Sunitinib Latest "Smart" Cancer Drug to Show Toxic Heart Side EffectsDec 18, 2007 | Parker Waichman LLP
Sunitinib, a so-called “smart” cancer drug, may be associated with toxic cardiac side effects, despite previous assumptions to the contrary. Researchers at Children's Hospital Boston, Dana-Farber Cancer Institute (Boston), and Thomas Jefferson University (Philadelphia) conducted a collaborative study, led by Ming Hui Chen, MD, MMSc, a cardiologist specializing in the cardiac health of cancer patients. Sunitinib is one of several new "smart" cancer drugs called tyrosine kinase inhibitors that target specific signaling molecules inside cancer cells that aid cancer spread. Another targeted cancer therapy, imatinib, was reported last year to be associated with heart failure in patients with chronic myelogenous leukemia. Chen is also affiliated with Brigham and Women's Hospital and Harvard Medical School. Children's has a long history of researching the cardiovascular effects of cancer drugs.
Sunitinib was originally thought to be relatively free of cardiac side effects; however, a new retrospective analysis, focused on cardiovascular events, revealed a risk for heart failure, myocardial infarction, and hypertension in 75 adult patients with imatinib-resistant, gastrointestinal stromal tumor (GIST) receiving multiple cycles of sunitinib in a phase I/II trial at Dana-Farber. Of the 75, six—or 8%--developed symptoms consistent with moderate-to-severe congestive heart failure; two suffered heart attacks. In all, eight—or 11%--experienced some sort of cardiovascular event while receiving sunitinib at Food & Drug Administration (FDA) -approved or lower doses; patients with preexisting coronary artery disease were more likely to develop cardiac problems. Nineteen percent of the 36 patients receiving the FDA-approved dose had decreases in left ventricular ejection fraction, a measure of the heart's pumping ability. In addition, 47%—35 of 75—developed hypertension, a common side effect with certain cancer drugs. The degree of hypertension—taking into account both the percentage of affected patients and the magnitude of the systolic blood-pressure increase—was notable, according to Chen.
Two biopsies revealed abnormalities in the heart cells' mitochondria (the structures responsible for energy production). Further studies, led by Maria Rupnick, MD, of the Children's Hospital Boston Vascular Biology Program, and Thomas Force, MD, from the Center for Translational Medicine and Division of Cardiology at Jefferson, examined heart-muscle cells from mice who had received the equivalent of a human dosage of sunitinib alone, and found direct evidence of cardiotoxicity. "Early identification of cardiac side effects is an important part of keeping patients on life-saving cancer therapy over the long-term," says Chen. "This sunitinib study highlights potential concerns with agents that are 'multi-targeted,' meaning they inhibit multiple factors involved in cancer progression," adds Force.
George Demetri, MD, a co-author on the paper and director of the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School said, "The most important element of this new work is the close, creative collaboration between our medical oncology and cardiology teams. As our molecular targeting involves more pathways, we can inform one another's fields and identify side effects early by working together across traditional disciplinary boundaries." Chen remains hopeful that this sort of multi-disciplinary approach, “from the patient's bedside to the basic cell biology laboratory, will lead to further pharmaceutical advances that will make these 'smart' cancer drugs even smarter."