5 Cardio-oncology: Network-Based Prediction …
77
5.1 Introduction
Cardiovascular disease (CVD) is a leading cause of death and the second leading
cause of mortality and morbidity in cancer survivors after recurrent malignancy in
the USA [1, 2]. Comorbidity between cardiovascular disease and cancer suggests
an underlying shared disease etiology, which can be both genetic and environmental
[3–5]. One critical issue regarding environmental factors is that comorbidity between
cardiovascular disease and cancer is typically associated with various anticancer
treatments [6], including cytotoxic chemotherapies [7], radiotherapy [8], molecularly
targeted therapies [9, 10], and immunotherapies [11, 12]. For example, a growing
number of cancer survivors (>5 million) are exposed with an increased lifetime risk
of anthracycline-induced cardiovascular complications [2, 13].
There are several different mechanisms-of-action (Fig. 5.1) for drug-induced cardiotoxicities, including both on-target [14] and off-target effects [9, 10]. For example,
previous studies in a genetically engineered mutant mouse model have suggested that
the loss of ERBB2 (erb-b2 receptor tyrosine kinase 2) in the heart can lead to heart
failure and increased susceptibility to cardiotoxicity of HER2 (human epidermal
growth factor receptor 2) inhibitors (e.g., trastuzumab) [14]. Most kinase inhibitors
often reveal ‘promiscuous’ profiles [15] via inhibiting many other kinases rather than
cancer-related targets, resulting in a high risk of off-target cardiotoxicities [16–18].
Furthermore, these reports may only represent the tip of the iceberg for cancer therapies [19]. We believe a key factor in the high risk of cancer treatment-related cardiotoxicities is the continued adherence to the classical ‘one gene (product), one drug,
one disease’ paradigm in the traditional oncological drug development and regulatory reviews [20–22]. For instance, imatinib, the first approved molecularly targeted
agent for the treatment of chronic myeloid leukemia, was reported to bind over 40
different human proteins, which associates with multiple cardiac complications [23,
24]. Ponatinib was approved for chronic myeloid leukemia with a fairly broad label
in the USA; however, later studies reported its cardiotoxicity due to its promiscuous
profiles on multiple kinases, including SRC (proto-oncogene tyrosine-protein kinase
Src), PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), and VEGFR (vascular endothelial growth factor receptor), which now
has led to its restricted use in patients with the BCR-ABL1
T315I or in whom other
kinase inhibitors are not effective [16–18].
The growing awareness of cancer treatment-related cardiotoxicities has led to the
emerging field of cardio-oncology (also known onco-cardiology), which centers on
screening, monitoring, and treating cancer patients with cardiac dysfunction before,
during, or after cancer treatment [2, 6]. Furthermore, it is also an exciting field
because there are no guidelines and no available US Food and Drug Administration
(FDA)-approved therapeutics for preventing and treating new cardiotoxicity in cancer
survivors. There is an increasing recognition that our current disease categorization
approaches are inadequate to describe the scope and patient heterogeneity of complex
diseases and understand the mechanism-of-action of therapeutics. Quantitative and
systems pharmacology (QSP) refers to a multidisciplinary approach for the emerging
77
5.1 Introduction
Cardiovascular disease (CVD) is a leading cause of death and the second leading
cause of mortality and morbidity in cancer survivors after recurrent malignancy in
the USA [1, 2]. Comorbidity between cardiovascular disease and cancer suggests
an underlying shared disease etiology, which can be both genetic and environmental
[3–5]. One critical issue regarding environmental factors is that comorbidity between
cardiovascular disease and cancer is typically associated with various anticancer
treatments [6], including cytotoxic chemotherapies [7], radiotherapy [8], molecularly
targeted therapies [9, 10], and immunotherapies [11, 12]. For example, a growing
number of cancer survivors (>5 million) are exposed with an increased lifetime risk
of anthracycline-induced cardiovascular complications [2, 13].
There are several different mechanisms-of-action (Fig. 5.1) for drug-induced cardiotoxicities, including both on-target [14] and off-target effects [9, 10]. For example,
previous studies in a genetically engineered mutant mouse model have suggested that
the loss of ERBB2 (erb-b2 receptor tyrosine kinase 2) in the heart can lead to heart
failure and increased susceptibility to cardiotoxicity of HER2 (human epidermal
growth factor receptor 2) inhibitors (e.g., trastuzumab) [14]. Most kinase inhibitors
often reveal ‘promiscuous’ profiles [15] via inhibiting many other kinases rather than
cancer-related targets, resulting in a high risk of off-target cardiotoxicities [16–18].
Furthermore, these reports may only represent the tip of the iceberg for cancer therapies [19]. We believe a key factor in the high risk of cancer treatment-related cardiotoxicities is the continued adherence to the classical ‘one gene (product), one drug,
one disease’ paradigm in the traditional oncological drug development and regulatory reviews [20–22]. For instance, imatinib, the first approved molecularly targeted
agent for the treatment of chronic myeloid leukemia, was reported to bind over 40
different human proteins, which associates with multiple cardiac complications [23,
24]. Ponatinib was approved for chronic myeloid leukemia with a fairly broad label
in the USA; however, later studies reported its cardiotoxicity due to its promiscuous
profiles on multiple kinases, including SRC (proto-oncogene tyrosine-protein kinase
Src), PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), and VEGFR (vascular endothelial growth factor receptor), which now
has led to its restricted use in patients with the BCR-ABL1
T315I or in whom other
kinase inhibitors are not effective [16–18].
The growing awareness of cancer treatment-related cardiotoxicities has led to the
emerging field of cardio-oncology (also known onco-cardiology), which centers on
screening, monitoring, and treating cancer patients with cardiac dysfunction before,
during, or after cancer treatment [2, 6]. Furthermore, it is also an exciting field
because there are no guidelines and no available US Food and Drug Administration
(FDA)-approved therapeutics for preventing and treating new cardiotoxicity in cancer
survivors. There is an increasing recognition that our current disease categorization
approaches are inadequate to describe the scope and patient heterogeneity of complex
diseases and understand the mechanism-of-action of therapeutics. Quantitative and
systems pharmacology (QSP) refers to a multidisciplinary approach for the emerging