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p53 Restoration in Ovarian Carcinoma Harnessing a Genetic Aberration

  • Author(s): Minion, Lindsey
  • Advisor(s): Greenfield, Sheldon
  • et al.
No data is associated with this publication.

Ovarian cancer is the most fatal gynecologic malignancy. The majority of deaths are in advance staged patients with high-grade serous histology. Most patients respond to primary surgery and chemotherapy yet experience recurrent disease. Chemotherapy remains central to recurrent treatment and is rarely curative. There is an unmet clinical need for additional treatment options. Advancements in tumor biology, particularly the genetic landscape of ovarian cancer, shape current researched therapeutic targets. The genotypic characterization of this malignancy is generalized by chromosomal disarray and p53 mutations. Mutations of p53 are ubiquitous across cancer. These mutations are a rational target for therapeutic exploration due to the frequency in ovarian carcinoma and its dominant role in tumor suppression. Small molecule compounds, including 38RNW, have been developed that bind to mutated p53 and partially restore wild-type tumor suppressor function. This translational approach leads to the hypothesis that 38RNW would synergistically combine with other drugs to induce apoptosis in an in-vitro model. Herein, a high throughput robotic nano-technology platform was implored to identify synergistic combinations with 38RNW in TOV-112D ovarian cancer cells. A Luciferase-base cell proliferation assay was implored to determine inhibitor effects in a high-throughput approach. Z-scores were calculated comparing plate averages of luciferase values to individual compounds or change in half-inhibitor concentration. 38RNW demonstrated strong synergistic activity with mammalian target of rapamycin/phosphatidylinositol 3-kinase (mTOR/PI3K) and polo-like kinase 1(Plk-1) inhibitors. The lead candidates warrant further investigation. Our long-term objective is to develop p53 restoration drug combinations for ovarian cancer treatment.

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This item is under embargo until September 12, 2024.