The Role of Exercise as a Prevention Treatment Strategy · 2015-04-15 · intensity exercise or ≥...

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The Role of Exercise as a The Role of Exercise as a

Prevention and Prevention and

Treatment Strategy for Treatment Strategy for

CancerCancer

Lee W. Jones, PhDLee W. Jones, PhDLee W. Jones, PhDLee W. Jones, PhD

‘Adults should engage in ≥ 150 min/wk of moderate‐

Kushi et al. CA Cancer J Clin, 2012

All Rights Reserved, Duke Medicine 2011

• Adults should engage in ≥ 150 min/wk of moderate‐intensity exercise or ≥ 75 min/wk of vigorous exercise, evenly spread throughout the week ’

• ‘…may reduce the risk of several types of cancer, including cancers of the breast, colon, and endometrium, as well as advanced prostate cancer & possibly, pancreatic cancer’

• ‘Exercise is a safe & feasible intervention for cancer patients both during & after therapy’

Rock et al. CA Cancer J Clin, 2012


patients both during & after therapy

• ‘…associated with significant improvements in physical functioning, fatigue, and multiple aspects of QOL’

• Strong evidence for exercise as an adjunct to improve symptom controlDo the effects of exercise extend beyond symptom Do the effects of exercise extend beyond symptom

control to impact tumor biology & clinical outcomes?control to impact tumor biology & clinical outcomes?

© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.

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Hawk et al. Clin Cancer Res, 2008

TRWGTRWG DescriptionDescription

1. Discovery Association between exposure (exercise) and clinical events

2. Credentialing Consensus of indicative findings across studies



3. Supporting tools Omic‐based approaches to provide mechanistic insight

4. Creation of modality Development and refinement of a promising lifestyle alteration intervention

5. Preclinical development Initial animal models to define biological plausibility & mechanisms of action

6. Phase II trials Preliminary human studies

7. Phase III trials Definitive phase III testing

StepStep DescriptionDescription




3i. Discovery data Findings derived from epidemiological data

3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms

Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research


using a combination of in vitro & in vivo platforms

4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype

4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)

4ii. ‘First time in man’ (phase I) studies

Use of animal data to inform phase I‐type studies with correlative science endpoints

5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS

6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival

















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• Holmes et al. JAMA, 2005

• N=2987 Nurses Health Study

DiscoveryDiscovery

70

80

90

100

y reduction

Padjusted <0.01


0

10

20

30

40

50

60

<3 3‐8.9 9‐14.9 15‐23.9 >24

Percent cancer mortalit

Self‐reported physical activity category (MET‐hrs/wk)
















HR from cancer‐specific death, 95% CI

Exercise & breast cancer‐specific mortality

CredentialingCredentialing


0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0

Adapted from BallardAdapted from Ballard‐‐BarbashBarbash et al. et al. JNCIJNCI, 2012; , 2012; BetofBetof et al. et al. Brain Brain BehavBehav ImmunImmun, 2012 , 2012

Lower mortality Higher mortality

SuggestiveSuggestive evidence that exercise is associated with evidence that exercise is associated with improved breast cancerimproved breast cancer‐‐specific outcome specific outcome


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HR from cancer‐specific death, 95% CI

Breast cancer

Exercise & cancer‐specific mortality

CredentialingCredentialing


0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0Lower mortality Higher mortality

GI

prostate

Adapted from BallardAdapted from Ballard‐‐BarbashBarbash et al. et al. JNCIJNCI, 2012; , 2012; BetofBetof et al. et al. Brain Brain BehavBehav ImmunImmun, 2012 , 2012

SuggestiveSuggestive evidenceevidence
















Differences by molecular features

p27p27‐‐ p27+p27+

Meyerhardt et al. CCR, 2009

<18 MET‐hrs.wk‐1 1.00 1.00

≥18 MET‐hrs.wk‐1 1.40 0.33

Molecular modifiers of the exercise – colorectal cancer prognosis relationship

Tools: discoveryTools: discovery


CTNNB1CTNNB1‐‐ CTNNB1+CTNNB1+

Morikawa et al. JAMA, 2011

<18 MET‐hrs.wk‐1 0.89 1.00

≥18 MET‐hrs.wk‐1 0.33 1.07


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Molecular modifiers of the exercise – breast cancer prognosis relationship

Differences by ER status

ERER++ ERER‐‐

Holmes et al. JAMA, 2005

<9 MET‐hrs.wk‐1 1.00 1.00

Tools: discoveryTools: discovery


<9 MET hrs.wk 1.00 1.00

≥9 MET‐hrs.wk‐1 0.50 0.91

Irwin et al. JCO, 2008

0 MET‐hrs.wk‐1 1.00 1.00

>0 MET‐hrs.wk‐1 0.20 1.26

Secondary analyses, limited statistical powerSecondary analyses, limited statistical power
















E07716

Voluntary wheel running

3 days

Effects of exercise in an orthotopic model of murine breast cancer (E0771; ER+)

Tools: preclinical developmentTools: preclinical development


C57/Bl‐6 female mice

(1 x106)

Sedentary control

1,500mm3

Nelson et al. in progress

1,500mm3


6


~2 weeks

8 weeks

Effects of exercise in GEM model of murine breast cancer (PyMT; ER+)



PyMT Sedentary control


~2 weeks

4T1( 6)


3

3 days

Effects of exercise in an orthotopic model of murine breast cancer (4T1; ER‐)



BALB/C

(1 x106)

Sedentary control

1,500mm3

Betof et al. submitted

1,500mm3

Effects of exercise on tumor growth in PyMT (ovxd) GEMM of murine breast cancer





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Effect of exercise on circulating levels of select growth factors (RTK ligands; PyMT)

IFN Collective

Control Runner0.0

0.5

1.0

1.5

2.0

IFN

pg

/mL

IL10 Collective

Control Runner0

25

50

75

IL10

(p

g/m

L)

IL12 collecitve

Control Runner0

50

100

150

IL12

(p

g/m

L)

P=0.0285P=0.3423

P=0.0009



Control Runner Control Runner Control Runner

IL1bCollective

Control Runner0.0

2.5

5.0

7.5

10.0

IL6 Collective

Control Runner0

25

50

75

100

IL6

(pg

/mL

)

KC/GRO Collective

Control Runner0

10

20

30

40

50

60

70

80K

C/G

RO

(p

g/m

L)

P=0.0009

P=0.4209

P=0.8509

Effect of exercise on select growth factors in tumor microenvironment (PyMT)

TNFa

N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3

P value 0.0926

mR

NA

CXCL12

N R0.00

0.25

0.50

0.75

1.00

1.25

P value 0.0087

(mann whitney)

mR

NA

RANKL

N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3

P value 0.0519

(mann whitney)

mR

NA



N R N R

IL6

N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3

P value 0.0303

(mann whitney)

mR

NA

IL7

N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.31.4

P value 0.2293

mR

NA

N R

CSF1

N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3

P value 0.0430mR

NA


Clinical translation (EXTRA trial)

HHistologically istologically confirmed solid confirmed solid

tumortumor

ildild

RRAANNDDOOMM

Darbepoetin Alfa (Control

EENND D

OOF F

MulitplexMulitplexELISA ELISA ––

LuminexLuminex ArrayArray



MildMild‐‐toto‐‐moderate moderate anemiaanemia

Baseline Baseline AssessmentAssessment

N=44N=44

MMIIZZAATTIIOONN

Darbepoetin Alfa + Aerobic Training (cycle ergometry, 60‐100% VO2peak for

12 weeks)

TTHHEERRAAPPYY

12 weeks

35 cytokines, 35 cytokines, chemokineschemokines, & , & angiogenicangiogenicfactorsfactors

44 44 –– paired paired prepre‐‐post post samplessamples

Glass et al. Cancer Res, submitted


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FactorFactor MedianMedian MinMin MaxMax MedianMedian MinMin MaxMax PP

HGF ‐54.73 ‐775.55 294.68 96.74 ‐296.93 475.43 0.008

IL‐4 ‐3.36 ‐155.81 72.58 3.79 ‐50.72 211.16 0.012

MIP1‐β ‐19.21 ‐1086.53 39.47 9.75 ‐1033.08 138.63 0.034

ExerciseExercise ControlControl



VEGF ‐0.96 ‐22.38 12.27 0.00 ‐15.31 32.70 0.043

TNF‐α 0.00 ‐11.29 12.02 0.00 ‐1.45 10.33 0.046

IFNα ‐8.79 ‐364.18 57.22 ‐4.69 ‐159.88 78.61 0.188

EGF ‐3.00 ‐8720.21 42.30 1.16 ‐1879.26 435.56 0.196

MCP1 ‐108.58 ‐2228.35 549.36 42.89 ‐1266.63 983.37 0.240

MIP1‐α ‐4.89 ‐710.65 53.61 ‐1.44 ‐246.03 45.17 0.240


MCF‐7 (ER+) MDA‐MB‐231 (ER‐)

12000

14000

16000

18000

20000

10000

12000

14000

*

**

Apoptosis (*serum from n=20 breast cancer pts)



0

2000

4000

6000

8000

10000

Day2 Day4 Day6

0

2000

4000

6000

8000

Day2 Day 4

Exercise Control


















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Working modelWorking model


Working modelWorking model


Exercise modulation of host Exercise modulation of host –– tumor interactiontumor interaction



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Exercise & triple negative breast cancer: translational

AIM 1 (PRE‐CLINICAL)• Mouse models of Trip Negative Bca

• C3Tag / 4T1

• ‘Dose‐response’ of aerobic training• Low / Moderate / High

AIM 3 (MECHANISTIC)• Utilizing tissue samples from animals (Aim 1) and clinical trial (Aim 2)

• Mechanistic identification and inhibition

Procurement of plasma & tumor tissue

Creation of modalityCreation of modality


AIM 2 (CLINICAL TRIAL – PHASE I)

• ‘Proof‐of‐Concept’ phase II ‘window of opportunity’ RCT

• Supervised aerobic training @ ‘firstin man dosing’ (informed by Aim 1)

Mechanistic Identification Plasma: Effects on circulating growth factors using ‘omics’ platforms

Tumor tissue: Effects on growth factors; cell survival pathways; Next Generation Sequencing

tumor tissue

Procurement of plasma & tumor tissue
















HHistologically istologically confirmed confirmed triple triple negneg

breast cancerbreast cancer

RRAANNDDOOMM

Standard of Care (Control)(neo / adjuvant chemotherapy)

EENND D

OOF F

Tumor tissue Tumor tissue outcomes (if outcomes (if appropriate)appropriate)

Potential phase II / III RCTPotential phase II / III RCT

Pre‐operative or adjuvant setting


‘Enriched’ ‘Enriched’ patient cohortpatient cohort

Physically Physically inactive / inactive / exercise exercise

intoleranceintolerance

MMIIZZAATTIIOONN

Std of Crae + Adjuvant Aerobic Training (dose informed by translational study)

TTHHEERRAAPPYY

~4 – 24 weeks

BloodBlood‐‐based based biomarkersbiomarkers

SignalSignal for DFSfor DFS


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Current paradigm for exercise – oncology research

Cancer survivorCancer survivor•• CancerCancer TypeType

CC ThTh

Sub‐set / Eligibility Criteria

Exercise Px


population(s)population(s) •• CancerCancer TherapyTherapy

•• YearsYears from from DiagnosisDiagnosis Control

Approach does not take into account expected (tumor) heterogeneity – exercise relationship

Proposed future paradigm for exercise – oncology research??

Clinical TestClinical Test toto

HostHostDNA mutation DNA mutation

(BRCA1)(BRCA1)Exercise Px A

Exercise Px B HostHost

BiomarkerBiomarker++


Clinical TestClinical Test to to SubSub‐‐Categorize Categorize

PatientsPatientsExercise Px A + Drug Px B

Exercise Px A +Drug Px C or unresponsive

(IL(IL‐‐6, TNF6, TNF‐‐α)α)

TumorTumorReceptor Receptor

status(ERstatus(ER++, HER2, HER2++))

TumorTumorMutant pathway Mutant pathway (PI3K, EGFR)(PI3K, EGFR)

Opportunities

1. Optimize efficacy (dose) of exercise therapy

2. Improved mechanistic understanding

3. Novel combinational approaches

1. Exercise – diet combinations


2. Exercise – drug combinations

4. Increased credence of lifestyle interventions in the oncology setting

Facilitate shift to matching right treatment to the right patient to optimize disease and health outcomes following a cancer diagnosis


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Jones Lab

Miranda West, MSWhitney Hornsby, PhDAmy Lane, MSCaroline Bishop, MSBeth Fowler, BSAarti Kenjale, MDLauren Valera, MS

il S h i S

AcknowledgementsAcknowledgementsBreast Tumor GroupJeff Peppercorn, MDKelly Marcom, MDKimberley Blackwell, MDGretchen Kimmick, MDNeil Spector, MD

PRT‐BTCHenry Friedman, MDAllan Friedman, MD

Dewhirst Laboratory

Allison Betof, MD, PhD (c)

Lascola Laboratory

Nixon Laboratory

Poss Laboratory

O’Donnell LaboratoryErik Nelson, PhD


Emily Schwitzer, BSKaitlin Ray, BSGraeme Koelwyn, BSMichael Peace, DVMOliver Glass, BS

CardiologyPamela Douglas, MDBill Kraus, MDJason Allen, PhD

Katy Peters, MD, PhDDavid Reardon, MD

GU Tumor GroupDan George, MDAndy Armstrong, MDSteve Freedland, MDBrant Inman, MD

Thoracic Tumor GroupJeff Crawford, MDJennifer Garst, MD

BiostatisticsJames Herndon, PhDApril Coan, MPHBill Barry, PhDGloria Broadwater, MS


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