Research Update

Pediatric Brain Tumor Research in the Symons Laboratory

The Feinstein Institute for Medical Research, Manhasset, NY

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The Project To Cure Foundation has supported pediatric brain tumor research at the Feinstein Institute for over a decade. Work performed in the Symons laboratory over the past several years already has led to a new therapeutic approach for patients with astrocytoma that is currently tested in a clinical trial carried out by Dr. Mark Atlas, Head of the Neuro-Oncology division at Cohen Children’s Medical Center. This trial investigates the effect of mebendazole, a drug that was previously used to treat worm infections.

 

Over the past year we have identified two drugs that should allow us to limit the severe side effects of radiation therapy in kids with brain tumors. One of these is simvastatin, a drug that is used by millions of people to lower cholesterol levels and prevent cardiovascular disease. The other one is an inhibitor of a MIF, a protein that is involved in inflammation. Both drugs revert some of the corrupting effects that tumor cells have on the immune system. Indeed, in the presence of a tumor, some components of the immune system, instead of attacking tumor cells, provide them with factors that promote tumor resistance to radiation and chemotherapy. Although the MIF inhibitor is still in experimental development, simvastatin is already clinically approved and we therefore should be able to start new clinical trials as soon as we finish our preclinical studies. 

 

Recently, we developed another approach to sensitize pediatric brain tumors to current therapeutic approaches. This new treatment is based on the observation that some small pieces of RNA (called microRNA) are down-regulated in brain tumors and other cancers. We found that when we reintroduced a specific microRNA, called miR-34a, in a wide range of glioblastoma tumor cells, these cells became much more sensitive to both radiation and chemotherapy. In collaboration with the biotech company EngeneIC, we also succeeded in delivering this microRNA to glioblastoma tumors using nanocells that are derived from bacteria. Remarkably, whereas all the tumors that were treated with chemotherapy alone grew back within a short time after treatment, most of the tumors treated with chemotherapy in combination with the microRNA nanocells completely disappeared. The nanocell delivery vehicle is currently in early stage clinical trials. We therefore hope to be able to test our new treatment in the clinic in the near future.   

 

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.

Published Articles

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