Creating Cancer Therapeutics with Decreased Risk for Cardiovascular Disease
by Amanda Chase, PhD
July 1, 2022
Tremendous advances in cancer treatment have led to improved survival rates. However, as survival increased, there has been an unforeseen increase in life-threatening toxicities to cancer drugs such as cardiovascular disease. Up to a third of cancer survivors experience cardiovascular disease as an unintended consequence of their cancer treatment. Not only older, less specific cancer drugs, but also modern, molecularly targeted therapeutics such as tyrosine kinase inhibitors (TKIs) are cardiotoxic.
Of the TKIs, Ponatinib is among the most cardiotoxic yet is a first-line therapy for a subset of patients with a commonly mutated forms of the BCR-ABL oncogene that causes chronic myeloid leukemia (CML). In a recent publication in Cancer Research, a journal of the American Association for Cancer Research, investigators engineered analogues of ponatinib that are considerably less cardiotoxic, showing it is possible to design safer drugs for cancer.
Cancer is characterized by cells in the body growing uncontrollably, and this can happen in nearly any part of the body. CML is a type of cancer that starts in blood-forming cells of the bone marrow. There is a change (mutation) that occurs in early versions of stem cells that make other blood cells (red blood cells, some white blood cells). This mutation fuses two genes yielding the BCR-ABL oncogene. The activity of BCR-ABL turns bone marrow cells into a CML cell that continuously grows and divides, and eventually moves into the blood. The 5-year survival rates for CML increased up to 90% after approval of the first therapy, a TKI, to inhibit BCR-ABL. While this was highly successful, some patients develop resistance due to a second mutation of the BCR-ABL that renders it resistant to inhibition by the cancer drugs. The TKI Ponatinib was developed to block this mutated form of BCR-ABL and is effective. However, Ponatinib also causes many patients to develop severe and potentially fatal cardiovascular disease, including the development of heart failure. Therefore, there is a critical need for technology that can lead to safer forms of Ponatinib as well as other related drugs that carry unacceptably high risk of heart disease.
Investigators from the Stanford Cardiovascular Institute, led by Mark Mercola and co-first authors Anna Hnatiuk and Arne Bruyneel, and from the Center for Experimental Therapeutics, Knight Cancer Institute at Oregon Health Sciences University, led by Sanjay Malhotra and co-first authors Dhanir Tailor and Mallesh Pandrala, addressed this crucial need in their Cancer Research manuscript. The investigators first modeled the toxicity using high throughput assays that recapitulated the heart and vascular side effects of the drug. Using these assays, they succeeded in developing hybrid versions of ponatinib that incorporated the desirable anti-tumor properties of ponatinib combined with the less toxic properties of related inhibitors that do not kill the T315I mutant tumors. The new compounds were effective both in vitro and against human tumors grown in mice, yet did not cause adverse effects on the cardiovascular system. In a further step, investigators compared the engineered, safer Ponatinib analogues to Ponatinib and discovered possible mechanisms that explain how Ponatinib causes cardiovascular toxicity.
Together, the work from these investigators represents an important therapeutic opportunity for safer CML treatment, especially for those patients who have the T315I mutation. It also presents an approach that shows the potential to reduce cardiotoxicity that is prevalent among cancer therapies.
Other Stanford Cardiovascular Institute investigators include Ricardo Fernandez, Dries Feyan, Michelle Vu, Prashila Amatya, Isabel Morgado, and Ronglih Liao.