Feinstein Institute for Medical Research, CCMC, Northwell Health Targeting biologically relevant pathways in malignant glioma.

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The most common childhood brain tumors are called gliomas. Despite advances in research, the prognosis for aggressive pediatric gliomas remains poor. Due to the effects of cancer or the treatment required, survivors of childhood brain tumors often have severe neurologic, neuro-cognitive, and psychosocial sequelae. Thus, the development of a novel strategy for therapy is the top priority. Developing new and improved treatments for malignant gliomas is highly dependent on a better understanding of its biology. 

 

Research in my laboratory aims to understand how genes in normal brain development are hijacked, causing brain cells to grow into a tumor, and why these tumors are so resistant to treatment. Our work employs both human tumor cells and mouse brain tumor models, with the ultimate goal of developing more effective therapy. 

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The vital discovery made from our current research on “Targeting DUB as novel therapy against malignant glioma” was invited for a presentation at the 51st Child Neurology Society Meeting in October 2022. The importance of our research has also been recognized by the Scholar Research Award, Hyundai Hope On Wheel grant, the Zankel Foundation, and the AWSM Award.

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Based on the knowledge of the molecular mechanisms uncovered through our ongoing research, this work will supply new and essential discoveries relevant to gliomas. These will help develop new treatments that ultimately improve the outcome of these fatal tumors. 

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Support from Project To Cure will help advance this translational research and develop a novel preclinical model to test and validate new targeted therapeutic strategies for pediatric malignant gliomas. 

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Research supported by the Project To Cure Foundation has thus far led to the publication of nine research papers, see below.

 

Publications supported by the Project To Cure Foundation:

 

1. Salhia B et al. The guanine nucleotide exchange factors Trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. 2008, American Journal of Pathology, 173:1828-38.

2. Zavarella S et al. Role of Rac1-regulated signaling in medulloblastoma invasion. 2009, Journal of Neurosurgery Pediatrics, 4: 97-104.

3. Vanan I et al. Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion. 2012. Cellular and Molecular Neurobiology, 32: 1199-208.

4. Kwiatkowska A et al. Role of the small GTPase RhoG in glioblastoma cell invasion. 2012. Molecular Cancer, 11:65 doi:10.1186/1476-4598-11-65.

5. Murray DW et al. Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation. 2014. British Journal of Cancer, 110:1307-15.

6. Miller IS et al. Semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia. 2014. PLOS ONE, 9(5):e95885.

7. Markowitz  D et al. Pharmacological inhibition of the protein kinase MRK/ZAK radiosensitizes medulloblastoma. 2016. Molecular Cancer Therapy, 15: 1799-808.  

8. De Witt M et al. Repurposing mebendazole as a replacement for vincristine for the treatment of brain tumors. 2017. Molecular Medicine, epub.

9. Markowitz D, Ha G, Ruggieri R and Symons M. 2017. Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism. Onco Targets Ther. 10: 5633-5642.