Animal Models, Breast Cancer, Clinical Trials, Neuro-Oncology, Phase I
Co-Leader, Experimental and Developmental Therapeutics Program
Funding Agency National Cancer Institute Title Novel ERbeta agonists for the treatment of gliomas Status Active Period 8/2014 - 7/2019 Role Principal Investigator Grant Detail Funding Agency Food and Drug Administration Title Efficacy of TH-302, with Molecular Imaging and Biomarker Correlates of Response in Bevacizumab Resistant Glioblastoma Status Active Period 8/2014 - 7/2018 Role Principal Investigator Grant Detail Glioblastoma (GBM) is the most common and most aggressive of the primary malignant brain tumors in adults. Annually there are approximately 13,000 cases of GBM diagnosed, with historical 1 year and 5 year survival rates of 34.6% and 4.75%. While concomitant chemoradiotherapy with temozolomide remains the standard of care for initial treatment, all patients eventually require salvage therapy, and angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) pathway are standard in this setting. The proposed study is a dual center, single-arm, non-blinded, prospective study of combination therapy bevacizumab and TH-302 in up to 33 GBM patients. Bevacizumab will be administered at 10mg/kg as established standard of care. The planned dose for TH-302 is 480mg/m2 every 2 weeks (6 week cycle) until disease progression. The primary endpoint is the proportion progression-free at 4 months, with secondary end points of median progression-free survival (PFS), median overall survival (OS), safety, and quality of life (QOL). The three specific aims are to: 1) establish the efficacy of TH-302 in GBM patients progressing on bevacizumab, 2) characterize hypoxic volume, cerebral blood flow, and oxygen extraction fraction (OEF) in patients undergoing treatment with TH-302, and 3) correlate changes in known molecular markers of bevacizumab de novo resistance, acquired resistance, and tumor hypoxia with tumor response, time to progression, and patient survival.
Funding Agency CPRIT Title NanoTx Therapeutics New Company Product Development Award Status Active Period 5/2015 - 1/2018 Role Principal Investigator Grant Detail Funds are made available to support the establishment of a new company with the goal of development and commercialization of liposomally encapsulated therapeutic radionuclides for the treatment of cancer, Funding Agency Cancer Prevention & Research Institute of Texas Title Overcoming CXCL12 Mediated Resistance in Glioblastoma Status Active Period 12/2013 - 12/2017 Role Principal Investigator Grant Detail The most significant recent advance for glioblastoma has been the application of antiangiogenic agents. Unfortunately, more than half of these tumors are de novo resistant and all eventually develop resistance when initially sensitive. Evidence points to the root cause of angiogenesis, hypoxia, as a driving force for resistance to anitangiogenics. The chemokine CXCL12 is strongly induced by HIF-1a under conditions of hypoxia, and in clinical trials of antiangiogenic agents, serum levels of CXCL12 significantly increase with disease progression and mark resistance to therapy. While CXCR4 was once thought to be CXCL12?s sole receptor, more recently CXCR7 was deorphanized and appears to mediate a number of CXCL12 dependent normal physiologic processes. Of relevance to anitangiogenic resistance, one process that CXCR7 is involved in is maintaining survival of neural progenitor cells under conditions of hypoxia induced by stroke. Further along these lines, data supports a possible role for CXCR7 in preventing apoptosis of glioma cells when exposed to alkylator chemotherapy. Thus, newer data seems to support that the rise in CXCL12 in patients serum at the time of progression on antiangiogenics is more than coincidental, and further that CXCR7 rather than CXCR4 may be in part mediating antiangiogenic resistance in these patients. In our own studies in orthotopic glioblastoma xenografts receiving a monoclonal antibody against vascular endothelial growth factor (VEGF), we found that animals had increased survival when treated concomitantly with CXCR7 inhibitor CCX771. No improvement in survival was seen with the use of CXCR4 inhibitor AMD3100, despite confirmation that adequate tissue penetration across the blood brain barrier was present as well as presence of CXCR4 expression within the tumor and tumor endothelium. These findings, as well as emerging roles for CXCR7 in survival of progenitor cells, has led us to hypothesize that CXCL12 receptors CXCR4 and CXCR7 have uniqu