Combining Stroma-Targeted !erapies with Radiation to Prevent Resistance
Dan G. Duda, DMD, PhDHarvard Medical School
New Cancer Targets – NCT ConferenceSesptember 23, 2013
Con"icts of Interest
§None
Courtesy of Dr. Lance L. Munn
Tumor Microenvironment Shapes Tumor Progression and Response to !erapy
Successful Phase III Trials of Antiangiogenics
Upd
ated
from
Car
mel
iet &
Jai
n, N
atur
e (2
011)
DRUG INDICATION IMPROVEMENT IN RR* (%) IMPROVEMENT IN PFS* (MONTHS) IMPROVEMENT IN OS* (MONTHS)
BEVACIZUMAB Metastatic colorectal cancer (with chemotherapy) 10 4.4 4.7
0 1.4 1.4 7.8 2.8 2.5
14.1 2.6 2.1Metastatic non-squamous NSCLC (with chemotherapy) 20 1.7 2.0
10.3-14.0 0.4-0.6 NSMetastatic breast cancer (with chemotherapy) 15.7 5.9 NS
9-18 0.8-1.9 NS 11.8-13.4 1.2-2.9 NS
9.9 2.1 NSRecurrent GBM (monotherapy) Currently only phase 2 data reportedCurrently only phase 2 data reportedCurrently only phase 2 data reportedMetastatic RCC (with IFNα) 18 4.8 NS
12.4 3.3 NSSUNITINIB Metastatic RCC 35 6.0 4.6
GIST 6.8 4.5 NSPNET 9.3 4.8 ?
SORAFENIB Metastatic RCC 8 2.7 NSUnresectable HCC 1 NS 2.8Unresectable HCC 2 1.4 2.3
PAZOPANIB Metastatic RCC 27 5.0 N/AAdvanced soft tissue sarcoma 6.0 3.0 NS
VANDETANIB Advanced medullary thyroid cancer 43 6.2 N/AAXITINIB Advanced RCC 10 2.0 N/AREGORAFENIB Chemo-refractory metastatic colorectal cancer 0.6 0.2 1.4
AFLIBERCEPT Chemo-refractory metastatic colorectal cancer 8.7 2.2 1.4
CABOZANTINIB Advanced medullary thyroid cancer 25 7.2 NS
RAMUCIRUMAB Metastatic gastric and gastroesophageal junction cancers* 0.8 0.8 1.4
Successful Phase III Trials of Anti-cancer Targeted Agents
DRUG APPROVED INDICATION IMPROVEMENT IN RR* (%)
IMPROVEMENT IN PFS* (MONTHS)
IMPROVEMENT IN OS* (MONTHS)
CETUXIMAB Metastatic colorectal cancer (with chemotherapy) 0.9 1.9 (NS)CETUXIMAB
10 0 NS
CETUXIMAB
Metastatic non-squamous NSCLC (with chemotherapy) NS 1.2
CETUXIMAB
Metastatic head and neck cancer (with radiation) 4.7 19.7
CETUXIMAB
NS 2.7
ELOTINIB Metastatic non-squamous NSCLC (monotherapy) 8 0.4 2ELOTINIB
Metastatic pancreatic adenocarcinoma (with chemotherapy) 1 0 0
TRASTUZUMAB Metastatic HER2+ breast carcinoma (with chemotherapy) 17 3 5.1TRASTUZUMAB
Advanced HER2+ gastric carcinoma (with chemotherapy) 12.9 1.2 2.7
LAPATINIB Metastatic breast carcinoma (with chemotherapy) 9.8 8.5 NS
GEFITINIB Metastatic non-squamous NSCLC (versus chemotherapy) Japanese population 43 5.4 6.9 (NS)GEFITINIB
Metastatic non-squamous NSCLC (versus chemotherapy) 9.7 NS NS
VEMURAFENIB Metastatic melanoma with the BRAF V600E mutation 43 3.7 8
CRIZOTINIB ALK-positive non-squamous NSCLC No phase III data availableNo phase III data availableNo phase III data available
VISMODEGIB Metastatic basal cell carcinoma No phase III data availableNo phase III data availableNo phase III data available
Multidisciplinary Translational TrialsAgent / Cancer Type
Rectal Cancer
Ovarian Cancer
Breast Cancer Liver cancer Sarcoma Brain tumors Lung
Cancer Schwannoma Insulinoma
Bevacizumab(Genentech)
Phase I/IICompleted
Phase IICompleted
Phase IICompleted (ER+ & TN)
Phase IIPlanned(HER2+)
Phase IICompleted
Phase IIOngoing
Phase IICompleted
Phase I Completed
Phase II Completed
Cediranib(AstraZeneca)
Phase IICompleted
(HCC)
3 x Phase IICompleted
Phase IIICompleted
Sunitinib(Pfizer)
Phase IICompleted
(HCC)
Sorafenib(Bayer/Onyx)
Phase IIOngoing(HCC)
Phase IICompleted
Vandetanib(AstraZeneca)
Phase IICompleted
Phase IICompleted
Vatalanib(Novartis)
Phase ICompleted
Ramucirumab (ImClone)
Phase IICompleted
(HCC)
Plerixafor
(Genzyme) &
Bevacizumab
Phase IIOngoing
Cabozantinib Phase IIOngoing
Phase IIPlanned(CCA)
Phase IIOngoing
Highlighted trials – analyses ongoing
Candidate Biomarkers Exist
Duda, Angiogenesis Foundation e-Publication CME series 2011
Agent / Cancer Type Rectal Cancer Sarcoma Brain tumors Pancreatic
CancerProstate Cancer HCC
Radiation with bevacizumab(Genentech)
Phase IICompleted
Phase IICompleted
Phase IIOngoing
Radiation with cediranib(AstraZeneca)
2 x Phase IICompleted
Radiation with vatalanib(Novartis)
Phase ICompleted
Radiation therapy Phase IICompleted*
Study off trialPhase II planned&
Phase IIongoing*
Clinical studies at MGH and DFCI
*Proton beam therapy&Radium-223 chloride (Ra-223)
Challenges
§ How do we personalize these therapies?
§ How do we schedule them with radiation therapies?
§ How do these therapies work and how do they fail?
Weinberg & Hanahan. Hallmarks of cancer: the next generation. Cell 2011
Overview
1. Treatment resistance: Role of in"ammatory factors
Overview
1. Treatment resistance: Role of in"ammatory factors
2. Treatment resistance: Role of paracrine signals
Overview
1. Treatment resistance: Role of in"ammatory factors
2. Treatment resistance: Role of paracrine signals
3. Concluding thoughts
Overview
Nature Reviews Neuroscience 2007
How Relevant is Vasculogenesis in Tumors?
Jain & Duda, Cancer Cell 2003
Ang1
CD31-Tie2+
CD31+Tie2+
BMDC Contribution to Tumor Vessels
Tie2-GFP and Actb-GFP BMT Models to Detect BMD-ECs
Duda et al., Blood 2006
Nature Reviews Neuroscience 2007
Is Vasculogenesis Mediating Treatment Resistance?
LI Does Not Signi#cantly Affect the Vasculature but Increases Myeloid BMDC In#ltration
How do in!ammatory factors impact tumor resistance?
Effect of Myelosuppression on Tumor Growth
I
II
Effect of Myelosuppression on Tumor Growth
I
II
54A Lung Tumor Growth After 20Gy of LI
SDF1α expression 2 days after 20Gy of LI
Only concomitant CXCR4 Blockade Delays Tumor Growth
Kozin et al., Cancer Res 2010
MCa8 mammary carcinoma in FVB mice
Only concomitant CXCR4 Blockade Delays Tumor Growth
Kozin et al., Cancer Res 2010
MCa8 mammary carcinoma in FVB mice
Proposed Model of Tumor Growth after Irradiation
JNCI J Natl Cancer Inst 2012;104:899-905
© The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
Willett et al., Nat Med 2004Willett et al., J Clin Oncol 2005Duda et al., J Clin Oncol 2006
Willett, Duda et al., J Clin Oncol 2009Willett, Duda et al., Nat Clin Pract Oncol 2007
Xu, Duda et al., Cancer Res 2009Willett et al., Oncologist 2010Duda et al., Oncologist 2010
Phase I/II Trial of Bevacizumab with Chemoradiation in Advanced Rectal Cancer
Laser Capture Micro-dissection of Macrophages and Cancer Cells from Serial Biopsies
Fold change (qPCR)
* p<0.05** p<0.01Xu, Duda et al.,
Cancer Res 2009
Cancer type Agent(s) plasma SDF1α Reference
Locally advanced rectal cancer
Bevacizumab with chemoradiation DFS Xu, Duda, di Tomaso et
al, Cancer Res (2009)
Locally advanced HER2– breast cancer
Bevacizumab with chemotherapy
pCR(in Triple Neg. pts.)
Tolaney et al, ASCO (2012)
Advanced HCC Sunitinib OS Zhu et al, Clin Oncol (2009)
Advanced sarcoma Sorafenib RR Raut, Boucher, Duda et al, PLoS One (2012)
Advanced GBM Cediranib Radiographic progression Batchelor et al, J Clin Oncol (2010)
On-treatment Increase in SDF1α as a Potential Escape Pathway for Anti-VEGF !erapy
di Tomaso et al., Cancer Res 2011; Lu-Emerson et al., Neuro-Oncol 2013
SDF1α (CXCL12) pathway
Duda D G et al. Clin Cancer Res 2011;17:2074-2080
©2011 by American Association for Cancer Research
BMS-936564 (MDX1338)
Nox-A12
AMD3100 (pleraxifor)
BKT140CCX662
How about metastasis formation?
Willett, Duda et al., Oncologist 2010
Neoadjuvant Bevacizumab with Chemoradiation Does Not Prevent Metastasis
Willett, Duda et al., Oncologist 2010
Neoadjuvant Bevacizumab with Chemoradiation Does Not Prevent Metastasis
C-08 (2,672 pts)
Willett, Duda et al., Oncologist 2010
Neoadjuvant Bevacizumab with Chemoradiation Does Not Prevent Metastasis
C-08 (2,672 pts)
AVANT (3,451 pts)
Dawson et al., Nature 2009Duda et al., Cancer Res 2010
Does SDF1α/CXCR4 pathway mediate the involvement of BMDCs in metastasis?
Inducible CXCR4 de#ciency
Hiratsuka, Duda et al., PNAS 2011Dawson, Duda et al., Nature 2009
*p < 0.05
CXCR4 blockade signi#cantly inhibits lung metastasis after primary tumor resection
0
6
12
18
0
25
50
75
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Num
ber o
f met
asta
ses
Volu
me
of m
etas
tase
s
** *
*
TRAMP-C1 prostate cancer
Hiratsuka et al., PNAS 2011
*p < 0.05
CXCR4 blockade signi#cantly inhibits lung metastasis after primary tumor resection
0
6
12
18
0
25
50
75
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Num
ber o
f met
asta
ses
Volu
me
of m
etas
tase
s
** *
*
TRAMP-C1 prostate cancer
0
5
10
15
20
0
5
10
15
20
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Num
ber o
f met
asta
ses
Volu
me
of m
etas
tase
s
* **
E0771 breast cancer
Hiratsuka et al., PNAS 2011
*p < 0.05
CXCR4 blockade signi#cantly inhibits lung metastasis after primary tumor resection
0
6
12
18
0
25
50
75
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Num
ber o
f met
asta
ses
Volu
me
of m
etas
tase
s
** *
*
TRAMP-C1 prostate cancer
0
5
10
15
20
0
5
10
15
20
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Ctrl
BMT
CXCR4-KO
BMT
CXCR4/TK-KO
BMT
Num
ber o
f met
asta
ses
Volu
me
of m
etas
tase
s
* **
E0771 breast cancer
0
30
60
90
0
3
6
9
12
PBS(WT)
PBS(TK)
AMD(WT)
AMD(TK)
PBS(WT)
PBS(TK)
AMD(WT)
AMD(TK)
Num
ber o
f met
asta
ses
Volu
me
of m
etas
tase
s
AMD3100 (AMD)
VEGFR1-TK-KO BMT (TK)
**
Hiratsuka et al., PNAS 2011
BMDCs and SDF1a/CXCR4 may be valid targets for inihition of tumor resistance and distant progression
Targeting paracrine interactions
Does the tumor rely on host-derived signals for
progression?
Day
Blood
1 14 28-42
Proton Therapy (5 x 5 Gy QD)
5
Capecitabine (825 mg/m2 PO BID)
Surgery
Tissue
7
Hong et al., unpublished data
Phase I/ II Trial of Neoadjuvant Proton with Chemotherapy in Pancreatic Adenocarcinoma
!
Local recurrence
Hong et al., ASCO 2013
!
Local recurrence
!
Distant metastasis
Hong et al., ASCO 2013
!
Local recurrence
!
Distant metastasis
Hong et al., ASCO 2013
Follow-up Time (Months)
Ove
rall
Surv
ival
0 6 12 18 24 30 360
.2
.4
.6
.8
1No KRASG12D mutationKRASG12D mutation
P=0.024
Follow-up Time (Months)
Ove
rall
Surv
ival
0 6 12 18 240
.2
.4
.6
.8
1HGF�1500 pg/mlHGF>1500 pg/ml
P=0.019
KRASG12D mutation and elevated HGF are associated with poor survival
Hong et al., ASCO 2013
Are HGF and cMET expressed in PDAC?
Are HGF and cMET expressed in PDAC?
! !
HGF cMET
Courtesy Dr. Deshpande (MGH)
PlGF/NRP1 in Medulloblastoma
NEJM 2013Snuderl et al, Cell 2013
Stroma-mediated signals may drive tumor progression as well as treatment resistance
Concluding thoughts
Concluding thoughts
• Host-derived factors and tumor stroma mediate cancer progression and therapeutic resistance
Concluding thoughts
• Host-derived factors and tumor stroma mediate cancer progression and therapeutic resistance
• Pathways of evasion should be con!rmed in clinical studies, which in turn should inform preclinical studies
Concluding thoughts
• Host-derived factors and tumor stroma mediate cancer progression and therapeutic resistance
• Pathways of evasion should be con!rmed in clinical studies, which in turn should inform preclinical studies
• Mechanistically based biomarkers of resistance may help guide trial design
Steele Lab at MGH
Steele Lab at MGH
FundingR21CA139168, R01CA159258, P01CA80124 & Federal Share Proton Beam NCI Grants
American Cancer Society RSG-11-073-01-TBG American Association for Cancer Research
Cancer Research Institute
Agent / Cancer Type Rectal Cancer Brain tumors Breast
Cancer HCC Sarcoma Ovarian Cancer LungCancer Schwannoma
Bevacizumab(Genentech)
Cediranib(AstraZeneca)
Sunitinib(Pfizer)
Sorafenib(Bayer/Onyx)
Ramucirumab (ImClone)
Vatalanib(Novartis)
Vandetanib(AstraZeneca)
Plerixafor (Genzyme)
Proton Therapy
MGH/DF Clinical Collaborators and Patients
WillettHorowitz
Krop ZhuYoon
Batchelor
Heist Plotkin
Eder
Gerstner
Wen
Meyerhardt Hong