Novel RTK Targeting Strategies in Glioblastoma

Summary

Principal Investigator: Roger Abounader
Abstract: DESCRIPTION (provided by applicant): Receptor tyrosine kinase (RTK) pathways are deregulated in a majority of glioblastoma (GBM), the most common and most deadly primary malignant brain tumor. Consequently, a number of clinically applicable RTK inhibitors have been developed. However, these inhibitors failed to significantly improve the clinical outcomes of GBM patients. The main reasons for this failure are signal redundancy due to co-activation of several RTKs and compensatory mechanisms that lead to resistance to RTK inhibition. In this competitive renewal application, we build on our previous findings and propose to explore new mechanisms and strategies for improving the efficacy of MET and other RTK inhibitions in GBM therapy. More specifically, we propose to comprehensively uncover the factors that determine sensitivity and resistance to MET inhibition with clinically applicable drugs and use the acquired knowledge to test new and more efficient combination therapies. We also propose to explore two conceptually novel approaches for RTK targeting in GBM therapy that are based on two recent exciting discoveries from our lab. We propose four specific aims. In Aim 1, we will identify the not well known factors that determine sensitivity to MET inhibition. We will use RNA-seq, reverse phase antibody arrays, and PCR to comprehensively identify the genetic and molecular factors that determine responsiveness to clinically applicable small molecule kinase inhibitor (crizotinib) and MET neutralizing antibody (MetMAb) in GBM cells, stem cells, animal models and MetMAb clinical trial-derived human tumors. In Aim 2, we will comprehensively elucidate the mechanisms of resistance to MET inhibition by the above drugs and develop new combination therapies that overcome resistance. In Aim 3, we will study and develop ligand pre-treatment as a new strategy for improving the efficacy of MET, EGFR and PDGFR inhibitors. This is based on a recent intriguing discovery form our lab that shows that short-term pre-treatment of RTKs with their respective ligands enhances the anti-tumor effects of their inhibitors. In Aim 4, we will explore the role of microRNA-134 (miR- 134) in RTK signaling and experimental therapy. This is based on the recent discovery in our lab of miR-134 as a new tumor suppressive hub that mediates the effects of RTKs in GBM and that is required for the anti-tumor effects of their inhibitors. For Aims 3 and 4, we will develop and test new pre-clinical approaches for the systemic and local deliveries of RTK ligands and microRNAs to GBM xenografts using focused ultrasound and microbubbles/nanoparticles as well as convection enhanced delivery. Altogether, successful completion of the proposed studies would lead to a better understanding of the mechanisms of MET and RTK-induced malignancy and to the development of novel and more efficient RTK targeting strategies for GBM therapy.
Funding Period: 2002-12-01 - 2018-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Functional and molecular interactions between the HGF/c-Met pathway and c-Myc in large-cell medulloblastoma
    Yunqing Li
    Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
    Lab Invest 88:98-111. 2008
  2. pmc Cooperation between c-Met and focal adhesion kinase family members in medulloblastoma and implications for therapy
    Fadila Guessous
    Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA
    Mol Cancer Ther 11:288-97. 2012
  3. pmc The role of microRNAs in glioma initiation and progression
    Ying Zhang
    University of Virginia, Department of Microbiology, Charlottesville, VA 22908, USA
    Front Biosci (Landmark Ed) 17:700-12. 2012
  4. pmc Oncogenic effects of miR-10b in glioblastoma stem cells
    Fadila Guessous
    Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
    J Neurooncol 112:153-63. 2013
  5. pmc Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition
    Ying Zhang
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA
    Clin Cancer Res 19:1433-44. 2013
  6. pmc The p53-microRNA-34a axis regulates cellular entry receptors for tumor-associated human herpes viruses
    Alexander V Kofman
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
    Med Hypotheses 81:62-7. 2013
  7. pmc A novel PTEN/mutant p53/c-Myc/Bcl-XL axis mediates context-dependent oncogenic effects of PTEN with implications for cancer prognosis and therapy
    Xiaoping Huang
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA
    Neoplasia 15:952-65. 2013
  8. pmc microRNA-34a promotes DNA damage and mitotic catastrophe
    Alexander V Kofman
    Department of Microbiology, Immunology and Cancer Biology University of Virginia Charlottesville, VA USA Aging Cancer Interface Group LDS Medical Center St Petersburg, Russia
    Cell Cycle 12:3500-11. 2013
  9. pmc microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma
    JungEun Kim
    Authors Affiliations Departments of Microbiology, Immunology and Cancer Biology, Neurology, and Cancer Center, University of Virginia, Charlottesville, Virginia Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom and Department of Neurosurgery, Brigham and Women s Hospital, Boston, Massachusetts
    Cancer Res 74:1541-53. 2014
  10. pmc Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma
    Y Zhang
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA
    Cell Death Differ 21:720-34. 2014

Research Grants

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
  2. UAB / UMN SPORE in Pancreatic Cancer
    Donald J Buchsbaum; Fiscal Year: 2013
  3. CELLULAR AND MOLECULAR MECHANISMS OF GASTROINTESTINAL CANCERS
    Lopa Mishra; Fiscal Year: 2013
  4. In Vivo Cellular and Molecular Imaging Center@Stanford
    Sanjiv S Gambhir; Fiscal Year: 2013
  5. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
  6. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
  7. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
  8. Mayo Clinic Breast Cancer SPORE
    JAMES NEWELL INGLE; Fiscal Year: 2013
  9. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
  10. Overcoming resistance to BRAF(V600E) targeted therapies in melanoma
    David E Fisher; Fiscal Year: 2013

Detail Information

Publications22

  1. ncbi Functional and molecular interactions between the HGF/c-Met pathway and c-Myc in large-cell medulloblastoma
    Yunqing Li
    Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
    Lab Invest 88:98-111. 2008
    ..The findings provide a potential explanation for the high frequency of c-Myc overexpression in medulloblastoma and suggest a cooperative role for c-Met and c-Myc in large-cell anaplastic medulloblastoma formation...
  2. pmc Cooperation between c-Met and focal adhesion kinase family members in medulloblastoma and implications for therapy
    Fadila Guessous
    Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA
    Mol Cancer Ther 11:288-97. 2012
    ....
  3. pmc The role of microRNAs in glioma initiation and progression
    Ying Zhang
    University of Virginia, Department of Microbiology, Charlottesville, VA 22908, USA
    Front Biosci (Landmark Ed) 17:700-12. 2012
    ..The present review summarizes the published literature on the role of miRNAs in gliomas with a focus on their role in GSCs...
  4. pmc Oncogenic effects of miR-10b in glioblastoma stem cells
    Fadila Guessous
    Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
    J Neurooncol 112:153-63. 2013
    ..Targeting miR-10b might therefore inhibit glioblastoma stem cells, which are thought to be at the origin of glioblastoma and to contribute its recurrence and resistance to therapy...
  5. pmc Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition
    Ying Zhang
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA
    Clin Cancer Res 19:1433-44. 2013
    ..The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors...
  6. pmc The p53-microRNA-34a axis regulates cellular entry receptors for tumor-associated human herpes viruses
    Alexander V Kofman
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
    Med Hypotheses 81:62-7. 2013
    ..We hypothesize that p53-microRNA-34a axis may alter susceptibility of cells to infection with some viruses that are detected in tumors and either proven or suspected to be associated with tumor initiation and progression...
  7. pmc A novel PTEN/mutant p53/c-Myc/Bcl-XL axis mediates context-dependent oncogenic effects of PTEN with implications for cancer prognosis and therapy
    Xiaoping Huang
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA
    Neoplasia 15:952-65. 2013
    ..The data also indicate that the combined mutational status of PTEN and p53 influences cancer prognosis and anticancer therapies that target PTEN and p53...
  8. pmc microRNA-34a promotes DNA damage and mitotic catastrophe
    Alexander V Kofman
    Department of Microbiology, Immunology and Cancer Biology University of Virginia Charlottesville, VA USA Aging Cancer Interface Group LDS Medical Center St Petersburg, Russia
    Cell Cycle 12:3500-11. 2013
    ..These properties of miR-34a can potentially be exploited for DNA damage-effecting therapies of malignancies. ..
  9. pmc microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma
    JungEun Kim
    Authors Affiliations Departments of Microbiology, Immunology and Cancer Biology, Neurology, and Cancer Center, University of Virginia, Charlottesville, Virginia Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom and Department of Neurosurgery, Brigham and Women s Hospital, Boston, Massachusetts
    Cancer Res 74:1541-53. 2014
    ..Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy...
  10. pmc Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma
    Y Zhang
    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA
    Cell Death Differ 21:720-34. 2014
    ..We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B. ..
  11. pmc When tumor cells make blood vessels: implications for glioblastoma therapy
    Alexander V Kofman
    Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA
    Future Oncol 7:841-3. 2011
    ..Future strategies for GBM therapy will likely require the combined targeting of normal ECs and TDECs, as well as the development of strategies that prevent the conversion of tumor cells into vascular ECs...
  12. pmc The roles of viruses in brain tumor initiation and oncomodulation
    Alexander Kofman
    Department of Microbiology, University of Virginia, P O Box 800168, Charlottesville, VA 22908, USA
    J Neurooncol 105:451-66. 2011
    ....
  13. pmc PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations
    Yunqing Li
    Department of Neurology, University of Virginia, Charlottesville, Virginia 22908, USA
    Cancer Res 68:1723-31. 2008
    ..The findings also provide an explanation for the low frequency of simultaneous mutations of PTEN and p53 in human cancer...
  14. ncbi Signaling pathways in medulloblastoma
    Fadila Guessous
    Department of Neurology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Cell Physiol 217:577-83. 2008
    ..Here we review the involvement of these pathways in medulloblastoma malignancy with a focus on their mode of deregulation, prognostic value, functional effects, cellular and molecular mechanisms of action, and implications for therapy...
  15. ncbi Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy
    Yunqing Li
    Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
    Mol Cancer Ther 8:376-85. 2009
    ....
  16. pmc Interactions between PTEN and receptor tyrosine kinase pathways and their implications for glioma therapy
    Roger Abounader
    Departments of Neurology and Microbiology, University of Virginia Health System, Charlottesville, VA 22908, USA
    Expert Rev Anticancer Ther 9:235-45. 2009
    ..This article reviews the known molecular and functional interactions between PTEN and RTK pathways and their implications for glioma therapy...
  17. pmc MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes
    Yunqing Li
    Departments of Microbiology, Neurology and Pathology, University of Virginia, Charlottesville, VA 22908, USA
    Cancer Res 69:7569-76. 2009
    ..They show that miR-34a suppresses brain tumor growth by targeting c-Met and Notch. The results also suggest that miR-34a could serve as a potential therapeutic agent for brain tumors...
  18. pmc Molecular distinctions between stasis and telomere attrition senescence barriers shown by long-term culture of normal human mammary epithelial cells
    James C Garbe
    Life Sciences Divisions, Lawrence Berkeley National Laboratory, Berkeley, California, USA
    Cancer Res 69:7557-68. 2009
    ..Additionally, the ability to maintain long-term growth of genomically stable multilineage pre-stasis HMEC populations can greatly enhance experimentation with normal HMEC...
  19. pmc An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth
    Fadila Guessous
    Departments of Microbiology, University of Virginia, Charlottesville, USA
    Anticancer Agents Med Chem 10:28-35. 2010
    ..These findings suggest that targeting c-Met with small molecule kinase inhibitors is a promising approach for brain tumor therapy...
  20. pmc XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC
    Ying Zhang
    University of Virginia, Department of Microbiology, PO Box 800168, Charlottesville, Virginia, 22903, USA
    IDrugs 13:112-21. 2010
    ....
  21. pmc microRNA-34a is tumor suppressive in brain tumors and glioma stem cells
    Fadila Guessous
    Department of Microbiology, University of Virginia, Charlottesville, VA, USA
    Cell Cycle 9:1031-6. 2010
    ..Altogether, the data suggest that miR-34a is a tumor suppressor and a potential potent therapeutic agent that acts by targeting multiple oncogenic pathways in brain tumors and by inducing the differentiation of cancer stem cells...
  22. pmc MicroRNA-608 and microRNA-34a regulate chordoma malignancy by targeting EGFR, Bcl-xL and MET
    Ying Zhang
    Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America
    PLoS ONE 9:e91546. 2014
    ..These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. UAB / UMN SPORE in Pancreatic Cancer
    Donald J Buchsbaum; Fiscal Year: 2013
    ..The application has strong institutional support from UAB and UMN, excellent pancreatic cancer populations and concurrence with federal guidelines. ..
  3. CELLULAR AND MOLECULAR MECHANISMS OF GASTROINTESTINAL CANCERS
    Lopa Mishra; Fiscal Year: 2013
    ..Significantly, this program promises to yield new therapies targeted at these difficult-to-treat lethal cancers at the bench, and then to translate the results rapidly into clinical care, at the bedside. ..
  4. In Vivo Cellular and Molecular Imaging Center@Stanford
    Sanjiv S Gambhir; Fiscal Year: 2013
    ..The ICMIC@Stanford team is committed to cancer research and clinical translation of state-of-the-art molecular imaging strategies for improving clinical cancer management. ..
  5. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
    ..The program represents an integrated effort to improve screening with the overall aim of averting deaths from breast cancer while minimizing harms. ..
  6. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
    ..The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new drug targets and pre-clinical models that recapitulate key aspects of the human disease. ..
  7. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
    ..We believe that this SPORE group, as a multidisciplinary, highly interactive and accomplished team, will have a substantial impact on improving the clinical outcome of leukemia patients. ..
  8. Mayo Clinic Breast Cancer SPORE
    JAMES NEWELL INGLE; Fiscal Year: 2013
    ..abstract_text> ..
  9. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  10. Overcoming resistance to BRAF(V600E) targeted therapies in melanoma
    David E Fisher; Fiscal Year: 2013
    ..abstract_text> ..
  11. Nanoplatform Delivery of MDA-7 and Brachytherapy for Treatment of Brain Tumors
    Michael D Shultz; Fiscal Year: 2013
    ..The skills and knowledge obtained through the proposed mentoring will be invaluable to the success of the applicant and lead to unique and innovative projects in future endeavors. ..
  12. Molecular and Clinical Approaches to Colon Cancer Precursors
    SEAN VAHRAM TAVTIGIAN; Fiscal Year: 2013
    ..abstract_text> ..
  13. Combining Anti-Invasive and Anti-Angiogenic Therapies for the treatment of GBM
    PANAGIOTIS Z ANASTASIADIS; Fiscal Year: 2013
    ..Ultimately this strategy may provide additional survival benefit for patients with this deadly disease. ..
  14. Brain Tumor-Penetrating Nanoparticle Delivery with MR-Guided Focused Ultrasound
    Richard J Price; Fiscal Year: 2013
    ..Our next step would be to test the safety of the MR-guided BPN delivery approach in large animals (pig) using the University of Virginia's clinical Insightec Exablate system, followed by the initiation of a clinical trial. ..
  15. Model-based predictions of responses RTK Pathway therapies
    Joe W Gray; Fiscal Year: 2013
    ..abstract_text> ..
  16. Bevacizumab Delivery to Glioblastoma with MR-Guided Focused Ultrasound
    Richard J Price; Fiscal Year: 2013
    ..Clinical trials involving FUS application to the brain have been approved for othr indications at UVa, so there is a clear precedent for translation of his work at our institution. ..
  17. Targeting the Urokinase Receptor in Glioblastoma Multiforme
    Steven L Gonias; Fiscal Year: 2013
    ..Although this project has a basic science foundation, our objectives are highly translational. Ultimately, our goal is to complete the pre-clinical studies necessary to justify targeting uPAR for therapeutics development in GBM. ..
  18. DF/HCC Kidney Cancer SPORE
    David McDermott; Fiscal Year: 2013
    ..The overall goal of the DF/HCC Kidney Cancer SPORE is the translation of biological and technological advances into clinically meaningful advances for patients with kidney cancer. ..
  19. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013
    ....
  20. Wisconsin Center of Excellence in Genomics Science
    Michael Olivier; Fiscal Year: 2013
    ..Data, technology, and software will be widely disseminated by multiple mechanisms including licensing and commercialization activities. ..
  21. Genetic Mouse Models of Glioma
    Luis F Parada; Fiscal Year: 2013
    ..The hope is that by identifying these genes, we might begin to find suitable drug targets and develop therapies that would eliminate or inhibit the growth of these devastating tumors. ..