The overarching hypothesis of our translational program is that judicious manipulation of the tumor microenvironment can improve treatment outcome. This application builds upon discoveries made by the Program investigators during the current funding period (2006-2011), that the local and distal stroma collaborate with cancer cells to thwart the effectiveness of anti-VEGF treatments (current Projects 1 and 2) and/or to reduce the delivery and effectiveness of conventional therapeutics (current Project 3). The new Projects 1, 2 and 3 leverage our observation that both common (SDF1a/CXCR4) and specific (ANG2, IL-6, MEK) pathways are activated during anti-VEGF treatments of human glioblastoma, colorectal and hepatocellular carcinomas and this activation correlates with tumor progression during anti-VEGF treatment. Remarkably, the source of these molecules and their target cells are different in each disease, underscoring the need for careful, systematic and separate, yet complementary, molecular and cellular dissection of these pathways for improving outcome in each tumor type. Project 4 leverages the finding that paracrine interactions between tumor-associated fibroblasts and cancer cells contribute to desmoplasia and reduce the blood supply in pancreatic tumors via angiotensin 11 and its downstream effectors, including SDF1a/CXCR4. To this end, all four Projects will test the causal role of the proposed pathways by genetic and pharmacologic inhibition. The pathophysiological consequences on the tumors will be examined using cutting-edge imaging technologies, also developed during the current grant period. Each Project will be supported by (i) a common Bioengineering &Biostatistics Core (Core A), which will continue to provide statistical support and state-of the- art imaging enabling molecular, cellular, anatomical and functional dissection of tumors in their natural microenvironment;(ii) a shared Molecular, Cellular and Morphological Core (Core B) to complement the imaging approaches;(iii) a common Surgery and Animal Core (Core C) known for developing innovative pre clinical models that faithfully capture the clinical situation;and (iv) an Administrative Core (Core D) to provide administrative support and facilitate exchange and dissemination of scientific information.

Public Health Relevance

The proposed translational studies are extremely important and timely as they will advance our basic understanding of the tumor microenvironment as well as inform trial design and help interpret the data from our planned clinical trials with (i) plerixfor - an FDA-approved anti-CXCR4 agent - for glioblastoma, colorectal and liver cancer, (ii) with anti-ANG2 antibody for glioblastoma, and (iii) with FDA-approved angiotensin II receptor blockers for pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA080124-12
Application #
8463128
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (J1))
Program Officer
Mohla, Suresh
Project Start
2001-08-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
12
Fiscal Year
2013
Total Cost
$2,155,490
Indirect Cost
$899,983
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Padera, Timothy P; Meijer, Eelco F J; Munn, Lance L (2016) The Lymphatic System in Disease Processes and Cancer Progression. Annu Rev Biomed Eng 18:125-58
Datta, Meenal; Via, Laura E; Chen, Wei et al. (2016) Mathematical Model of Oxygen Transport in Tuberculosis Granulomas. Ann Biomed Eng 44:863-72
Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh et al. (2016) Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci U S A 113:4476-81
Chng, Kern Rei; Chan, Sock Hoai; Ng, Amanda Hui Qi et al. (2016) Tissue Microbiome Profiling Identifies an Enrichment of Specific Enteric Bacteria in Opisthorchis viverrini Associated Cholangiocarcinoma. EBioMedicine 8:195-202
Incio, Joao; Liu, Hao; Suboj, Priya et al. (2016) Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy. Cancer Discov 6:852-69
Kunert, Christian; Baish, James W; Liao, Shan et al. (2016) Reply to Davis: Nitric oxide regulates lymphatic contractions. Proc Natl Acad Sci U S A 113:E106
Park, Kyung Ran; Monsky, Wayne L; Lee, Chang Geol et al. (2016) Mast Cells Contribute to Radiation-Induced Vascular Hyperpermeability. Radiat Res 185:182-9
Singhal, Prabhat K; Sassi, Slim; Lan, Lan et al. (2016) Mouse embryonic fibroblasts exhibit extensive developmental and phenotypic diversity. Proc Natl Acad Sci U S A 113:122-7
Askoxylakis, Vasileios; Ferraro, Gino B; Kodack, David P et al. (2016) Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment. J Natl Cancer Inst 108:
Pinter, Matthias; Trauner, Michael; Peck-Radosavljevic, Markus et al. (2016) Cancer and liver cirrhosis: implications on prognosis and management. ESMO Open 1:e000042

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