Nanoparticle therapy blocks tumor angiogenesis without cardiac side effects

Preclinical cancer study has implications for inhibiting atherosclerotic plaque growth

Uncontrolled angiogenesis (new blood vessel growth) plays a critical role in the growth and spread of cancer. | Image courtesy of The Angiogenesis Foundation

The formation of new blood vessels, known as angiogenesis, is essential for embryonic tissue development, wound healing and regenerative functions.  But when this normal process goes awry, the oxygen and nutrients carried though blood vessels can spur tumor cells to multiply uncontrollably and lead to cancer in distant tissues.

Cancer medications inhibiting excessive growth of new blood vessels frequently target vascular endothelial growth factor (VEGF), the main driver of blood vessel formation in tumors.  While VEGF inhibitors have been a breakthrough in treating many cancers, the medications also cause cardiotoxic side effects, such as hypertension and blood clots, in some patients.

Seeking to improve selective targeting of tumor-associated vessels and the safety profile of anti-angiogenesis therapy, a team of scientists, including USF Health Heart Institute Director Samuel Wickline, MD, investigated the role of the developmentally critical transcription factor Etv2 in tumor angiogenesis. VEGF signaling helps blood vessels survive and maintain stability when disease is not present in addition to regulating tumor angiogenesis. But, Etv2 appears to be expressed only in cancer tissue in adults, making the molecular control mechanism an attractive target, said Dr. Wickline, a professor of cardiovascular sciences and medical engineering at USF Health Morsani College of Medicine.

Findings of the preclinical study, led by Washington University School of Medicine in St. Louis, were reported last year in JCI Insight.

Testing a new target

The researchers found that optimal tumor growth requires reactivation of dormant Etv2, and Etv2-deficient tumor blood vessels resembled normal, stable vessels when mice without tumors were compared to those in which the Etv2 gene was knocked out (disabled). They then injected into tumor-bearing mice nanoparticles carrying small interfering RNA (siRNA) specifically designed to hit and silence Etv2, with the intent of switching off the signaling needed to feed the tumor’s blood supply and fuel VEGF-induced tumor growth.

The treatment worked to block tumor angiogenesis without creating cardiovascular side effects associated with VEGF inhibitors.  More research is needed, but the study authors concluded that combining Etv2 inhibition with chemotherapy or immunotherapy may improve future cancer treatments.

Samuel Wickline, MD, director of the USF Health Heart Institute, and USF Health biomedical engineer Hua Pan, PhD, design nanoparticles to precisely deliver therapeutic molecules to specific cell types associated with inflammatory diseases.

A balance of signals circulating in the microenvironment around each cell tightly regulates angiogenesis.  When no longer needed to establish the cardiovascular system and drive blood supply to the embryo’s developing organs, angiogenesis switches off. In adults, angiogenesis primarily switches on for a limited time to restore blood flow to tissues or organs after injury.  A hallmark of cancer, however, is an angiogenesis switch that never turns off.

“While a tumor (early cancer) is still growing slowly we want to turn off angiogenesis to prevent new blood vessel growth and metastasis,” Dr. Wickline explained. “The idea behind this particular nanotechnology targeting Etv2 is that the treatment selectively inhibits the angiogenesis associated with cancer progression, and not other physiological angiogenesis processes that are needed for repair of tissues anywhere else in the body.”

Potential applications for atherosclerosis

Dr. Wickline’s laboratory built the nanoparticle peptide-siRNA structure capable of precisely delivering a message to silence Etv2 in tumors.  That same nontoxic delivery system can carry other therapeutic molecules to various specific cell types in the body associated with inflammatory diseases, including cardiovascular disorders.

The researchers plan to test whether Etv2 may also be a good nanotherapy target for blocking angiogenesis in atherosclerosis, which leads to fatty plaques building up in the arteries. That’s because abnormal blood vessel growth also provides nutrients to the inflammatory cells inside atherosclerotic plaques and plays a crucial role in plaque rupture that can cause heart attacks and stroke.

“Just like inhibiting angiogenesis starves a tumor of its blood supply,” Dr. Wickline said, “we also want to find ways to starve plaques of the blood supply to keep them from getting bigger and more dangerous.”