Haykowsky and Lee W. Jones Jessica M. Scott, Susan Lakoski

Haykowsky and Lee W. JonesJessica M. Scott, Susan Lakoski, John R. Mackey, Pamela S. Douglas, Mark J.

Molecularly Targeted Cancer TherapeuticsThe Potential Role of Aerobic Exercise to Modulate Cardiotoxicity of

doi: 10.1634/theoncologist.2012-0226 originally published online January 18, 20132013, 18:221-231.The Oncologist

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ABSTRACT

Molecularly targeted therapeutics (MTT) are the future ofcancer systemic therapy. Theyhavealreadymoved frompalli-ative therapy for advanced solidmalignancies into the settingof curative-intent treatment for early-stage disease. Cardio-toxicity isa frequentandpotentially seriousadversecomplica-tion of some targeted therapies, leading to a broad range ofpotentially life-threatening complications, therapy discontin-uation, and poor quality of life. Low-cost pleiotropic interven-tions are therefore urgently required to effectively preventand/or treat MTT-induced cardiotoxicity. Aerobic exercisetherapyhas theuniquecapacity tomodulate,without toxicity,

multiple gene expression pathways in several organ systems,including a plethora of cardiac-specificmolecular and cell-sig-nalingpathways implicated inMTT-inducedcardiac toxicity. Inthis review, we examine themolecular signaling of antiangio-genic andHER2-directed therapies thatmay underpin cardiactoxicity and the hypothesized molecular mechanisms under-lying the cardioprotective properties of aerobic exercise. It ishoped that this knowledge can be used to maximize the ben-efits of small molecule inhibitors, while minimizing cardiacdamage in patients with solid malignancies. The Oncologist2013;18:221–231

Implications for Practice: Cardiotoxicity, a frequent and devastating adverse complication of somemolecularly targeted thera-pies (MTTs), can lead to potentially life-threatening cardiovascular complications, therapy discontinuation, and poor quality oflife. In non-cancer patients with left ventricular dysfunction and heart failure, aerobic exercise is one of themainstay clinical in-terventions for the prevention and treatment of cardiovascular disease. However, few studies have investigated the efficacy ofaerobicexercise in thepreventionand/or treatmentofMTT-inducedcardiac injury. This topic isofparticular importancebecausecardiac function isa strongpredictorof cardiovascularandall-causemortality,qualityof life, and fatigue,andmaybeevencancer-specificmortality. Here,weprovide a comprehensive overviewof cardiacmolecular and cell-signaling pathways specific toMTT-induced cardiac toxicity. This review also outlines many pertinent aerobic exercise-induced molecular signaling pathways thatmayuniquelyprevent and/or treatMTTcardiac injury.Overall, informationpresented in this reviewprovides critical informationfor basic scientists, clinicians, and exercise oncology researchers who are investigating the application of exercise in cancer con-trol.

INTRODUCTION

The emergence of molecularly targeted therapeutics (MTTs)hasrevolutionizedthemanagementofsolidmalignancies.An-tiangiogenic and human epidermal growth factor receptor 2(HER2)-directedMTTsareapprovedby theU.S. FoodandDrugAdministration (FDA) for the treatment of several solidmalig-nancies, either as monotherapy or in combination with stan-dard chemotherapy [1, 2]. The biologic selectivities of thesedrugs were expected to substantially reduce off-target toxic-ity, although it is now apparent that MTTs cause adverse car-diovascular consequences, such as hypertension andprogressive left ventricular (LV) dysfunction, ultimately lead-ing to symptomatic heart failure.

Several excellent reviews have described the biologic andmolecular mechanisms underlying MTT-induced cardiotoxic-ity and risk for cardiotoxicity [1–8]; however, comparably lit-tleattentionhasbeen focusedonstrategies topreventand/ormitigate anticipated injury. MTTs target multiple cellularpathways including highly coordinated myocardial molecularsignaling. Pleiotropic interventions will therefore be requiredto effectively prevent and/or treat MTT-induced cardiotoxic-ity. Aerobic exercise therapy has the unique capacity tomod-ulate, without toxicity, multiple gene expression pathways inseveral organ systems, including aplethora of cardiac-specificmolecular and cell-signaling pathways implicated in MTT-in-

Correspondence: JessicaM. Scott, Ph.D., Exercise Physiology and Countermeasures, NASA Johnson Space Center, Universities Space ResearchAssociation, 2101 NASA Parkway, Houston, TX 77058, USA. Telephone: 281-483-8398; Fax: 281-483-4181; e-mail: [email protected] March 29, 2012; accepted for publication September 5, 2012; first published online in The Oncologist Express on January 18, 2013.©AlphaMed Press 1083-7159/2013/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2012-0226

ThePotential RoleofAerobic Exercise toModulateCardiotoxicityofMolecularly TargetedCancerTherapeuticsJESSICAM. SCOTT,a SUSAN LAKOSKI,b JOHN R.MACKEY,c PAMELA S. DOUGLAS,dMARK J. HAYKOWSKY,c LEEW. JONESdaNASA Johnson Space Center, Universities Space Research Association, Houston, Texas, USA; bUniversity of Texas SouthwesternMedical Center, Dallas, Texas, USA; cUniversity of Alberta, Edmonton, Alberta, Canada; dDukeUniversityMedical Center, Durham,North Carolina, USADisclosures of potential conflicts of interestmay be found at the end of this article.

KeyWords. Exercise • Cardiotoxicity • Molecular therapeutics • Solidmalignancies

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duced cardiac toxicity. Here we reviewmolecular signaling ofantiangiogenic and HER2-directed therapies that may under-pin cardiac toxicity and the hypothesized cardioprotectiveproperties of aerobic exercise.

THEBIOLOGY OF TYROSINEKINASESReceptor tyrosine kinases (RTKs) are enzymes that act as criti-calmediators of normal cellular signal transduction and regu-latediverse cellularprocesses including cell cycleprogression,metabolism, transcription, and apoptosis (reviewed exten-sively elsewhere [9, 10]). All RTKs are embedded in plasmamembranes and consist of an extracellular ligand-binding do-mainandan intracellular kinasedomain.RTKsarenotonly keyregulators of normal cellular processes, but they also are cen-tral to malignant transformation and tumor proliferationwhen constitutively activated via gene amplification, overex-pression, or mutations [11]. Strategies for the prevention orinterception of deregulated RTK signaling include the devel-opment of selective agents that target either the extracellularligand-binding domain or the intracellular tyrosine kinasebinding region [2, 4]. Monoclonal antibodies (mAbs) are de-signed to inhibit kinaseactivationbybinding to theextracellu-lar portion of RTKs or by binding to growth factor ligands thatactivate RTKs. Mechanistically, anti-RTK mAbs block the li-gand-receptor interaction, thus inhibiting activation of the ty-rosine kinase domain, and/or induce downregulation ofreceptor expression [12]. In contrast, small-molecule tyrosinekinase inhibitors (TKIs) bind to the intracellular portion ofRTKs, thereby inhibiting the phosphorylation of downstreamsubstrates.

MECHANISMS OFHER2-DIRECTEDTHERAPYCARDIAC INJURYOverexpression and/or gene amplification of the RTK HER2(also known as ErbB2) is present in approximately 20% ofwomenwith breast cancer [13], aswell as approximately 10%and 5%of patients with non-small cell lung cancer, [14] andgastric cancer, respectively [15]. Randomized trials demon-strate that HER2-directed agents cause significant im-provements in disease-free survival and overall survivalamong women with early [16, 17] and metastatic [18]HER2-positive breast cancer. However, trastuzumab (thefirst FDA-approvedHER2-directedmAb) andpertuzumab (anewer mAb in phase III testing) are associated with cardiactoxicity (Table 1).

HER2-DIRECTEDTHERAPY INHIBITION OF CARDIACMOLECULAR SIGNALINGWe focus here on the putative role of ErbB2 and transforminggrowthfactor� (TGF�) signalingasmajorpathwaysmediatinganti-ErbB2 cardiotoxicity (Fig. 1).

ErbB2ErbB2belongstothefamilyofhumanepidermalgrowthfactor(EGF) receptorscomprisedof theEGFreceptor (ErbB1),ErbB2,ErbB3, and ErbB4 [19]. Hyperactivation of the ErbB2/ErbB3/PI3K complex in tumor cells leads to upregulation of the phos-phatidylinositol 3-kinase (PI3K)-Akt pathways resulting incellular proliferation [20], increased mitogen-activated pro-tein kinase (MAPK) activity causing protein hypertrophy [21],and reduced cytostasis via CCAAT/enhancer-binding protein

(C/EBP�) [22]. The antiproliferative activity of HER2-directedtherapy is therefore based on disruption of the ErbB2-ErbB3complex in tumor cells, thus reducing intracellular Akt activity[19, 23] and MAPK signaling [24]. Conversely, HER2-directedtherapy dramatically alters cardiomyocyte function and/orsurvival via inhibition of Nrg1/ErbB/Akt signaling.

The essential role of ErbB2 signaling for cardiomyocyteproliferation was first revealed through germline deletion ofErbB2 receptors inmice, which proved lethal inmid gestationwith failure of proper ventricle formation [25]. Transgenicmice with cardiac-specific deletion of ErbB2 after cardiac de-velopment survive embryogenesis [25] but develop progres-sive cardiomyopathy in adulthood [16]. In the healthy heart,neuregulin-1� (Nrg1) is released by endocardial and myocar-dial endothelialmicrovascular cells and binds to ErbB4on car-diomyocytes leading to activation of the ErbB2/ErbB4/PI3K/Akt complex. HER2-directed agents inhibit Nrg1release [26] and significantly decrease both total and phos-phorylated Akt in neonatal rat cardiomyocytes [27], thuspotentially limiting cell growth, glucose uptake, and pro-tein regulation [28–30] and ultimately triggering the pro-gression of heart failure [31].

TGF�During carcinogenesis, TGF� signaling initially preventsmalignant progression via the small mother against decap-entaplegic (Smad) pathway [32]. Eventually, malignantcells overexpressing ErbB2 circumvent the growth-sup-pressive effects of TGF� by downregulating TGF� receptorsoralteringdownstreampathways [22]. In theheart, TGF� reg-ulates ventricular remodeling (cardiomyocyte hypertrophy)via activation of the Smad/3 and4 complexes andmatrixmet-alloproteinases [33]. Inhibition of ErbB2 signalingwith trastu-zumab also activates TGF� and C/EBP� signaling in breastcancer cells [22]. Whether trastuzumab induces TGF� andC/EBP� signaling in cardiomyocytes is unknown; however, in-creased cardiac TGF� and C/EBP� expression results in path-ological remodeling [34].

AEROBIC EXERCISE-INDUCED CARDIOPROTECTION FROMHER2-DIRECTEDAGENTSFigure 2 outlines the modulation of ErbB and TGF� signalingthrough aerobic exercise. The cardioprotective properties ofincreasedNrg1/ErbB signaling arewell described [26, 29]. Forexample, drug-induced enhancement of myocardial Nrg1/ErbB signaling significantly improved both cardiac perfor-mance and survival in four different rodent models of LVfailure [31]and induceddifferentiatedcardiomyocytes topro-liferate [35]. In vitro studies in isolated cardiac endothelialcells (themain sourceofNrg1 in theheart) showthatmechan-ical strain increases endothelial Nrg1 synthesis and release[36],whereasNrg1 release is directly inhibited by angiotensinII and adrenergic agonists [37]. Aerobic exercise increases en-docardialmechanical strain [38]withaconcomitant reductioninangiotensin II [39]. Interestingly, Lebrasseuretal. [40] foundthat resistance or aerobic exercise increased proteolytic pro-cessing of mature Nrg1 transmembrane protein to solubleNrg1 in rat skeletal muscle. Thus, we contend that increasedNrg1synthesis in theventricle in responsetoexercise-inducedmechanical stress will evoke suppression of neurohormonalfactors, leading to cardioprotection.

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Figure 1. Mechanisms underlying HER2-directed therapy cardiotoxicity. Inhibition of ErbB receptorswith HER2-directed therapies im-pacts numerous signaling pathways resulting in suppression of myofilament protein synthesis via the PI3K-Akt pathway (pathway A),suppression of protein hypertrophy via the MAPK pathway (pathway B), suppression of cell survival via Src/Fak pathway (pathway C),suppression of myofilament protein synthesis and upregulation of protein degradation via TGF-�1 and C/EBP� signaling (pathway D),and alterations in cardiac energymetabolism via downregulation of AMPK (pathway E).

Abbreviations: AMPK, AMP-activated protein kinase; C/EBP�, CCAAT/enhancer binding protein; Fak, focal adhesion kinase;MAPK,mitogen-activatedprotein kinase;Nrg1,Neuregulin-1�; PI3K, phosphatidylinositol 3-kinase; Smad, smallmotheragainstdecapentaple-gic; TGF�, transforming growth factor�.

Table 1. Incidence of cardiotoxicity in HER2-directed and angiogenesis inhibitor clinical trials

Agent Class Target Malignancy Heart failureSubclinical decline inejection fraction (≥ 10%)

Hypertension(≥ grade I)

HER2-directed

Trastuzumab mAb ErbB2 ErbB2� breast cancer,MGC (phase III)

1.7%–4% (early) �89, 908.3%–20% (advanced)�16, 91–95��

2.1%–14% (early) �89�16%–18% (advanced)�16, 92–96�

NA

Lapatinib TKI ErbB1, ErbB2 ErbB2� breast cancer,NSCLC (phase II)

0.2% (advanced) �97� 1.4%–5% (advanced)�97, 98�

4% (advanced) �99�

Pertuzumab mAb ErbB2 ErbB2� breast cancer(phase II)

9% (advanced) �100� 1.2%–54% (advanced)�91, 100–102�

NA

Angiogenesis inhibitors

Bevacizumab mAb VEGF RCC, NSCLC, glioblastoma,CRC, breast

2.2%–3% (advanced)�103, 104�

2%–14% (early) �105–1070.8%–23.5% (advanced)�103, 104, 108��

2%–12% (early) �106, 109�17.9%–35% (advanced)�103, 104, 110�

Ramucirumab mAb VEGFR RCC (phase II), breast(phase III)

NA NA 13.5% (advanced) �111�

Sunitinib TKI VEGFR 1–3, c-kit,PDGFR

RCC, GIST 2.7%–11% (advanced)�62, 112�

4%–47% (advanced)�62, 112�

5%–47% (advanced)�62, 113, 114�

Sorafenib TKI VEGFR 2, PDGFR,Raf1

RCC,melanoma NA 18.9% (advanced) �115� 7.2%–43% (advanced)�116–119�

Pazopanib TKI VEGFR, c-kit, PDGFR RCC, breast (phase II) NA NA 14%–40% (advanced )�120, 121�

Cediranib TKI VEGFR 1–3, c-kit RCC, breast, and liver (allphase II)

NA NA 21%–81% (advanced)�122–124�

Vandetanib TKI VEGFR, EGFR MTC, NSCLC (phase III),mHRPC (phase II)

NA NA 14%–29% (advanced)�125–127�

Motesanib TKI VEGFR, PDGFR, c-kit MBC (Phase II) NA 9% (advanced) �128� 12% (advanced) �128�

Axitinib TKI VEGFR, PDGFR, c-kit Pancreatic, (phase III),MBC (phase II)

NA 1.8% (advanced) �129� 7%–27.9% (advanced)�129, 130�

Abbreviations: CRC, colorectal cancer; GIST, gastrointestinal stromal tumor; HF, heart failure;mAb,monoclonal antibody;MBC,metastatic breastcancer;MGC,metastatic gastric cancer;mHRPC,metastatic hormone-refractory prostate cancer;MTC,metastaticmedullary thyroid cancer, NA,not available; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor.

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Aerobic exercisemay alsomodulate a number ofmyocar-dial intracellular processes, thus overcoming HER2-inhibitorreceptor blockade.McMullen et al. [41, 42] elegantly demon-strated that exercise increases myocardial Akt, with subse-quent attenuation of pathologic LV remodeling, fibrosis, andprotein degradation. Whether similar processes occur dur-ing administration of targeted cancer therapeutics has notbeen investigated; however, exercise training increasesmyocardial PI3K activity [43] with an effective reduction ininfarct size and cardiomyocyte apoptosis in rats subjectedto myocardial ischemia reperfusion [44], as well as improveslifespan in mice with dilated cardiomyopathy [45]. These in-vestigations provide evidence for the protective effects ofPI3K/Akt signaling insettingsof targetedtherapy-inducedcar-diac stress.

Finally, aerobic exercise inhibits TGF� and C/EBP� signal-ing to effectively prevent and/or attenuate pathological car-diac hypertrophy in various mouse models. For instance,aerobicexerciseattenuates isoprenaline-induced increases inmyocardial levels of TGF� andC/EBP�mRNA,with parallel in-hibition of pathological myocardial hypertrophy [34]. Exer-cise-induced reduction of TGF� and C/EBP� expression, inturn, increases both cardiomyocyte size and cell division re-sulting in physiological hypertrophy [34]. Interestingly, exer-cise or experimental downregulation of C/EBP� expressionhas also been shown to upregulate GATA4, a regulator of car-diomyocyte proliferation during myocardial regeneration inzebrafish [46]. Thesedata indicate that aerobic exercise inhib-

its TGF-�1andC/EBP�expressionandupregulatesGATA4, ul-timately leading to modulation of protein degradation andupregulation of protein synthesis.

In the only human study examining MTTs and exercise todate, our group found that 16 weeks of supervised aerobictraining failed to attenuate trastuzumab-induced LV dilationand reduced ejection fraction in patients with HER2-positiveoperable breast cancer [47]. This observation is in contrast toworkbyusandothersdemonstrating thataerobic trainingcanreverseLVremodeling inpatientswithstableheart failure [48,49]. These discordant findings were likely due to the fact thatparticipants in the trastuzumab trial attended an insufficientnumber of training sessions anddid not receive a high enoughtraining stimulus to achieve beneficial adaptations.

MECHANISMS OFANGIOGENESIS INHIBITIONDIRECTEDTHERAPY-INDUCED CARDIAC INJURYAngiogenesis, the formation of new capillary blood vessels, ispredominantly regulated via vascular endothelial growth fac-tor (VEGF) and is fundamental for bothphysiologic andpatho-logic processes (reviewed extensively in references [50, 51]).VEGF inhibition, alone or in combination with conventionalchemotherapy, is now approved by the FDA as first-line ther-apy for abroad rangeof advancedsolidmalignancies [50]. Theincidence andmagnitude of cardiac injury withmultitargetedTKIs is particularly high, whereas treatment with monoclonalmAbs appears to cause comparably less injury (Table 1).

Figure 2. Mechanisms underlying modulation of HER2-directed therapy cardiotoxicity through aerobic exercise. Aerobic exercise in-duces cardioprotection via upregulation of Nrg1 synthesis and release, thus activating pathways A–C; inhibition of TGF-�1 and C/EBP�signaling and upregulation of GATA4 (pathway D); and activation of AMPK expression (pathway E).

Abbreviations: AMPK, AMP-activated protein kinase; C/EBP�, CCAAT/enhancer binding protein; Fak, focal adhesion kinase;MAPK,mitogen-activatedprotein kinase;Nrg1,Neuregulin-1�; PI3K, phosphatidylinositol 3-kinase; Smad, smallmotheragainstdecapentaple-gic; TGF�, transforming growth factor�.




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Figure 3. Mechanismsunderlying anti-angiogenic therapy cardiotoxicity. InhibitionofVEGF signalingwith tyrosine kinase inhibitor-directedtherapies impacts numerous signaling pathways resulting in inhibition of angiogenesis, and protein synthesis and degradation via the PI3K-Akt-NO pathway; and inhibition of cell proliferation and differentiation via theMAPK-ERK pathway. Monoclonal inhibitors include bevaci-zumaband ramucirumab;multikinase inhibitors include sunitinib, axitinib, pazopanib,motesanib, vadetanib, and sorafenib.

Abbreviations:MAPK,mitogen-activated protein kinase; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; VEGF, vascular endo-thelial growth factor.

Figure4. Mechanismsunderlying anti-angiogenic therapy cardiotoxicity throughaerobic exercise. Aerobic exercise induces cardiopro-tection via upregulation of VEGF expression; a nitric oxide-dependant increase in endothelial progenitor cells; and activation of STAT3resulting in erythropoietin secretion and binding to cardiac progenitor cells, causing differentiation into endothelial cells.

Abbreviations: CPC, cardiac progenitor cells; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PI3K, phosphatidylinositol3-kinase; EC, endothelial cell; EPO, erythropoietin; VEGF, vascular endothelial growth factor.




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ANTIANGIOGENIC THERAPY INHIBITION OF CARDIAC ANDVASCULARMOLECULAR SIGNALINGPutative pathways underlying the cardiotoxic properties ofmonoclonal andmultitargetedagents are illustrated inFigure3.

Monoclonal InhibitionCirculatingVEGFbinds to its receptorsplateletderivedgrowthfactor receptor (PDGFR), VEGFR1 (also known as Flt-1), andVEGFR2 (also knownas Flk-1orKDR).Monoclonal therapeuticinhibition of the VEGF pathway is achieved via antibodies tar-geting a VEGF ligand (e.g., bevacizumab binding to VEGF), de-coy receptors for VEGF (e.g., aflibercept), or antibodiestargeting the extracellular domain of VEGFRs (e.g., ramuci-rumab binding to VEGFR2), thus limiting endothelial cellsprouting, migration, proliferation, and tube formation [52].Of importance, suppression of VEGF/VEGFR signaling causespathological alterations in cardiac and vascular tissues [53,54]. For instance, global VEGF knockout in rodents causes em-bryonic lethality [55],whereas postnatalmurine downregula-tion of myocardial VEGF expression initiates a cascade ofevents leading toprogressivediastolicandsystolic LVdysfunc-tion [43]. Cardiac-specific VEGF knockoutmice display abnor-malcardiacmusclecapillaritynumber [56]andclassic features

of cardiomyopathy (i.e., reduced cardiac output, fractionalshortening, decreased dP/dt) [57]. Physiologically, cardiomyo-cyte binding of VEGF activates Akt, initiating signaling pathwaysregulatingnitricoxide (NO)synthase,angiogenesis, andprogeni-tor cell differentiation into cardiomyocytes [58–60]. Anti-VEGFagents likely inhibit vascular NO release, thus promoting vaso-constriction, increased peripheral resistance, and increasedblood pressure, [53], as well as limiting endothelial progen-itor cell (EPC) [59] and cardiac progenitor cell (CPC) [61] de-velopment and ultimately restraining cardiomyocytedifferentiation.Unfortunately, limited clinical data andmech-anistic information are available to substantiate these poten-tial pathways.

Multitargeted InhibitionMultitargetedTKIsmay lead toagreater incidenceandmagni-tude of cardiotoxicity due to binding of multiple proteinsand/or downstream pathways (Table 1). For instance, Chu etal. [62]demonstrated that sunitinib,which targetsVEGFR1–3,c-kit, and PDGFR, leads to profound structural and functionalabnormalities in cardiomyocyte mitochondria, leading to adecrease in ATP production. In addition, blockade of VEGFR2with TKIs decreases endothelial nitric oxide synthase (eNOS)

Table 2. Potential future research directions to assessmodulation ofmolecularly targeted therapeutic cardiotoxicity with

aerobic exercise

Underlyingmechanisms ofMTT-related cardiotoxicity

• Elucidate the specific actions of HER2-inhibitors onmyocardial Nrg1 release and ErbB downstreampathways

• Examinewhether anti HER2 agents upregulatemyocardial TGF� and C/EBP� signaling and consequently downregulate GATA4signaling

• Determine the effects of anti-angiogenic agents onmyocardial and vascular VEGF expression and VEGFR signaling

• Examine the impact ofMTT on other tissues, such as skeletal muscle

• Delineate the longitudinal cardiac consequences in patients receivingMTTs

Underlyingmechanisms of aerobic exercise-induced cardioprotection

• Perform translational exercise-cardiotoxicity studies to elucidatewhether aerobic exercise:

• Upregulatesmyocardial Nrg1 and PGC1-� expression

• Decreasesmyocardial TGF� and C/EBP� signaling and increases GATA4 signaling

• Increasesmyocardial downstream effector signaling (e.g., endothelial progenitor cell, cardiac progenitor cell)

• Evaluate aerobic exercise intensity required to prevent/treat cardiotoxicity

• Establishmost effective timing (before, during, or following therapy) to perform aerobic exercise training

• Examinewhether integrating resistance and aerobic exercise can protect peripheral as well as central factors

• Monitor antineoplastic indices during aerobic exercise training to ensure antineoplastic goals ofMTTs aremet

Potential ResearchModels

• Neonatal rat ventricularmyocytes

Model should be used to examinemolecularmechanisms underlying cardiomyocyte hypertrophy, stress, and failure as a result ofMTT-induced toxicity

• Zebrafish

Ideal for cardiotoxicity-aerobic exercise studies given that the underlying cardiac development, patterning, genes, functions, anddisease characteristics are similar to humans, and has recently been established as novel exercisemodel

• Knockout/transgenic rodents

Genetically downregulated or upregulated pathways in rodents should be used to establish exercise-induced cardioprotectivesignaling pathways

• Patient populations

Adequately poweredmulticenter RCTswith appropriate cardiac endpoints are required to evaluate the relative efficacy ofaerobic exercise training to prevent/treat cardiotoxicity

Abbreviations:MTT,molecularly targeted therapeutic; RCT, randomized controlled trial.




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activationandNOrelease,promotingvasoconstrictionand in-creased blood pressure [63]. Of significance, the combinedcardiac and vascular injury may enhance the severity of car-diac injury. Izumiya et al. [64] demonstrated that VEGF inhibi-tion contributed to progression from compensatory cardiachypertrophy to LV failure under hypertensive conditions.Chronic hypertension ultimately leads to a compensatory in-crease inmyocardial musclemass tomaintain normal cardiacoutput [65]. In both hypertensive and pre-hypertensivestates, there is slow but steady hypertrophy of the LV [66],leading to a decreased ability to relax initially during exerciseand subsequently at rest [67]. Whether concentric remodel-ing occurs in patients receiving antiangiogenic therapies hasnot been investigated.

AEROBIC EXERCISE-INDUCED CARDIOPROTECTION FROMANGIOGENESIS INHIBITIONAerobic exercise-induced increase in vascular andmyocardialVEGF/VEGFR signaling may prevent/treat antiangiogenesis-induced cardiotoxicity. These conceptual pathways are illus-trated in Figure 4. Upregulation of myocardial VEGF usingnaked DNA gene therapy enhances capillary density and de-creasesendothelial cell andcardiomyocyteapoptosis, leadingto improvements in cardiac function in a diabetic rat model[43]. Aerobic exercise augments the aging-induced [68] andinfarct-induced [69] decrease in VEGF mRNA and protein ex-pression in murine cardiac tissue. Increased VEGF expressionoccurs viaupstreamperoxisomeproliferator-activated recep-tor-� coactivator-1� (PGC-1�) through the transcription fac-tor estrogen-related receptor-� and is independent of

hypoxia-inducible factor 1�-induced VEGF expression [70].Aerobicexercise rapidlyupregulatesPGC-1�mRNAinskeletalmuscle,witha concomitant increase inmitochondrial contentleading to resistance to fatigue and a higher number of oxida-tive fibers [71]. Thus, because PGC-1� is obligatory for the ex-ercise-induced increase in VEGF expression, it is evident thatPGC-1� has a particularly prominent role in regulating train-ing-induced VEGF expression.

An additional putative cardioprotective mechanism is ex-ercise-induced augmentation in the production andmobiliza-tion of CPCs and EPCs via acute increases in interleukin-6 (IL-6), NO, and VEGF-dependent mechanisms [72–74]. Aerobic

exercise leads to an NO-dependent increase in circulatingEPCs inmice and humans [72], thus contributing to neovascu-larizationandvascular repair, leading to improvedendothelialfunction and myocardium recovery after ischemia [75–78].IL-6 also playsmultiple functions in angiogenesis and vascular

Aerobic exercise rapidly upregulates PGC-1� mRNAin skeletalmuscle,with a concomitant increase inmi-tochondrial content leading to resistance to fatigueand a higher number of oxidative fibers. Thus, be-cause PGC-1� is obligatory for the exercise-inducedincrease inVEGFexpression, it is evident that PGC-1�has a particularly prominent role in regulating train-ing-induced VEGF expression.

Table 3. Future challenges for research investigating the effects of and mechanisms of aerobic exercise in MTT-induced

cardiac toxicity

Preclinical studies

• Many of the availableMTTs are humanized agents. Thus, whether the cardiotoxicmechanistic action of these agents is the samein rodentmodels is questionable. Investigators should strive to test themurine versions of selected agents whenever possible.

• Within available rodentmodels, strains have inherently different exercise capacities whichmay also contribute to distinct cardiacadaptations to exercise training �131, 132�. These disparitiesmay account for discordant findings between investigations.

• Cardio-oncology investigations often use eithermale or female animals only. However, there are sexually dimorphiccardiovascular adaptations to exercise training in bothmice and rats �133–135�, which limitsmechanistic implications for eithermale or female patients.

• Mechanistic investigations are often conducted in animals that are young and otherwise healthy. In contrast, cancer patients aretypically older with the presence of concomitant comorbidities which exacerbate treatment-induced cardiotoxicity �136�.

• No threshold of exercise intensity for inducing observable cardiac adaptations has been identified in any clinical disease �137�.Most animal cardio-oncology exercise studies utilize continuous treadmill running characterized by fixed speed, inclination, andduration �138�. Elucidation of the dose-response relationship of exercise on cardiac function in rodents and how this translates tothe clinical setting are urgently required.

Clinical studies

• Overt cardiac events are relatively uncommon in cancer patients receivingMTTs; asymptomatic events aremore frequent.Nevertheless, given the current event ratewith standard detection techniques, large trials will be required to examine the effectof exercise on reducing the event rate. This issue could be somewhat addressed using biomarker enriched trials in which patientsonly at high-risk of events are recruited. Established biomarkers to identify such high-risk patients are not yet available butcurrently under investigation �8�.

• Cancer patients typically receiveMTTs in combinationwith other agents, particularly cytotoxic agents, possibly confounding theeffects of exercise onMTT-induced cardiotoxicity �139�, making interpretation challenging.

• Although numerous studies have demonstrated excellent adherence and safety profiles withmoderate intensity exercise �140�,no studies to date have examinedwhether patients receivingMTTs can successfully adhere or tolerate structured exercisetraining prescriptions incorporatingmoderate or high intensity training.

• The clinical impact of exercise on the antitumor efficacy ofMTTs in patients is unknown. Investigations determining theinteraction between exercise and tumor outcomes are critical in both rodent and human studies �141�.

Abbreviations:MTT,molecularly targeted therapeutic.




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remodeling and may stimulate EPC proliferation, migration,and tube formation following exercise [73, 79].

Importantly, this upregulation in EPCs and CPCs has beenimplicated in cardiomyocyte healing processes. Kolwicz et al.[80] found that exercise increased CPC proliferation by�200% and augmented the presence of KIT-positive cells (astem cell factor crucial for themobilization of progenitor cellsto sites of injury) in the heart. Togetherwith signal transducerand activator of transcription 3 (STAT3), this exercise-inducedincrease in CPC proliferationmay play a key role in cardiomy-ocyte proliferation, differentiation, and survival [81]. STAT3activation has been shown to mediate cardiac hypertrophyand protect cells in response to cardiomyopathy induced byischemiaordrug treatment [82–84]. Significantly, exercise in-creases STAT3 activation [85, 86], causing release of erythro-poietin into the cardiacmicroenvironment that, in turn, bindstoCPCs,causingdifferentiation intoendothelial cells [87].Pre-sumably, these endothelial cells can then be activated byVEGF to express matrix metalloproteinases, which degradethe vascular basement membrane to form new capillary net-works [88]. Collectively, we speculate that aerobic exercisemay increase PGC-1� and VEGF secretion and STAT3 activa-tion, with the resultant release, mobilization, and homing ofCPCs during angiogenesis inhibitor therapy.

CONCLUSIONMolecularly targeted therapeutics are the future of cancersystemic therapy; they have already moved from palliativetherapy for advanced solidmalignancies into the settingof cu-rative-intent treatment for early-stagedisease. Cardiotoxicityis a frequent and potentially serious adverse complication ofsome targeted therapies, leading to a broad range of poten-tially life-threatening complications, therapydiscontinuation,andpoorquality of life. Low-cost,multitargeted interventionsarethereforeurgently requiredtomitigatetheseadversecon-sequences. Evidence reviewed here indicates that aerobic ex-ercise is a nontoxic, pleiotropic therapy that affects diversecardiac signaling pathways implicated in the cardiotoxicity in-duced by anti-HER2 and antiangiogenic therapy. It is impor-tant to stress that the current evidence base is emergentwith

asmall numberof studies;manyareasofMTT-inducedcardio-toxicity remain tobedefinedandaddressed.A summaryof fu-ture investigations needed to define the nature andmagnitude of the cardioprotective effects of exercise in thesetting ofMTT is provided in Table 2. Future challenges for re-search investigating the effects of aerobic exercise in MTT-induced cardiac toxicity are provided in Table 3.

Although clinical and research interest in aerobic exercisehas increaseddramatically over the past decade, amore thor-ough understanding of themyocardial signaling pathways ac-tivated by exercise will be needed to improve cardiovascularoutcomes. Collectively, such researchwill lead tomechanisti-cally driven clinical trials. Importantly, adequately poweredmulticenter randomized controlled trials are required to eval-uate the relative efficacy of aerobic exercise training to pre-vent/treat cardiotoxicity. These investigations, in turn, willinform exercise prescription rehabilitation guidelines for pa-tientswith cancer,whereby themost effective exercise inten-sity and timing (before, during, or following therapy) areestablished.Weanticipate that exercisewill complementmo-lecularly targeted therapeutics to improve thehealth and lon-gevity of patients with solidmalignancies.

ACKNOWLEDGMENTSThiswork is supported inpartbygrants fromtheNationalCan-cer Institute (CA143254, CA142566, CA138634, CA133895,CA164751 to L.W.J.), funds from George and Susan Beischer(L.W.J.), and a Natural Sciences and Engineering ResearchCouncil postdoctoral fellowship (J.M.S.).

AUTHOR CONTRIBUTIONSConception/Design: JessicaM. Scott, LeeW. JonesManuscriptwriting: JessicaM.Scott, SusanLakoski, JohnR.Mackey, Pamela S.Douglas,Mark J. Haykowsky, LeeW. Jones

Final approval ofmanuscript: JessicaM. Scott, Susan Lakoski, JohnR.Mackey,Pamela S. Douglas,Mark J. Haykowsky, LeeW. Jones

DISCLOSURESJohnR.Mackey:RocheOncology;PamelaS.Douglas:Atritech/BostonScientific, Edwards Lifesciences (RF); CardioDX,UniversalOncology (OI).Theother authors indicatedno financial relationships.(C/A)Consulting/advisory relationship; (RF)Research funding; (E) Employment; (H)Honoraria

received; (OI)Ownership interests; (IP) Intellectual property rights/inventor/patentholder; (SAB)

Scientific advisoryboard

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