Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the curative potential of chemo-radiation, one third of patients relapse and many develop devastating treatment-induced morbidities. Thus, new targets for treatment are urgently needed. We recently discovered that placental growth factor (PlGF) is highly expressed in the MB-cancer cels and MB-associated stromal cells. Furthermore, our preliminary data suggest that secretion of sonic hedgehog (Shh) by MB cells induces stromal PlGF expression in a paracrine manner. Finally, we found that PlGF blockade significantly inhibits MB growth and spread to the spinal cord in orthotopic human xenografts of MB. Building on these exciting preliminary findings, we now propose to unravel the mechanisms of response to anti-PlGF therapy in multiple subtypes of MBs using genetically engineered mouse models (GEMM), human MB cell lines and state-of-the-art imaging. Our long- term goal is to translate these findings to the clinic to treat MB.
In Aim 1, we will dissect the mechanism o regulation of PlGF expression in MB by the Shh pathway, a major driver of tumorigenesis in MB.
In Aim 2, by analyzing the PlGF signal transduction axis in MB cells, we will determine how PlGF governs MB cell survival and growth. Lastly, in Aim 3 we will determine whether anti-PlGF therapy leads to improved tumor control and mouse survival in GEMMs and orthotopic models of genetically defined MBs. To realize these aims, we have developed powerful, non-invasive, high-resolution imaging technologies that provide unprecedented molecular, cellular, structural and functional insight (Nature Medicine 2001, 2003, 2004, 2009) and reveal various steps of tumor progression (Nature Reviews Cancer 202;Nature Methods 209, 2010). We will use these techniques and the unique collective expertise of our multi-disciplinary team to uncover the role of PlGF pathway in MB using GEMMs, available through our collaborators. Similar to our findings on VEGF blockade in other solid tumors, our findings on PlGF-blockade will inform future clinical trials in MB (Nature Medicine 2004;New England Journal of Medicine 2009).

Public Health Relevance

The current treatment options for medulloblastoma-the most prevalent form of pediatric brain cancer-cause devastating morbidities and result in tumor relapse in a significant fraction of patients. By revealing its mechanism of action, the proposed study aims to demonstrate PlGF as a novel therapeutic target for medulloblastoma. Our findings will directly inform the design and help interpret the results of potential clinical trials of antiPlGF therapy in medulloblastoma patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA163815-03
Application #
8677810
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Welch, Anthony R
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Lu-Emerson, Christine; Duda, Dan G; Emblem, Kyrre E et al. (2015) Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol 33:1197-213
Batista, Ana; Riedemann, Lars; Vardam, Trupti et al. (2015) Targeting the Tumor Microenvironment to Enhance Pediatric Brain Cancer Treatment. Cancer J 21:307-13
Naxerova, Kamila; Jain, Rakesh K (2015) Using tumour phylogenetics to identify the roots of metastasis in humans. Nat Rev Clin Oncol 12:258-72
Chen, Ou; Riedemann, Lars; Etoc, Fred et al. (2014) Magneto-fluorescent core-shell supernanoparticles. Nat Commun 5:5093
Jain, Rakesh K (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:605-22
Seano, Giorgio; Chiaverina, Giulia; Gagliardi, Paolo Armando et al. (2014) Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis. Nat Cell Biol 16:931-41, 1-8
Huang, Yuhui; Goel, Shom; Duda, Dan G et al. (2013) Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73:2943-8
Snuderl, Matija; Batista, Ana; Kirkpatrick, Nathaniel D et al. (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065-76
Batchelor, Tracy T; Gerstner, Elizabeth R; Emblem, Kyrre E et al. (2013) Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A 110:19059-64
Chauhan, Vikash P; Jain, Rakesh K (2013) Strategies for advancing cancer nanomedicine. Nat Mater 12:958-62

Showing the most recent 10 out of 13 publications