Dipg-60. Ppm1d Mutation Mediates Tumorigenesis and Is a Therapeutic Target in Diffuse Intrinsic Pontine Glioma (dipg)
Year: 2018
Type: conference-abstract
Abstract: While diffuse intrinsic pontine glioma (DIPG), the most common pediatric brainstem tumor, exhibits transient responsiveness to radiation (XRT), overall survival is <2% within two years of diagnosis. PPM1D is a serine/threonine protein phosphatase that is important in DNA damage response (DDR). But, publications have shown that PPM1D mutants promote growth of adult cancer cells. And, mutation of PPM1D exists in up to 25% of DIPGs. We hypothesized that PPM1D mutation promotes DIPG growth. And, PPM1D inhibition enhances the anti-tumor effects of XRT. Under cell culture conditions, stably-transduced PPM1D mutants promoted proliferation of murine and PPM1D wild-type human DIPG cells, DIPG VI. Mice orthotopically xenografted as neonates with de novo PPM1D-mutated human DIPG cells, DIPG7, or with DIPG VI cells stably-transduced with a PPM1D mutant, exhibited significantly reduced survival compared to mice xenografted with empty vector-transduced DIPG VI cells. Conversely, PPM1D knockdown significantly suppressed proliferation of PPM1D-mutated DIPG cells. Treatment with a small molecule PPM1D inhibitor suppressed growth of PPM1D-mutated, but not PPM1D wild-type DIPGs in neurosphere cultures, on immunocompetent organotypic brain slices (OBS), and in OBSs derived from symptomatic, orthotopically-xenografted mice. Oral or intraventricular treatment of mice bearing orthotopically xenografted DIPG7 cells with a PPM1D inhibitor resulted in a significant reduction in DIPG proliferation. PPM1D inhibition had similar effects to XRT alone on DIPG growth inhibition and augmented the anti-proliferative and pro-apoptotic effects in DIPG when combined with XRT in vitro. These results suggest that PPM1D is a druggable target alone and in combination with XRT in DIPG.
Source: Neuro-Oncology
Authors: Mwangala Akamandisa, Kai Nie, Jing Wen, Rita Nahta, Dolores Hambardzumyan, Robert Castellino
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2809681792