Glioblastoma multiforme (GBM) is among the most aggressive and frequent primary brain tumors in adults. Patients with GBM have an extremely poor prognosis. None of the current treatments for glioblastomas (including surgery, radiation therapy, and chemotherapy) are effective, and median survival is only 15 months. Researchers are seeking to understand glioblastoma biology more fully in order to identify novel molecular targets for blocking GBM tumor growth. One such target is the neurokinin 1 receptor (NK1R), a G protein-coupled receptor that mediates the effects of substance P. NK1R exits in two spliced forms: the full- length form, which has 407 amino acids, and the truncated form, which ends at amino acid 311. Delineation of signal transduction pathways utilized by NK1R in GBM cells indicates that this receptor activates at least seven targets (EGFR, IGF-1R, Src, Akt, NF-kB, IL-6, and VEGF) previously identified as playing key roles in GBM growth. Blockade of NK1R inhibits GBM growth in cell lines as well as in GBM stem cells. In 2009, our laboratory made a key discovery: a fraction of the NK1R in GBM is constitutively active. Our recent data indicate that this activity arises from the truncated form of NK1R. Intriguingly, a 2005 study showed that the expression of the truncated form of NK1R, but not of the full-length form, in normal breast cells results in a transformed phenotype. We have found that the truncated NK1R is present, with varying levels of expression, in every primary GBM tumor that we have tested. This observation raises the possibility that the levels of truncated NK1R in GBM may predict disease severity and hence survival. Therefore, aim 1 of the proposed studies will examine the expression of the truncated form of NK1R in GBM tumors from patients for whom we have survival data.
Aim 2 of the proposed study will determine whether the pharmacology of truncated NK1R differs from that of full-length NK1R. The proposed studies will bring us one step closer to testing NK1R-based therapies in GBM patients. The unique combination of the PI's expertise in NK1R biology and the resources available at Duke's Preston Robert Tisch Brain Tumor Center ensures successful completion of these studies.
Glioblastoma multiforme (GBM) is a deadly brain tumor and patients diagnosed with GBM die within 2 years. Current treatments for glioblastomas include surgery, radiation therapy, and chemotherapy, but these are ineffective and we need to develop new ways to block GBM growth. Our laboratory has shown that NK1R is a good target to inhibit the growth of GBM and the proposed studies will determine the pharmacology of the truncated form of NK1R and whether its expression in GBM tumor predicts patient survival.
|Brown, Kristine E; Chagoya, Gustavo; Kwatra, Shawn G et al. (2015) Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development. J Neurochem 133:730-8|