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Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53

Satish K Ramraj1, Sugantha P Elayapillai1, Richard C Pelikan2

  • 1Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK.

International Journal of Cancer
|December 18, 2019
PubMed

Insights

This study explores a novel ovarian cancer maintenance therapy using SHetA2 and PRIMA-1MET drugs. The combination therapy showed significant efficacy in preventing tumor development with no observed toxicity, suggesting a promising new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Current ovarian cancer maintenance therapies have limitations in toxicity and overall survival impact.
  • Targeting missense mutant p53 is a potential strategy for improving ovarian cancer treatment.
  • Mortalin (HSPA9) is implicated in inhibiting p53 function in cancer cells.

Purpose of the Study:

  • To investigate the synergistic effect of SHetA2 (releasing mutant p53 from mortalin inhibition) and PRIMA-1MET (reactivating mutant p53) in ovarian cancer.
  • To evaluate this combination therapy as a maintenance strategy for ovarian cancer.
  • To determine if the therapeutic effect is dependent on mutant p53 status.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) data for TP53 and HSPA9/mortalin status in ovarian tumors.
  • In vitro testing of SHetA2 and PRIMA-1MET in ovarian cancer cell lines and normal cells using various assays (isobolograms, cytometry, Western blots, ELISAs).
  • In vivo study in mice with ovarian cancer cells, evaluating tumor establishment and survival rates after drug administration.

Main Results:

  • Fifty-eight percent of TP53 mutations in high-grade serous ovarian cancers were missense; mortalin levels increased with tumor progression.
  • SHetA2 induced p53 accumulation in cancer cells, while PRIMA-1MET reduced SHetA2 resistance, showing synergistic effects with elevated ROS/ATP.
  • Combination therapy resulted in a 67% tumor-free rate in mice, significantly higher than individual drugs or controls, with no observed toxicity.

Conclusions:

  • The combination of SHetA2 and PRIMA-1MET demonstrates synergistic efficacy in inhibiting ovarian cancer growth and tumor establishment in a mutant p53-dependent manner.
  • This dual-drug approach shows additive effects in preventing tumor development without toxicity, supporting its potential as a maintenance therapy.
  • Further development of SHetA2 and PRIMA-1MET, alone and in combination, is warranted for ovarian cancer maintenance therapy.
Keywords:
PRIMA-1SHetA2high-grade serous ovarian cancermortalinp53

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