Emerging paradigms in cardiomyopathies associated with cancer therapies

Abstract

The cardiovascular care of cancer patients (cardio-oncology) has emerged as a new discipline in clinical medicine, given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies such as anthracyclines and radiation have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of targeted cancer therapies, which were initially thought to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, or overexpression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting human epidermal growth factor receptor-2 (mutated or overexpressed in breast cancer), BCR-ABL (chronic myelogenous leukemia and some cases of acute lymphoblastic leukemia), and c-Kit (gastrointestinal stromal tumor). Other agents targeting more complex malignancies, such as advanced solid tumors, have had successes, but have not extended life to the degree seen with chronic myelogenous leukemia. Years before the first targeted therapy, Judah Folkman correctly proposed that to address solid tumors one had to target the inherent neoangiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the catch-22. Nevertheless, cardio-oncology has the potential to be transformative as the human cardiomyopathies that arise from targeted therapies can provide insights into the normal function of the heart.

Keywords: HER2-targeted therapies; angiogenesis inhibitors; anthracyclines; cancer; cardio-oncology; cardiomyopathy; chemotherapies.

Figure 1

Schematic of the mechanisms of doxorubicin-mediated cardiomyopathy. See text for details.

Figure 2

Angiogenesis Inhibitors (VSP Inhibitors) being tested in human cancer trials. While these agents are being referred to as VEGF Signaling Pathway (VSP) inhibitors, drugs such as sunitinib inhibit many other receptor tyrosine kinases allowing them to be approved for the treatment of other cancers while at the same time creating the possibility for a wide range of “off-target” toxicities. (Illustration Credit: Ben Smith).

Figure 3

Ultra-structural evidence of mitochondrial injury in mice treated with the VSP inhibitor sunitinib (A), and significant reversibility of that injury in a patient after withdrawal of sunitinib (B). A. Mice were treated with doses of sunitinib that would mimick levels in humans. Note the mitochondrial injury on transmission EM (right panel). B. Left: Transmision EM images from a patient who developed profound heart failure while receiving sunitinib. Note the marked mitochondrial injury. Right: Repeat biopsy showing marked resolution of injury one month after discontinuation of sunitinib and addition of standard heart failure treatment.

Figure 3

Ultra-structural evidence of mitochondrial injury in mice treated with the VSP inhibitor sunitinib (A), and significant reversibility of that injury in a patient after withdrawal of sunitinib (B). A. Mice were treated with doses of sunitinib that would mimick levels in humans. Note the mitochondrial injury on transmission EM (right panel). B. Left: Transmision EM images from a patient who developed profound heart failure while receiving sunitinib. Note the marked mitochondrial injury. Right: Repeat biopsy showing marked resolution of injury one month after discontinuation of sunitinib and addition of standard heart failure treatment.

Figure 4

Novel FDA-approved and investigational HER2 targeted agents being used for the treatment of breast cancer (Illustration Credit: Ben Smith).