Abstract 172: Limiting medulloblastoma progression by hindering the Hedgehog signaling pathway with novel atypical protein kinase C inhibitors

Abstract

Abstract Medulloblastoma is the most common pediatric brain tumor, constituting 20% of all childhood brain cancers (Clin. Cancer Res. 2008, 14 (4), 971-976., Oncogenesis 2019, 8 (11), 1-11). It is a highly invasive tumor that originates in the cerebellum and has the ability to metastasize throughout the central nervous system early in its course. The median age of diagnosis is 5 years, with 80% of cases being diagnosed in the first 15 years (Asian J. Neurosurg. 2015, 10 (1), 1-4). Current treatment options include maximal safe resection, chemotherapy and craniospinal radiation (J. Neurosurg. Pediatr. 2019, 24(4), 353-363). Despite such aggressive therapeutic treatments, nearly 30% of afflicted patients succumb to this disease, and survivors cope with the long-term side effects of these treatments that have significant impacts on their quality of life (J. Neurosurg. Pediatr. 2019, 24(4), 353-363). This underscores the need for less invasive and more effective treatment methods to improve overall patient outcomes. We believe that oncogene expression resulting from the Hedgehog (Hh) signaling pathway is responsible for upregulating malignant cancer cell growth, cell survival, and migration. Preliminary dose curve studies, in which D341 and D283 medulloblastoma cell lines were treated with novel atypical protein kinase C (aPKC) inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD) and 3,4-diaminonapthalene-2,7-disulfonic acid (DNDA) (Int. J. Oncol. 2017, 51(5), 1370-1382), have been shown to significantly decrease cell proliferation with increasing inhibitor concentration. Cell line D341 showed 44.2% inhibition when treated with 10 µM of ACPD and 75.2% inhibition when treated with 1 µM of DNDA while cell line D283 showed a 63.2% inhibition at 5 µM of ACPD and 73.6% inhibition at 10 µM. Future studies will be conducted to determine the inhibition mechanism of the Hh pathway in medulloblastoma by probing for different cell cycle and oncoprotein markers using Western blotting, employing the WST-1 assay to evaluate cell viability and cytotoxicity, and implementing migration and invasion assays. Citation Format: Luke Lajmi, Sloan Breedy, Wishrawana S. Ratnayake, Mildred Acevedo-Duncan. Limiting medulloblastoma progression by hindering the Hedgehog signaling pathway with novel atypical protein kinase C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 172.