Tehran, Dr. Moslehi moved to Wisconsin with his family when he was ten, eventually settling in Connecticut. He originally wanted to be a journalist and landed an unpaid summer internship at the New Haven Register. To pay the bills, he also found a day job in a Yale laboratory performing blots for Lyme disease, where he was first exposed to medicine.

“I realized that academic medicine was like journalism in many ways,” said Dr. Moslehi. “You wrote a lot, which was very enticing.” At Johns Hopkins University, he changed his major from journalism to biology, then earned his medical degree from the University of Connecticut School of Medicine.

Throughout his career, Dr. Moslehi has thrived at the intersection of different disciplines. During medical school he spent an extra research year as a Sarnoff Fellow at Harvard Medical School, which inspired him to become a physician-scientist. And while he had a difficult time deciding between cardiology and oncology, he found a way to weave them together.

After completing his internal medicine residency at Johns Hopkins Hospital and cardiology fellowship at Brigham and Women’s Hospital, Dr. Moslehi finished a postdoctoral research fellowship at the Dana-Farber Cancer Institute in Boston. He worked in the lab of William Kaelin, MD, who won the Nobel Prize in 2019 for his work on how our bodies sense hypoxia, or low oxygen availability.

Dr. Moslehi’s time at Dana-Farber was fruitful for another reason. “Most of my colleagues were oncologists, and some had cancer patients with heart problems,” he recalled. To help out, Dr. Moslehi started seeing these patients, and soon realized this was a new frontier. “Thinking outside the box has a lot to do with your environment,” he said. “When you talk to people who don’t do exactly what you do, you learn a lot. In this case, I realized that cancer patients were generally doing better than even five years earlier because of new drugs. However, they encountered many new cardiovascular problems that had never been described. That’s when I realized this was a young but exploding field.”

Dr. Moslehi discussed his vision with one of his mentors, Kenneth Baughman, MD, who recruited him in 2009 to establish a cardio-oncology clinic at Brigham and Women’s Hospital. “We both recognized that because of the novelty, there would be a research perspective as we uncovered these new cardio-oncology problems,” said Dr. Moslehi. “I took it on as a mission. As an academic physician, it’s rewarding to discover what problems patients have, then try to solve them in the lab.”

After five years co-directing that program, Dr. Moslehi was recruited to Vanderbilt University Medical Center in Nashville, leading their cardio-oncology program, co-directing the Vanderbilt Program for Optimizing Immuno-Oncology Therapy (V-POINT), as well as starting his own basic research laboratory.

New Treatments, New Diseases

The field of cardio-oncology is about 15 years old and is growing exponentially. “The cardiovascular care of cancer patients emerged because of the success our oncology colleagues have had in treating cancer,” said Dr. Moslehi. “If you are diagnosed with biopsy-proven breast cancer in the U.S., your chance of being cancer-free in five years is greater than 90 percent, a number unimaginable a decade ago. It’s similar in prostate cancer. New treatments have revolutionized cancer treatment, and one in 20 people in this country are now cancer survivors.”

As survivors age, other health concerns come to the fore, including cardiovascular health. Many cancer therapies have adverse effects on the heart, partly because what’s good for killing cancer can be bad for heart health. “My lab did a lot of work on angiogenesis, or new blood vessel growth,” said Dr. Moslehi. “As a cancer doctor you’re trying to kill blood vessels [that feed the tumor], but if you’re a cardiologist, you need those blood vessels to supply the heart and body.” Radiation can also increase the risk of heart disease, as he described in an editorial about breast cancer survivors who faced increased risk for heart attack decades after treatment.

Then there are new therapies like cancer immunotherapies, which harness a patient’s own immune system to target and kill cancer cells. These powerful therapies have transformed cancer care, yielding sometimes dramatic, even miraculous results. But there is a dark side: sometimes there is collateral damage to healthy tissue, in ways never seen before. “With these new treatments we’ve seen new toxicities, including cardiovascular issues that represent a new frontier,” said Dr. Moslehi.

For example, myocarditis is inflammation of the heart, usually caused by a virus. But some cancer patients develop immunotherapy-associated myocarditis, particularly those who receive a type of immunotherapy called immune checkpoint inhibitors (ICIs). Dr. Moslehi and his colleagues first identified this clinical syndrome, creating the International ICI-Myocarditis Registry, which has collected data on more than 800 cases so far. They also created CardioOnc.org, a website with educational content for both doctors and patients which was highlighted in the Washington Post.

Dr. Moslehi and his team delved into the cause of ICI-myocarditis, finding that abnormal T-cell activation in the heart was critical in this rare but potentially life-threatening condition. “When you remove the immune system’s brake pedal so it can attack cancer, sometimes you end up with ‘friendly fire’ that affects other organs,” he said. His laboratory created mouse models of this syndrome and investigated possible therapies, finding that abatacept, a rheumatoid arthritis drug, could help calm this overexuberant immune response. More recently, he and his former fellow, Joe-Elie Salem, MD, PhD, now professor at Sorbonne University in Paris, treated a patient with a combination of abatacept and ruxolitinib to reduce inflammation from ICI-associated myocarditis, and have gone on to successfully treat an additional 50 patients.

The underlying mechanisms of how this potentially life-threatening condition develop have been poorly understood, but Dr. Moslehi and his colleagues are discovering new clues. For example, he and Justin Balko, PharmD, PhD, an associate professor of medicine at Vanderbilt University, recently studied a mouse model and patient samples. Their findings suggest that patients who develop myocarditis have expanded CD8+ T cells which target a specific cardiac muscle protein called alpha-myosin.

“Everyone has this antigen, but not everyone develops T cells which target alpha-myosin,” said Dr. Moslehi. “It’s an example of using the models to identify the antigen and the possible trigger toward myocarditis. One can imagine developing therapeutics to potentially vaccinate susceptible people against ICI-myocarditis, the way we tolerize people with allergy shots.” Identifying the antigen would also allow cardio-oncology teams to screen patients at high risk for developing ICI-myocarditis, enabling clinicians to monitor those patients especially closely, or to titrate their medications to reduce the risk of complications. “It would be game-changing if we could predict which people can get the ICI therapies safely,” he said.

Interestingly, ICI-myocarditis is more common among women than men. Dr. Moslehi’s lab, along with a group at The University of Texas MD Anderson Cancer Center, recently discovered that sex hormones appear to inhibit the expression of two cardioprotective proteins in the heart which may help to lower the risk for developing ICI-myocarditis. Their findings suggest that restoring these factors might offer an effective treatment strategy. “To our knowledge, this is the first time we’ve been able to identify a contributor to the sex differences we see with immune-based therapies,” he said.

Dr. Moslehi is excited about the possibility of applying these cardio-oncology discoveries to other forms of myocarditis, including garden-variety myocarditis in the general population, myocarditis that develops among COVID patients, and the underlying reasons that young men have demonstrated higher risk for the rare but potentially serious side effect of some COVID vaccines. Dr. Moslehi hopes to establish a myocarditis center of excellence at UCSF, applying the latest techniques to better understand the biology of the disease and develop improved diagnostic and therapeutic strategies.

The Next Frontier

Dr. Moslehi joined the UCSF Division of Cardiology faculty in October 2021 and founded the Section of Cardio-Oncology and Immunology. His core team currently includes UCSF cardiologists Mandar Aras, MD, PhD, and Alan Baik, MD, as well as Jaya Mallidi, MD, MHS, director of Inpatient Cardiology at Zuckerberg San Francisco General Hospital and Trauma Center (ZSFG), who is developing a cardio-oncology group at ZSFG.

“Our goal is to not only provide excellent cardiovascular care to cancer patients, but also to use the lessons learned from the clinic – and our oncology colleagues – to understand heart disease in general,” said Dr. Moslehi. “The two biggest groups of new cancer drugs are immune-based therapies and drugs that target cancer metabolism. We're well-positioned at UCSF to learn about the side effects of these drugs, and to better understand other types of inflammatory and metabolic heart disease.”

The opportunity to work with experts in a range of fields helped inspire him to join the UCSF faculty. “UCSF has such a depth of science,” said Dr. Moslehi. “The UCSF Department of Medicine is one of the best out there, and has really great pulmonary and rheumatology groups.” His group partners with the UCSF Helen Diller Family Comprehensive Cancer Center, and each cardio-oncologist has at least one clinic based at the UCSF Bakar Precision Cancer Medicine Building, in addition to other sites.

“UCSF also has by far the best immunology program in the world,” said Dr. Moslehi. He is especially pleased to be part of UCSF’s Bakar ImmunoX Initiative, a highly collaborative program that powers interdisciplinary immunology research through sharing data, infrastructure, and state-of-the-art technology, as well as the UCSF CoLabs Initiative, a centralized hub of experts and specialized equipment.

Interconnected Systems

Part of Dr. Moslehi’s vision is to discover the mechanisms underlying cardiac side effects of cancer therapies, using these to shed light on common types of heart disease not caused by cancer therapies. “One of our major goals is to apply the new immunology techniques in cardio-oncology to other forms of inflammatory heart disease, and to really understand the immunological basis of cardiac disease,” he said, noting that COVID-19-associated cardiac issues are just the latest example of the complex interplay between immunology and cardiology. “From cardio-oncology, we can learn a lot about cardiovascular biology.”

Another example is work by his lab which described how vascular endothelial growth factor (VEGF) inhibitors, which include drugs such as Avastin, are designed to clamp down on tumors’ abilities to aggressively develop a network of blood vessels to feed themselves. Their cardiovascular side effects can include high blood pressure – a phenomenon reminiscent of pre-eclampsia, a serious pregnancy complication whose hallmark is also high blood pressure. Researchers are now investigating whether addressing disruptions in the VEGF signaling pathway could alleviate severe pre-eclampsia.

“A lot of the basic research in the last 30 years has focused on mice, where we knock out genes to understand how that affects cardiac function,” said Dr. Moslehi. “Unfortunately, that doesn’t always translate to humans. However, oncology drugs are targeted agents which go after specific molecules and pathways. If we study the cardiovascular side effects in patients, we can learn a lot about human cardiovascular biology. That can help fuel new rounds of innovation for the next best treatments for conditions such as heart failure.”

Dr. Moslehi is a leader in the emerging field of cardio-immuno-oncology, which studies the complex interrelations among these three fields, and how cardiovascular side effects of cancer therapies modulate the immune system. Adding to that rich complexity, he also studies how metabolism interfaces with these other dimensions. “Many cancer drugs, such as PI3 kinase inhibitors, target metabolism and can cause diabetes,” he said. “We think we can better understand diabetic heart disease by studying these patients.”

Research about connections between cancer and metabolic disease has a long history. In the 1920s, Nobel laureate Otto Warburg discovered that cancer cells devoured glucose, or blood sugar, to fuel their growth. He also found that they turned this fuel into energy, or metabolized it, through a relatively inefficient process that does not use oxygen.

Other scientists have since found that many genes that cause cancer and uncontrollable cell division also instruct cancer cells to gorge themselves on glucose. “It turns out that this abnormal metabolism also has effects on the cardiovascular system,” said Dr. Moslehi. “We have described new conditions that arise from therapies targeting cancer metabolism and think these have relevance to other forms of metabolic disease. That’s why we’ve incorporated both metabolism and immunology as new aspects of our section.”

Precision Cardio-Oncology

Another interesting aspect is that cardiovascular disease and cancer share many risk factors, including cigarette smoking, obesity, high cholesterol, diabetes, a sedentary lifestyle and aging. “If the risk factors for the two biggest causes of death – heart disease and cancer – are similar, it gives us an incredible opportunity to treat these common risk factors and prevent both diseases,” said Dr. Moslehi. “This would have an enormous public health impact.” Dr. Moslehi and his colleagues developed a prevention strategy they dubbed the “ABCDE Approach” to help prevent cardiovascular disease in cancer survivors, and which may also help prevent cancer recurrence.

And in an intriguing twist, scientists recently discovered that an acquired genetic mutation called clonal hematopoiesis of indeterminate potential (CHIP) was associated with doubling the chances of a heart attack or stroke, even in the absence of other risk factors. The CHIP mutation becomes increasingly common with age and is linked to leukemia. The good news is that most patients with CHIP mutations do not die of cancer, but the bad news is that many are at elevated risk of cardiovascular disease. Researchers hypothesize that these mutations drive increased inflammation and atherosclerosis.

Dr. Moslehi recently recruited Amy Lin, MD, PhD, a longtime mentee who recently completed a postdoctoral fellowship in the Dana-Farber Cancer Institute lab of Benjamin Ebert, MD, PhD, a world expert in CHIP mutations. Dr. Lin also serves as medical director of TenSixteenBio, a Bay Area biotech startup which seeks to discover therapeutic targets, identify high-risk patients, and develop tailored therapies for patients with CHIP mutations. “Amy wanted to stay connected with academia and patients, so she will spend part of her week in our CHIP Clinic,” said Dr. Moslehi. “It’s very helpful having one of the main directors of a company that’s at the forefront of discovery on our team. It will accelerate our ability to offer patients the opportunity to participate in the latest clinical trials.”

One important goal for the new section is to provide a precision medicine approach for each patient. “Oncologists have done a great job of using genetic tests to identify which patients will respond to which drugs,” said Dr. Moslehi. “However, we currently have no idea who will have cardiovascular issues arising from those drugs. We should learn from the oncologists about how to best develop personalized care.” He notes the importance of closer collaborations between oncologists and cardiologists in designing clinical trials, monitoring cardiovascular outcomes, and tailoring treatment plans that optimize the risk-benefit ratio for each patient.

Helping Cancer Survivors Thrive

Dr. Moslehi is a leader in discovering how to best care for the heart health of cancer patients, not just during cancer treatment but over the long haul. His group recently received a large R01 grant from the National Institutes of Health to study long-term cardiovascular effects of ICIs. The goal is not only to prevent acute cardiovascular events, but also minimize or prevent long-term damage.

“For every patient who receives immune checkpoint inhibitors and has fulminant myocarditis, there may be 10 patients who have subacute myocarditis and generally do well [during cancer treatment],” said Dr. Moslehi. “But what happens to that patient long-term after they’ve beaten the cancer?” Dr. Moslehi has served on the National Comprehensive Cancer Network’s survivorship committee, helping to draft guidelines to prevent and manage heart disease associated with cancer treatment. Similarly, he is part of a multidisciplinary team which developed guidelines for improving research of prostate cancer survivorship, including cardiovascular care.

Dr. Moslehi is passionate about cultivating the next generation of physician-scientists, and has helped launch the careers of leading cardio-oncologists in the U.S. and Europe, including former fellows Dr. Salem and Wouter Meijers, MD, PhD. In 2022, his team launched a new cardio-oncology fellowship program, and recruited their first cohort of fellows: Amir Munir, MD, and Yen-Chou Chen, MD, MBA. “One of my main goals when I came to UCSF was to develop future leaders in cardio-oncology who will research and innovate,” he said. The mission of this new fellowship is to train the next generation of leaders in cardio-oncology, including diverse academic physician-scientists who will help advance the field.

“Cardio-oncology is a new frontier which marries science, research and clinical medicine,” said Dr. Moslehi. “I can’t think of another area of cardiology where we have so many new clinical entities that have never before been described. You can’t open up a textbook and read about these diseases, because they didn’t exist 10 years ago.”

Dr. Moslehi is the inaugural holder of the William Grossman, MD Distinguished Professorship in Cardiology. “I am really excited that Dr. Javid Moslehi has joined the UCSF faculty,” said Dr. Grossman, Charles and Helen Schwab Endowed Chair in Cardiology. “He is a pioneer in the new field of cardio-oncology, making major discoveries that will not only improve the cardiac care of patients with cancer, but also illuminate our understanding of the underlying mechanisms of cardiovascular disease and how to best prevent and treat it. This will be a great boon not only for our patients here at UCSF, but around the world.”

“By joining our Division, Dr. Moslehi is making important contributions to the UCSF ecosystem and will continue our tradition of pathbreaking research and innovative patient care,” said Jeffrey Olgin, MD, Ernest Gallo-Kanu Chatterjee Distinguished Professor in Clinical Cardiology and chief of the UCSF Division of Cardiology.

“It’s been incredible to become part of the broader ecosystem of UCSF,” said Dr. Moslehi. “The people are what make this place so special. Everyone is so smart and collaborative, and we have such a rich pipeline of fellows who will be leaders of the next generation. I was expecting a lot when I came to UCSF, but I’ve been blown away by how great it is.”

Outside of medicine, Dr. Moslehi enjoys reading non-fiction, traveling, hiking, and playing tennis with his wife, dermatologist Katherine Redding, MD, MSPH. They recently became parents to their daughter, Noor Louise.

 

- Elizabeth Chur