Cardiovascular Toxicities Due to Molecularly Targeted Cancer Therapeutics

Cardiovascular Toxicities Due to Molecularly Targeted Cancer Therapeutics

Vishnu Chintalgattu, PhD, and Aarif Y. Khakoo, MD, MBA

Department of Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

The promise of molecularly targeted cancer therapy is based upon the premise that by specifically inhibiting molecules associated with tumor growth, such therapies will be highly effective in treating cancer without adversely affecting normal organs. This action is in contrast to that of traditional chemotherapeutic agents, such as anthracyclines, which are very effective in the treatment of a number of malignancies, yet often result in a cancer survivor with devastating cardiac disease. Cardiotoxicity associated with anthracycline cancer therapies has been recognized since the 1970s,1 and the cardiotoxic effects have been extensively studied in both clinical and preclinical settings.2 Although such studies have been instrumental in the development of management strategies to minimize the cardiotoxic effects of anthracyclines, the dose-dependent, irreversible cytotoxic effects of these drugs on various noncancerous tissues, including the heart, is still a major concern.

Targeted cancer therapies such as tyrosine kinase inhibitors (TKIs) are typically aimed at molecules that are overexpressed in cancer cells,3 but the fact remains that many such molecules are biologically active in noncancerous tissues and may play a role in the normal physiology of diverse organ systems, including the cardiovascular system. Many drugs currently in development or in clinical trials would be predicted, on theoretical grounds, to lead to cardiotoxicity (Table 1). These drugs are designated as “potentially cardiotoxic” based upon murine loss of function studies using tissuespecific knockout mouse models in which deletion of the indicated target results in cardiac pathology under basal conditions or under stress. Francis and colleagues report on cardiotoxicity manifesting as reversible, severe cardiac dysfunction in a young woman with acute lymphoblastic leukemia treated sequentially with several small-molecule TKIs.4

All of the agents in this case study (imatinib [Gleevec, Novartis], nilotinib [Tasigna, Novartis], and dasatinib [Sprycel, Bristol-Myers Squibb]) target the ABL tyrosine kinase, although each agent has inhibitory activity against several other tyrosine kinases as well. Of these agents, imatinib is the most well-studied in regard to cardiovascular effects. Kerkelä and coworkers reported that cardiac dysfunction in a small group of imatinibtreated patients showed compelling mechanistic overlap with toxicity in imatinib-treated mice at clinically relevant dosages.5 They attributed this toxicity to inhibitory effects on ABL kinase in the heart, which result in activation of the cardiac endoplasmic reticulum stress response. Subsequently, we and others have demonstrated that in patients with gastrointestinal stromal tumor6 or chronic myelogenous leukemia,7 clinically significant cardiotoxicity due to imatinib monotherapy is uncommon. However, our study also revealed that hearts from imatinib-treated mice had a substantial reduction in activation of established cardioprotective kinases.6

Taken together, the findings from our group and from Kerkelä and coworkers5 suggest that imatinib may impair aspects of cardiac function that are directly relevant to the adult cardiac response to pathologic stressors. Such mechanistic insights may have significant relevance to the reversible cardiomyopathy due to imatinib and other ABL kinase inhibitors described by Francis and colleagues.4 Notably, in contrast to the first-line monotherapy approach used in chronic myelogenous leukemia and gastrointestinal stromal tumor, the patient described was aggressively pretreated with multiple cytotoxic chemotherapies, including anthracycline-based chemotherapy and mitoxantrone. Furthermore, the patient developed cardiomyopathy against the background of other superimposed stressors, such as septic shock, cardiac arrest of unclear etiology, and severe mucositis requiring intubation. Thus, it is possible that the implicated TKIs may have contributed to cardiomyopathy in an additive manner in combination with prior anthracycline exposure, impairing the cardiac response to stress in the form of severe, noncardiac illness.

Such a possibility is of considerable relevance as the use of imatinib and other targeted therapies expands and these drugs become part of a combination regimen that includes other cytotoxic chemotherapeutic agents, an approach being explored in newer clinical trials.8 It is possible that in this setting, imatinib may be associated with a clinically significant cardiotoxicity, an effect not seen to date when imatinib has been used as monotherapy. Mechanistically, it appears that cardiotoxicity due to TKIs is unlikely to be a generic “class effect,” as proposed by Francis and colleagues4 and others who have designated such nonanthracycline-related cardiac toxicities as “type II cardiotoxicities.”9 Such a view overlooks the molecular specificity of the individual targeted agents. It is much more likely that the net cardiotoxicity of an individual TKI will be determined by its effects on critical pathways that regulate normal cardiovascular physiology or the cardiovascular stress response. For example, agents whose targets include vascular endothelial growth factor (VEGF) receptor, including the small-molecule inhibitors sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer Healthcare) and the monoclonal antibody bevacizumab (Avastin, Genentech), are all associated with a striking incidence of hypertension, which in some studies has occurred in nearly 50% of patients.10 The VEGF/VEGF receptor signaling system has been demonstrated in preclinical studies to be an important regulator of systemic vascular tone.11 Thus, hypertension due to such agents underscores the relevance of this signaling system in the maintenance of normal blood pressure in patients with cancer, and, perhaps, in patients without cancer. Similarly, both sunitinib and sorafenib, whose targets include platelet-derived growth factor receptor (PDGFR), have been reported to lead to clinically significant cardiac dysfunction in subsets of treated patients,10,12,13 suggesting that PDGFR signaling in the cardiomyocyte may play an important role in the cardiac response to stressors, such as hypertension, that are seen at high frequency with these agents.

Ultimately, precise molecular understanding of the identity and function of targets within the cardiovascular system whose inhibition leads to cardiovascular toxicity associated with novel targeted anticancer therapies will set the stage for the development of strategies to identify patients at high risk of cardiac toxicity due to these agents and to prevent such toxicities. Furthermore, the identity of such targets may be incorporated into future drug development efforts aimed at producing novel, highly effective cancer therapeutics with minimal cardiovascular toxicities. As more patients survive their cancer, the development of new therapies that are effective and have minimal long-term adverse cardiac effects is of the utmost importance.

References

1. Khakoo AY, Yeh ET. Therapy insight: management of cardiovascular disease in patients with cancer and cardiac complications of cancer therapy. Nat Clin Pract Oncol. 2008;5:655-667.

2. Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol. 2008;26:3777-3784.

3. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172-187.

4. Francis J, Ahluwalia MS, Wetzler M, et al. Reversible cardiotoxicity with tyrosine kinase inhibitors. Clin Adv Hematol Oncol. 2010;8:128-132.

5. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-916.

6. Trent JC, Patel SS, Zhang J, et al. Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate (IM) therapy. Cancer. 2010;116:184-192.

7. Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood. 2007;110:1233-1237.

8. Ribera JM, Oriol A, Gonzalez M, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 2010;95:87-95.

9. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23:2900-2902.

10. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011-2019.

11. Bhargava P. VEGF kinase inhibitors: how do they cause hypertension? Am J Physiol Regul Integr Comp Physiol. 2009;297:R1-R5.

12. Khakoo AY, Kassiotis CM, Tannir N, et al. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer. 2008;112:2500-2508.

13. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26:5204-5212.