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

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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: journals.permissions@oup.com.

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

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BMT

CXCR4-KO

BMT

CXCR4/TK-KO

BMT

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ses

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** *

*

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

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BMT

CXCR4-KO

BMT

CXCR4/TK-KO

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** *

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TRAMP-C1 prostate cancer

0

5

10

15

20

0

5

10

15

20

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BMT

CXCR4-KO

BMT

CXCR4/TK-KO

BMT

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* **

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

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BMT

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BMT

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** *

*

TRAMP-C1 prostate cancer

0

5

10

15

20

0

5

10

15

20

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BMT

CXCR4-KO

BMT

CXCR4/TK-KO

BMT

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* **

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)

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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