Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

Abstract

To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune‐based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T‐cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life‐threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer‐related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research‐practice gaps, addressing real‐world challenges and pinpointing real‐time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio‐oncology and crosses the interface between oncology and onco‐pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research‐practice gaps may advance research initiatives on the development of mechanism‐based diagnoses and treatments for the effective clinical management of cardiotoxicity.

Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

“…The Raf/MEK/ERK1/2 pathway is one of the most frequently dysregulated signaling pathways in cancer, in particular in melanoma, pancreatic, oral squamous cell, and colorectal cancers [36][37][38] . Cardiotoxicity as well as drug resistance are severe limitations of prolonged treatment with FDA approved drugs that target Raf/ MEK/ERK1/2 signaling in cancer 3,39,40 . To test, whether the apparently cardio-safe EDI might also be effective in cancer and may thus represent a possible treatment strategy circumventing cardiotoxic side effects, we studied the role of ERK T188 -phosphorylation in cancer.…”

“…Several pharmacological antibodies blocking the extracellular domain of the epidermal growth factor receptor tyrosine kinase or small molecules targeting kinases of this signaling cascade with differential selectivity are available. However, the wide therapeutic application of these compounds is limited by side effects, inducing the development of severe cardiomyopathy with decreased ejection fraction and the development of resistances to these compounds [2][3][4][5][6][7][8][9] . In the heart, the Raf/MEK/ERK1/2 cascade is involved in adverse remodeling, but is also responsible for cardiomyocyte survival and protection from stress-induced cardiomyocyte death.…”

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity

“…The most commonly used cancer therapeutics in modern medicine include the traditional surgery, radiotherapy, and conventional chemotherapy approaches; moreover, two new therapeutic modalities have been introduced in recent decades, namely molecularly targeted therapy and immunotherapy [7], as summarized in Figure 1. Traditional chemotherapy agents consist of non-specific cytotoxic treatments (e.g., alkylating agents and antimetabolites) that rapidly eliminate replicating cells, including not only tumor cells but also normal tissue cells, with a broad range of side effects that significantly limit their applications in cancer therapy.…”

“…">Anticancer Treatment and CardiotoxicityAnticancer treatment has accomplished remarkable progress in the last century resulting in improved quality of life and survival rates of cancer patients. These advances in cancer treatment, however, have been often accompanied by therapy-related complications, including secondary side effects on the whole organism [6].The most commonly used cancer therapeutics in modern medicine include the traditional surgery, radiotherapy, and conventional chemotherapy approaches; moreover, two new therapeutic modalities have been introduced in recent decades, namely molecularly targeted therapy and immunotherapy [7], as summarized in Figure 1. Traditional chemotherapy agents consist of non-specific cytotoxic treatments (e.g., alkylating agents and antimetabolites) that rapidly eliminate replicating cells, including not only tumor cells but also normal tissue cells, with a broad range of side effects that significantly limit their applications in cancer therapy.…”

Emerging Challenges of Radiation-Associated Cardiovascular Dysfunction (RACVD) in Modern Radiation Oncology: Clinical Practice, Bench Investigation, and Multidisciplinary Care

“…RACVD is a well-known treatment-related toxicity in the field of cardio-oncology (23-25). Other anti-cancer therapies, such as chemotherapy (26-29), targeted therapy (30- 33), and immunotherapy (34)(35)(36), may also induce cardiovascular dysfunctions (37)(38)(39). As a result, when these therapies are prescribed concurrently or sequentially with RT, the risk of RACVD is increased substantially, especially in vulnerable pediatric (40,41) or elderly cancer patients (42,43).…”