Combining Stroma-Targeted Therapies with Radiation to Prevent Resistance

Combining Stroma-Targeted Therapies with Radiation to Prevent Resistance Dan G. Duda, DMD, PhD Harvard Medical School New Cancer Targets NCT Conference Sesptember 23, 2013

Conflicts of Interest None

Tumor Microenvironment Shapes Tumor Progression and Response to Therapy Courtesy of Dr. Lance L. Munn

Successful Phase III Trials of Antiangiogenics 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 2.1 Metastatic non-squamous NSCLC (with 20 1.7 2.0 chemotherapy) 10.3-14.0 0.4-0.6 NS Metastatic breast cancer (with chemotherapy) 15.7 5.9 NS Recurrent GBM (monotherapy) 9-18 0.8-1.9 NS 11.8-13.4 1.2-2.9 NS 9.9 2.1 NS Currently only phase 2 data reported Metastatic RCC (with IFNα) 18 4.8 NS 12.4 3.3 NS SUNITINIB Metastatic RCC 35 6.0 4.6 GIST 6.8 4.5 NS PNET 9.3 4.8? SORAFENIB Metastatic RCC 8 2.7 NS Unresectable HCC 1 NS 2.8 Unresectable HCC 2 1.4 2.3 PAZOPANIB Metastatic RCC 27 5.0 N/A Advanced soft tissue sarcoma 6.0 3.0 NS VANDETANIB Advanced medullary thyroid cancer 43 6.2 N/A AXITINIB Advanced RCC 10 2.0 N/A REGORAFENIB 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 Updated from Carmeliet & Jain, Nature (2011)

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) 10 0 NS Metastatic non-squamous NSCLC (with chemotherapy) NS 1.2 Metastatic head and neck cancer (with radiation) 4.7 19.7 NS 2.7 ELOTINIB TRASTUZUMAB LAPATINIB Metastatic non-squamous NSCLC (monotherapy) 8 0.4 2 Metastatic pancreatic adenocarcinoma (with chemotherapy) Metastatic HER2+ breast carcinoma (with chemotherapy) Advanced HER2+ gastric carcinoma (with chemotherapy) 1 0 0 17 3 5.1 12.9 1.2 2.7 Metastatic breast carcinoma (with chemotherapy) 9.8 8.5 NS GEFITINIB VEMURAFENIB CRIZOTINIB VISMODEGIB Metastatic non-squamous NSCLC (versus chemotherapy) Japanese population Metastatic non-squamous NSCLC (versus chemotherapy) Metastatic melanoma with the BRAF V600E mutation ALK-positive non-squamous NSCLC Metastatic basal cell carcinoma 43 5.4 6.9 (NS) 9.7 NS NS 43 3.7 8 No phase III data available No phase III data available

Multidisciplinary Translational Trials Agent / Cancer Type Rectal Cancer Ovarian Cancer Breast Cancer Liver cancer Sarcoma Brain tumors Lung Cancer Schwannoma Insulinoma Bevacizumab (Genentech) Phase I/II Completed Phase II Completed Phase II Completed (ER+ & TN) Phase II Planned (HER2+) Phase II Completed Phase II Ongoing Phase II Completed Phase I Completed Phase II Completed Cediranib (AstraZeneca) Phase II Completed (HCC) 3 x Phase II Completed Phase III Completed Sunitinib (Pfizer) Sorafenib (Bayer/Onyx) Phase II Completed (HCC) Phase II Ongoing (HCC) Phase II Completed Vandetanib (AstraZeneca) Phase II Completed Phase II Completed Vatalanib (Novartis) Ramucirumab (ImClone) Plerixafor (Genzyme) & Bevacizumab Phase II Completed (HCC) Phase I Completed Phase II Ongoing Cabozantinib Phase II Ongoing Phase II Planned (CCA) Phase II Ongoing Highlighted trials analyses ongoing

Candidate Biomarkers Exist Duda, Angiogenesis Foundation e-publication CME series 2011

Clinical studies at MGH and DFCI Agent / Cancer Type Rectal Cancer Sarcoma Brain tumors Pancreatic Cancer Prostate Cancer HCC Radiation with bevacizumab (Genentech) Phase II Completed Phase II Completed Phase II Ongoing Radiation with cediranib (AstraZeneca) 2 x Phase II Completed Radiation with vatalanib (Novartis) Phase I Completed Radiation therapy Phase II Completed* Study off trial Phase II planned & Phase II ongoing* *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

Overview 1. Treatment resistance: Role of inflammatory factors

Overview 1. Treatment resistance: Role of inflammatory factors 2. Treatment resistance: Role of paracrine signals

Overview 1. Treatment resistance: Role of inflammatory factors 2. Treatment resistance: Role of paracrine signals 3. Concluding thoughts

How Relevant is Vasculogenesis in Tumors? Nature Reviews Neuroscience 2007

BMDC Contribution to Tumor Vessels Ang1 CD31- Tie2+ CD31+ Tie2+ Jain & Duda, Cancer Cell 2003

Tie2-GFP and Actb-GFP BMT Models to Detect BMD-ECs Duda et al., Blood 2006

Is Vasculogenesis Mediating Treatment Resistance? Nature Reviews Neuroscience 2007

LI Does Not Significantly Affect the Vasculature but Increases Myeloid BMDC Infiltration

How do inflammatory 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 MCa8 mammary carcinoma in FVB mice Kozin et al., Cancer Res 2010

Only concomitant CXCR4 Blockade Delays Tumor Growth MCa8 mammary carcinoma in FVB mice Kozin et al., Cancer Res 2010

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.

Phase I/II Trial of Bevacizumab with Chemoradiation in Advanced Rectal Cancer Willett et al., Nat Med 2004 Willett et al., J Clin Oncol 2005 Duda et al., J Clin Oncol 2006 Willett, Duda et al., J Clin Oncol 2009 Willett, Duda et al., Nat Clin Pract Oncol 2007 Xu, Duda et al., Cancer Res 2009 Willett et al., Oncologist 2010 Duda et al., Oncologist 2010

Laser Capture Micro-dissection of Macrophages and Cancer Cells from Serial Biopsies Fold change (qpcr) Xu, Duda et al., Cancer Res 2009 * p<0.05 ** p<0.01

On-treatment Increase in SDF1α as a Potential Escape Pathway for Anti-VEGF Therapy 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 Advanced sarcoma Sorafenib RR Advanced GBM Cediranib Radiographic progression Zhu et al, Clin Oncol (2009) Raut, Boucher, Duda et al, PLoS One (2012) Batchelor et al, J Clin Oncol (2010)

di Tomaso et al., Cancer Res 2011; Lu-Emerson et al., Neuro-Oncol 2013

SDF1α (CXCL12) pathway BMS-936564 (MDX1338) Nox-A12 AMD3100 (pleraxifor) BKT140 CCX662 Duda D G et al. Clin Cancer Res 2011;17:2074-2080 2011 by American Association for Cancer Research

How about metastasis formation?

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) Willett, Duda et al., Oncologist 2010

Dawson et al., Nature 2009 Duda et al., Cancer Res 2010

Does SDF1α/CXCR4 pathway mediate the involvement of BMDCs in metastasis?

Inducible CXCR4 deficiency Dawson, Duda et al., Nature 2009 Hiratsuka, Duda et al., PNAS 2011

CXCR4 blockade significantly inhibits lung metastasis after primary tumor resection TRAMP-C1 prostate cancer 18 75 Number of metastases 12 6 0 Ctrl BMT * * CXCR4-KO CXCR4/TK-KO BMT BMT Volume of metastases 50 25 0 Ctrl BMT * * CXCR4-KO CXCR4/TK-KO BMT BMT Hiratsuka et al., PNAS 2011 *p < 0.05

CXCR4 blockade significantly inhibits lung metastasis after primary tumor resection TRAMP-C1 prostate cancer 18 75 Number of metastases 12 6 0 Ctrl BMT * * CXCR4-KO CXCR4/TK-KO BMT BMT Volume of metastases 50 25 0 Ctrl BMT * * CXCR4-KO CXCR4/TK-KO BMT BMT 20 20 Number of metastases 15 10 5 * Volume of metastases 15 10 5 * * 0 Ctrl BMT CXCR4-KO BMT CXCR4/TK-KO BMT 0 Ctrl BMT CXCR4-KO BMT CXCR4/TK-KO BMT E0771 breast cancer Hiratsuka et al., PNAS 2011 *p < 0.05

CXCR4 blockade significantly inhibits lung metastasis after primary tumor resection TRAMP-C1 prostate cancer AMD3100 (AMD) 18 75 Number of metastases 12 6 0 Ctrl BMT * * CXCR4-KO CXCR4/TK-KO BMT BMT Volume of metastases 50 25 0 Ctrl BMT * * CXCR4-KO CXCR4/TK-KO BMT BMT Number of metastases 20 15 10 5 0 Ctrl BMT CXCR4-KO BMT * CXCR4/TK-KO BMT Volume of metastases 20 15 10 5 0 Ctrl BMT * CXCR4-KO BMT * CXCR4/TK-KO BMT Number of metastases 12 9 6 3 0 PBS (WT) AMD (WT) PBS (TK) * AMD (TK) Volume of metastases 90 60 30 0 PBS (WT) AMD (WT) PBS (TK) * AMD (TK) E0771 breast cancer VEGFR1-TK-KO BMT (TK) Hiratsuka et al., PNAS 2011 *p < 0.05

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?

Phase I/ II Trial of Neoadjuvant Proton with Chemotherapy in Pancreatic Adenocarcinoma Proton Therapy (5 x 5 Gy QD) Capecitabine (825 mg/m 2 PO BID) Surgery Day 1 5 7 14 28-42 Tissue Blood Hong et al., unpublished data

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

KRAS G12D mutation and elevated HGF are associated with poor survival 1.8 No KRAS G12D mutation KRAS G12D mutation 1.8 HGF 1500 pg/ml HGF>1500 pg/ml Overall Survival.6.4.2 0 P=0.024 Overall Survival.6.4.2 0 P=0.019 0 6 12 18 24 30 36 Follow-up Time (Months) 0 6 12 18 24 Follow-up Time (Months) 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 Snuderl et al, Cell 2013 NEJM 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 confirmed 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 confirmed 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 Funding R21CA139168, R01CA159258, P01CA80124 & Federal Share Proton Beam NCI Grants American Cancer Society RSG-11-073-01-TBG American Association for Cancer Research Cancer Research Institute

MGH/DF Clinical Collaborators and Patients Agent / Cancer Type Rectal Cancer Brain tumors Breast Cancer HCC Sarcoma Ovarian Cancer Lung Cancer Schwannoma Bevacizumab (Genentech) Cediranib (AstraZeneca) Sunitinib (Pfizer) Willett Krop Zhu Yoon Horowitz Heist Plotkin Sorafenib (Bayer/Onyx) Batchelor Ramucirumab (ImClone) Eder Vatalanib (Novartis) Vandetanib (AstraZeneca) Gerstner Plerixafor (Genzyme) Meyerhardt Hong Proton Therapy Wen