# Targeting Perp in PDAC tumor and cancer cachexia

> **NIH NIH K99** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $131,072

## Abstract

PROJECT SUMMARY/ABSTRACT
Pancreatic cancer is one of the deadliest cancers in the US, at a 5-year survival rate of ~11%. One of the
hallmarks of this cancer are the driver mutations, which include KRAS and p53 mutations. Mutations of p53, a
tumor suppressor, causes the tumor to become more invasive and chemoresistant. Moreover, a major
contributor of morbidity of pancreatic cancer patients, is cachexia, which is defined as an involuntary loss in
muscle and fat deposits. Cachexia is a devastating syndrome which affects about 80% of pancreatic cancer
patients and increases mortality and decreases quality of life. Most cachectic patients don’t qualify for
chemotherapy and if they do, they are refractory to them. Currently, cachexia is treated in the clinic with nutritional
supplements and appetite stimulants. However, there are no FDA-approved therapies for cachexia yet. Our
preliminary data implicated Perp, to be a potential target in the tumor and muscles in PDAC. We utilized age-
appropriate murine models of cancer and cachexia and observed Perp, a known p53 target gene, to be increased
in PDAC tumors. Further, we observed that inhibition of Perp decreased tumor proliferation/burden. Expression
of Perp demonstrated to be negatively correlated to patient survival. Moreover, patients with mutant p53, also
had an increased expression of Perp as compared to patients with wildtype p53.Inhibition of Perp in p53 mutant
tumors increased downstream p53 signaling targets, implying possible activation of p53-associated pathways.
Furthermore, we also observed increased expression of Perp in cachectic muscles, which decreased upon
preventing muscle loss. Subsequently, we also demonstrated increased expression of Perp to be an early event
in cancer conditioned-media mediated myotube atrophy. In this study, we will investigate the differential role of
Perp in tumor progression and chemoresistance in mutant p53 compared to wildtype p53 tumors. Next, we will
utilize genetic tools and murine models to target Perp in the muscles in vivo. The overarching goals of the first
two aims are to establish Perp as an efficient target in the tumor and muscle. In silico modeling of Perp provided
a list of compounds with binding affinities to two predicted binding sites of Perp. We shortlisted compounds which
were successful in decreasing tumor burden and rescuing muscle atrophy in vitro. In the third aim, we will further
characterize/modify these molecules for specificity, toxicity and stability and test them in preclinical models of
PDAC and cachexia. Development of novel therapies which have the potential to decrease tumor burden and
rescue muscle wasting will be beneficial in improving patient survival, chemotherapy tolerance and quality of life.

## Key facts

- **NIH application ID:** 10887270
- **Project number:** 1K99CA283277-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Aneesha Dasgupta
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $131,072
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887270

## Citation

> US National Institutes of Health, RePORTER application 10887270, Targeting Perp in PDAC tumor and cancer cachexia (1K99CA283277-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10887270. Licensed CC0.

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