# Targeting MDM4 in Rare Refractory Ovarian Cancer Sub-Types

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $189,338

## Abstract

Activation of wild-type (wt) p53 tumor suppressor is sufficient to kill tumor cells, even if other gene
defects are present. Cisplatin is a p53-dependent drug that is heavily used in treating cancer. However, in
several cancers harboring predominantly wt-p53, its benefit, if any, is short-lived. For instance, response rate
to cisplatin in the Clear Cell ovarian cancer (OvCa) sub-type is a low 25%, resulting in an overall survival of
only 10%. Thus, cisplatin resistance is a significant impediment, and this has created an unmet need to identify
novel strategies that would lead to targeted therapeutic options for rational development against the refractory
OvCa disease. A major factor in resistance is the loss of p53 function, and not necessarily through mutation.
This proposal is focused on wt-p53 since there is now acute awareness from our work and those of others that
this genotype is ubiquitous in many advanced clinically resistant cancers, such as mesothelioma and osteo-
sarcoma. In this proposal, our focus is on refractory OvCa harboring wt-p53, which is the genotype present
predominantly (~90%) in the rare OvCa sub-types, constituting 30% of all ovarian cancers. Importantly, these
sub-types occur at an earlier age and, therefore, death is observed in younger women. But, current therapy of
these sub-types remains empirical, due largely to profound knowledge gaps that exist in this disease.
 We have established that tumor cells become resistant to cisplatin when this drug fails to activate wt-
p53 due to silencing of the specific kinase that is vital for p53 phosphorylation and, thereby, p53-dependent
transactivation function. Normally, wt-p53 is maintained in an inactive state by its endogenous natural
inhibitors. The activity of partially released p53 through pharmacological targeting of such inhibitors, however,
is insufficient to exceed the critical threshold for apoptotic function. Since p53 phosphorylation is vital for fully
functionalizing p53 for its apoptotic function, we propose a novel hypothesis that targeted reduction in MDM4
will fully release p53 and allow access of the critical p53-site to endogenous active kinase(s) and induce
phosphorylation. We will test this hypothesis through two specific aims: 1) Establish basal phosphorylation of
p53 by targeting MDM4 in refractory OvCa sub-type tumor models in vitro and in vivo; 2) Identify the active
kinase that phosphorylates p53 and assess its potential role for therapy. We will utilize pharmacologic tools to
define tumor sensitivity following MDM4 modulation, biochemical and molecular tools to identify and modulate
the kinase and delineate the basis for reversal of cisplatin resistance, and graphically model antitumor effects
of rational combinations to establish synergy. This high-risk project has the potential to establish a conceptual
foundation for therapeutic activation of wt-p53 in rare OvCa that will enable follow-up studies and likely change
the trajectory of treatment outco...

## Key facts

- **NIH application ID:** 10786248
- **Project number:** 1R21CA286992-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** ZAHID H SIDDIK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $189,338
- **Award type:** 1
- **Project period:** 2023-12-20 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786248

## Citation

> US National Institutes of Health, RePORTER application 10786248, Targeting MDM4 in Rare Refractory Ovarian Cancer Sub-Types (1R21CA286992-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10786248. Licensed CC0.

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