Hedgehog Antagonists May Harm Cardiac Function as Well as Tumors

Allison Gandey

June 26, 2008

June 26, 2008 — Hedgehog antagonists are emerging as promising new anticancer therapeutics, but early research has identified a potential problem. The new drugs might impair more than just tumors; they appear to also damage cardiac function. The study, published online June 20 in the Journal of Clinical Investigation, might help explain why so many anticancer agents have harmful effects on the heart.

"Oncologists and cardiologists are coming at the same problem from opposite ends," lead author Kory Lavine, MD, from the Washington University School of Medicine, in St. Louis, Missouri, told Medscape Oncology. "We may be starting to understand the challenge this presents."

Could antiangiogenesis — the process of cutting the blood supply to tumors, and a mainstay of many cancer therapies — have other off-target effects on the cardiovascular system? Antiangiogenesis helps kill tumors, but can it harm the heart as well?

Dr. Lavine and his team suggest that this could be the case.

The hedgehog-signaling pathway is a chain of biochemical signals that regulates cellular growth and differentiation. Every organism in the animal kingdom has hedgehog genes; they play an essential role in helping cells mature to the appropriate form. The name hedgehog caught on when scientists observed the spiky hedgehog-like appearance of fly embryos.

Hedgehog Pathway Implicated in Different Types of Cancer

A number of studies suggest that abnormal activation of the hedgehog pathway is implicated in many different types of cancer. Drugs that impede hedgehog signaling are being tested against several of these cancers, including basal cell carcinoma, prostate cancer, pancreatic cancer, colorectal cancer, and medulloblastoma.

But Dr. Lavine and colleagues are the first to show that hedgehog signaling is essential in maintaining a healthy supply of blood vessels in the heart muscle of adult organisms.

The researchers had been studying how blood vessels in heart muscle develop in growing embryos. They recently found that the hedgehog-signaling pathway is vital to the development of the heart's blood supply. Now the team has shown that the hedgehog-signaling process is important, not just in the early development of the heart, but also in adult hearts, to maintain cardiac blood vessels.

"Given the profound effect of removing hedgehog signaling from the myocardium, caution should be taken in the development of these pharmaceuticals," write the authors. "It is possible that therapeutic effects of hedgehog antagonists may be achieved at levels of inhibition that do not impair cardiac function," they note.

May Also Be Essential to Maintain Blood Vessels in the Heart

The investigators found that completely blocking hedgehog signaling in the hearts of adult mice caused many small coronary blood vessels to disappear, leaving heart muscle short of oxygen and leading to heart failure. In mice with experimentally induced heart attacks, mildly inhibiting hedgehog signaling led to a worsening of their heart conditions.

"We gave mice small amounts of antibodies against hedgehog, and in those that had a recent myocardial infarction," Dr. Lavine explained in a news release, "this led to poorer heart function and some lethality."

During an interview with Medscape Oncology, Dr. Lavine elaborated: hedgehog signaling in the vasculature of the heart means that it could be a target for new drugs to treat heart disease.

The study also suggests that hedgehog signaling could be required to maintain blood vessels elsewhere in the body. Could hedgehog signaling be important in the brain, with its dense capillary network? And might this be useful in treating strokes?

But what will promoting hedgehog signaling mean for cancer patients? Will these products fuel tumor growth? And will new hedgehog antagonists that target tumors promote cardiotoxicity and strokes?

"This finding should serve as a warning that these drugs might have adverse effects," senior author David Ornitz, MD, from the Washington University School of Medicine, said in a news release. "It could be very important to monitor patients."

The researchers have disclosed no relevant financial relationships.

J Clin Invest. Published online before print June 20, 2008. Abstract

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