My areas of expertise are 1) the biology of local-derived stroma (tumor-associated vessels, fibroblasts) and distant stroma (bone marrow-derived cells or BMDCs) in tumor progression; and 2) the development of predictive biomarkers for targeted therapies for cancer. I aim to translate this knowledge into improved therapies by conducting preclinical and clinical studies in collaboration with MGH clinicians.
I am currently leading the following projects:
1. Overcoming Evasion from Sorafenib Treatment in Hepatocellular Carcinoma (HCC)
Sorafenib is the first systemic therapy approved for HCC. However, HCC rapidly evade sorafenib treatment, despite its multi-targeted activities. We are studying the pathways of evasion from sorafenib in HCC (P01/PPG Project 3). We are examining the role of MEK/ERK activation as a cell autonomous mechanism of escape. We are also studying how sorafenib-induced changes in HCC stroma lead to stromal-derived growth factor 1 alpha (SDF1alpha/CXCL12)-mediated changes in vascular structure and function, inflammation/bone marrow-derived cell infiltration and fibrosis, and if these mediate HCC escape from treatment. To this end, we have developed orthotopic models of metastatic HCC in immunocompetent mice, and have developed and acquired spontaneous genetically engineered mouse models of HCC through our collaborations at MGH Cancer Center. In parallel, we are exploring the potential roles of stroma-derived factors in HCC patients treated with sorafenib and other antiangiogenic agents in collaboration with Dr. Zhu of the MGH Cancer Center.
2. Impact of Tumor Stroma Activation after Radiation Therapy on Local Tumor Control and Metastasis
We have found that SDF1alpha/CXCR4 and HGF/cMET pathways can be activated by ionizing radiation in tumor stroma. Thus, we are currently evaluating the role of SDF1alpha/CXCR4 or HGF/cMET inhibition as a sensitizer for radiation therapy in preclinical models. Specifically, we are examining 1) the role of SDF1alpha and its receptors CXCR4 and CXCR7 in progression to metastasis after local radiotherapy (supported by an R01 grant); 2) the role of CXCR4 and bone marrow-derived cells in bone metastatic escape from palliative radiotherapy (funded through an ACS grant); and 3) the role of cMET inhibition in combination with radiotherapy in metastatic pancreatic adenocarcinoma models (supported by a Cummings Foundation grant). To this end, we have developed orthotopic models of prostate cancer, including a calvarial tumor model, which allows intravital microscopy imaging as well as orthotopic models of pancreatic adenocarcinoma. In parallel, we are exploring the potential roles of SDF1alpha/CXCR4 and HGF/cMET in prostate carcinoma, pancreatic adenocarcinoma, and HCC patients treated with radiotherapy in collaboration with MGH Cancer Center clinicians Drs. Efstathiou, Zhu and Hong (funded through NCI/Proton Beam Federal Share Program grants).
3. Biomarkers of Treatment Response
This project is carried out in the context of a large effort of clinical correlative studies (in over 25 clinical trials of antiangiogenic agents and/or radiotherapy), which include imaging, tissue and blood biomarker studies. This involves large teams of clinicians at MGH and Dana Farber Cancer Institute, and is funded through multiple collaborative grants from the NCI, DoD and NFCR. We are primarily focusing on the potential predictive biomarker value of soluble vascular endothelial growth factor (VEGF) receptor 1 (sVEGFR1 or sFLT1) and pharmacodynamics biomarker value of PlGF and sVEGFR2, and on the potential role of SDF1alpha and HGF as biomarkers of escape from anti-VEGF therapies or from radiotherapy.
I am teaching experimental techniques through daily supervision of postdoctoral research fellows, and graduate and undergraduate students. In the past ten years, I have been teaching in the MIT-HMS/HST Program, MGH-Chinese Oncologist Visiting Program, and ASTRO, ESTRO, RTOG and IASGO translational meetings for residents and clinicians, and in the yearly Methods in Bioengineering course that I am directing since 2002.