A Novel Therapeutic Mechanism of Imipridones ONC201/ONC206 in MYCN-Amplified Neuroblastoma Cells via Differential Expression of Tumorigenic Proteins.

Neuroblastoma is the most common extracranial nervous system tumor in children. It presents with a spectrum of clinical prognostic measures ranging from benign growths that regress spontaneously to highly malignant, treatment evasive tumors affiliated with increased mortality rates. MYCN amplification is commonly seen in high-risk neuroblastoma, rendering it highly malignant and recurrence prone. In our current study, we investigated the therapeutic potential of small molecule inducers of TRAIL, ONC201, and ONC206 in MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cell lines. Our results exhibit potent antitumor activity of ONC201 and ONC206 via a novel inhibition of EGF-induced L1CAM and PDGFRß phosphorylation in both cell lines. Drug treatment significantly reduced cellular proliferation, viability, migration, invasion, tumorsphere formation potential, and increased apoptosis in both cell lines. The protein expression of tumorigenic NMYC, Sox-2, Oct-4, FABP5, and HMGA1 significantly decreased 48 h post-drug treatment, whereas cleaved PARP1/caspase-3 and γH2AX increased 72 h post-drug treatment, compared with vehicle-treated cells in the MYCN-amplified IMR-32 cell line. We are the first to report this novel differential protein expression after ONC201 or ONC206 treatment in human neuroblastoma cells, demonstrating an important multitarget effect which may yield added therapeutic benefits in treating this devastating childhood cancer.

Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment.

Malignant nervous system cancers in children are the most devastating and worrisome diseases, specifically due to their aggressive nature and, in some cases, inoperable location in critical regions of the brain and spinal cord, and the impermeable blood-brain barrier that hinders delivery of pharmaco-therapeutic compounds into the tumor site. Moreover, the delicate developmental processes of the nervous system throughout the childhood years adds another limitation to the therapeutic modalities and doses used to treat these malignant cancers. Therefore, pediatric oncologists are charged with the daunting responsibility of attempting to deliver effective cures to these children, yet with limited doses of the currently available therapeutic options in order to mitigate the imminent neurotoxicity of radio- and chemotherapy on the developing nervous system. Various studies reported that c-Met/HGF signaling is affiliated with increased malignancy and stem cell enrichment in various cancers such as high-grade gliomas, high-risk medulloblastomas, and MYCN-amplified, high-risk neuroblastomas. Therapeutic interventions that are utilized to target c-Met signaling in these malignant nervous system cancers have shown benefits in basic translational studies and preclinical trials, but failed to yield significant clinical benefits in patients. While numerous pre-clinical data reported promising results with the use of combinatorial therapy that targets c-Met with other tumorigenic pathways, therapeutic resistance remains a problem, and long-term cures are rare. The possible mechanisms, including the overexpression and activation of compensatory tumorigenic mechanisms within the tumors or ineffective drug delivery methods that may contribute to therapeutic resistance observed in clinical trials are elaborated in this review.