Project Details
Description
Project Summary/Abstract
Malignant Glioma is the most commonly diagnosed adult central nervous system malignancy, and carries a poor
prognosis. The conventional treatment for malignant glioma is surgical resection followed by radiation therapy
(RT) and the chemotherapeutic drug, temozolomide (TMZ). Despite attempts to improve the probability of
survival in patients with this combination of therapies, there has been only modest success. Thus, there is urgent
need to develop a better therapy to improve patient outcomes. TMZ and RT cause cancer cell death by inducing
DNA damage; however, if DNA repair pathways are intact and effective, there is a high probability that a cell
may develop resistance to these treatments. Thus, understanding the underlying cause of treatment resistance
could lead to the development of more effective therapies and, ultimately, improve patients' prognosis. Therefore,
identifying novel genes that can be targeted to alleviate treatment resistance in malignant glioma will contribute
significantly to ongoing research efforts. We identified a novel role for sterile alpha motif and HD domain
containing-protein 1 (SAMHD1) in promoting DNA end resection to facilitate DNA double-strand break (DSB)
repair by homologous recombination (HR). SAMHD1 is a deoxynucleoside triphosphate (dNTP)
triphosphohydrolase with a well-defined role in restricting HIV-1 infection in nondividing cells by depleting dNTPs
required for reverse transcription. Our preliminary data indicate that SAMHD1 depletion in cancer cells causes
hypersensitivity to DNA DSB-inducing agents. We have also shown that SAMHD1 is recruited to DNA DSBs in
response to DNA damage. SAMHD1 interacts with CtIP following DNA damage and recruits CtIP to DNA DSBs
to facilitate DNA end resection and HR independent of its dNTPase activity. SAMHD1 is targeted for proteasomal
degradation by the viral accessory protein, Vpx. We have data showing that various cancer cell lines treated with
Vpx have diminished levels of SAMHD1 compared to endogenous levels, and subsequently, have increased
sensitivity to DNA damage inducing therapeutic agents. Strikingly, malignant glioma patients with low SAMHD1
levels show a significantly higher probability of overall survival. Furthermore, oligodendroglioma, astrocytoma
and glioblastoma tumor samples show significantly higher expression of SAMHD1 as compared to normal brain
tissue. Interestingly, GBM, the most aggressive form of glioma, expresses the highest level of SAMHD1. Taken
together, our preliminary findings suggest that SAMHD1 could be a potential therapeutic target for malignant
glioma treatment. As such, the overall objective of my proposal is to determine the mechanisms by which
SAMHD1 directs DNA DSB repair to mediate treatment resistance in malignant glioma and to see how we can
utilize this knowledge to improve glioma treatment.
Status | Not started |
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