Evaluating imipridone family small molecule inhibitors ONC201 and ONC212 toxicity in vitro for future treatment of glioblastoma

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  • May 15, 2019
Creator
  • Patel, Shrey
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering, Environmental Health Sciences
Abstract
  • Glioblastoma (GBM) is the most common and lethal malignant brain tumor. Current treatment involves surgical resection, radiation, and chemotherapy. Temozolomide (TMZ) is the only FDA approved systemic chemotherapeutic available and many tumors are known to have both extrinsic and intrinsic resistance to the TMZ. Resistance to TMZ has generated a pressing need for novel therapies. ONC201, an Akt/ERK dual inhibitor has shown promising preliminary results in phase II clinical trials and its potent analog, ONC212 is believed to be more clinically efficacious. However, in vitro studies with ONC212 are necessary prior to clinical application. Normal human astrocytes (NHA) and normal human astrocytes with mutant Ras (NHA Ras), along with 6 established glioblastoma human cell lines (U251, U87, U373, LN18, LN229, and D54MG) were each evaluated for toxicity with 3 individual drugs (TMZ, ONC201, and ONC212) and IC50 values were calculated from toxicity curves. TMZ was found to be less effective in cell lines with high MGMT expression (LN18). ONC212 was found to be more potent than ONC201 and has the potential to be a possible treatment option for GBM. Short-term goals involve repeating the experiment with glioblastoma stem cells which better mimic tumor structure with the potential of beginning in vivo animal studies and evaluating efficacy and blood brain barrier penetrance of ONC212, followed by clinical trials. The ultimate goal remains to develop effective novel therapies for patients with GBM.
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DOI
Resource type
Advisor
  • Miller, C. Ryan
Degree
  • Bachelor of Science in Public Health
Academic concentration
  • Environmental Health Sciences
Honors level
  • Honors
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2019
Language
  • English

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