# Reactivating p53 Function with a Novel Structure-based Peptide as a Therapeutic Approach for Overcoming Platinum Resistance

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2021 · —

## Abstract

Treatments that restore p53 activity could provide a breakthrough in cancer therapy given that p53 is mutated in
many cancers. Successful targeting of p53 is an unmet clinical need evidenced by the lack of FDA-approved
drugs in this category. We have collaboratively developed and tested ReACp53, a peptide that re-enables p53
function by preventing its aggregation. Our previous work demonstrated the efficacy of ReACp53 monotherapy
in targeting high-grade serous ovarian cancers (HGSOCs), which are tumors characterized by loss of p53
function. HGSOCs are deadly gynecologic malignancies that claim the lives of 14,000 U.S. women annually
despite radical surgeries and administration of carboplatin standard chemotherapy. We hypothesize that
ReACp53 can sensitize platinum-resistant HGSOCs to carboplatin. This combination therapy may prevent and
target recurrence of this aggressive cancer.
Building on our previous work, we propose the following aims that will facilitate clinical translation of our
therapeutic: (1) Determine if platinum-resistant ovarian cancer cells can be sensitized to carboplatin when treated
with ReACp53. A novel in vitro 3D miniring organoid drug assay will be used to test the sensitivity of 72 primary
HGSOCs in this aim. Subaim 1.1 will focus on testing this therapy in targeting newly-diagnosed HGSOCs
enriched for platinum-resistant cells following exposure to neoadjuvant carboplatin. This response will be
compared to matched pre-therapy tumor specimens from the same patient. In Subaim 1.2 we will test the
efficacy of this combination in targeting recurrent platinum-resistant HGSOCs. p53 mutation status in all
specimens will be correlated with drug response. Results will demonstrate if this therapeutic approach can be
efficacious in targeting platinum-resistant HGSOCs. (2) Determine the effect of p53 mutations on modulating
ReACp53 and carboplatin response using in vitro and in vivo tumor models. Here, we will take a genetic approach
by engineering platinum-resistant p53-null ovarian tumor cells to express known and common p53 mutations
reported in HGSOCs. Response of these tumor cells to combination therapy will be tested in vitro in Subaim 2.1
and in vivo in Subaim 2.2. Results will demonstrate if the addition of ReACp53 to carboplatin can potentiate cell
death in platinum-resistant ovarian cancer cells expressing common p53 mutations found in up to 30% of all
HGSOCs. (3) Test the efficacy of ReACp53 and carboplatin combination therapy in targeting platinum-resistant
HGSOC PDXs. p53 mutations are highly implicated in mediating platinum resistance in many carcinomas. Here,
we will test if the addition of ReACp53 to carboplatin can restore platinum sensitivity of recurrent human HGSOCs
using PDX models. In Subaim 3.1 PDXs will be established from platinum resistant HGSOCs, 3 sensitive and 3
resistant to combination therapy based on in vitro drug testing. In Subaim 3.2, mice bearing PDXs will be treated
with vehicle, ReACp53, carbopla...

## Key facts

- **NIH application ID:** 10075116
- **Project number:** 5I01BX004651-02
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Sanaz Memarzadeh
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075116

## Citation

> US National Institutes of Health, RePORTER application 10075116, Reactivating p53 Function with a Novel Structure-based Peptide as a Therapeutic Approach for Overcoming Platinum Resistance (5I01BX004651-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10075116. Licensed CC0.

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