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FINDING CURES TOGETHER<sup>SM</sup>

AACR-National Brain Tumor Society Career Development Award for Translational Brain Tumor Research

The AACR-National Brain Tumor Society Career Development Award for Translational Brain Tumor Research represents a joint effort to encourage and support junior faculty who are in the first five years of a faculty appointment (at the start of the grant term) to conduct brain tumor research and establish successful career paths in this field. The research proposed for funding must be translational in nature and have direct applicability and relevance to brain tumors. The grant provides $150,000 over two years ($75,000 per year) for direct research expenses.

2013 Grantee

Markus D. Siegelin, MD 
Markus D. Siegelin, MD
Assistant Professor, Columbia University Medical Center, New York, NY

CP-d/n-ATF5 as a Novel Potent Treatment for Malignant Glioma

"Glioblastoma multiforme (GBM) represents the most common primary brain tumor, which is known to be notoriously resistant to therapies. Current treatment regimens for this disease consist of surgery, radiation and chemotherapy (Temozolomide). Irrespective of the treatment almost all patients succumb to the disease within two years after diagnosis. Although significant advances have been achieved in the molecular biology of these tumors, especially in tumor genetics, no definite therapeutic breakthrough has been made so far. The AACR and the National Brain Tumor Society award will support me to establish a novel highly tumor-specific therapy for GBM by targeting the transcription factor ATF5 which is overexpressed in GBM compared to normal non-neoplastic astrocytes and neurons. Specific suppression of ATF5 leads to cell death in GBM cells, while sparing non-neoplastic cells. This concept was further extended by the introduction of a cell penetrating form of d-n/ATF5. To establish this compound as a tumor therapeutic, I intend to delineate the mechanism by which this reagent kills tumor cells and why normal non-neoplastic cells are not affected by this compound. In addition, my preliminary data suggest that inhibition of ATF5 sensitizes glioblastoma cells to other tumor specific drug compounds. In connection with combination therapies, these offer the advantage that when two drugs are combined at suboptimal dosages they may exert a stronger (synergistic) effect as compared to one drug alone and may have less unwanted side effects. In addition, if a tumor is resistant to a single drug compound the combinatorial drug regimen may overcome this therapeutic resistance towards the single drug. Therefore, I will test this novel d/n-ATF5 peptide in combination with other tumor specific drug compounds in several preclinical models of glioblastoma. It is my sincere hope that this research will significantly contribute to the field of cancer research with the ultimate goal to identify and translate promising therapeutic drug regimens into the clinic to help patients, their families and the society to combat this detrimental disease. I would like to express my sincere gratitude to the AACR and the National Brain Tumor Society for supporting my research and I would like to thank my mentor Dr. Lloyd A. Greene and my collaborator Dr. James Angelastro for their enthusiastic support."

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