# Novel therapeutics for targeting checkpoint dysfunction in cancer

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $382,469

## Abstract

Abstract
Normal cells employ several fundamental brake mechanisms to tightly coordinate the execution of different cell
cycle phases. Loss of these checkpoint controls is a hallmark of cancer. Our goal is to devise therapeutic
strategies targeting newly discovered checkpoint perturbation mechanisms in cancers harboring mutant p53.
Tumor suppressor p53 is a key regulator for G1 cell cycle checkpoint. Mutant p53 mediates gain of functions to
promote tumor progression and drug resistance. Nevertheless, how to target mutant p53 in cancer remains a
big challenge. Our preliminary study identifies several novel mechanisms by which mutant p53 interacts with a
checkpoint activator protein TopBP1 physically and functionally to perturb the checkpoint control, and induces
ACTL6A to promote cisplatin resistance. We propose that the mutant p53-TopBP1 axis is a valid therapeutic
target in cancer. We have developed two classes of novel TopBP1 inhibitors that can target the mutant p53-
TopBP1 axis. In this proposal, we will determine their therapeutic potential in targeting checkpoint dysfunction in
cancer. First, we will study how the mutant p53-TopBP1 axis perturbs replication control. Second, we will
determine the functional interaction between mutant p53 and ACTL6A in growth control and cisplatin resistance.
Third, we will investigate new combinations of targeted therapy against breast and ovarian cancers. The novel
TopBP1 inhibitors that we have developed will greatly enhance the feasibility and impact of this proposal. In
short, the proposed study will elucidate novel mechanisms of checkpoint perturbation and translate our
discoveries into new therapeutics for a broad range of cancers.

## Key facts

- **NIH application ID:** 10444747
- **Project number:** 2R01CA203824-06A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** FANG-TSYR LIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,469
- **Award type:** 2
- **Project period:** 2016-12-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444747

## Citation

> US National Institutes of Health, RePORTER application 10444747, Novel therapeutics for targeting checkpoint dysfunction in cancer (2R01CA203824-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444747. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*