# Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $474,168

## Abstract

CRC is the third leading cause of tumor-related deaths attributed to vital organ metastasis. CRC
patient survival is highly dependent on the cancer staging at the time of diagnosis and, despite
the recent progresses made in the clinical management of this disease, it remains a meagre 13%
for the patients diagnosed with cancer metastasis. Remarkably, resistance to the anti-cancer
therapy contributes heavily to the metastasis as ~90% of patients with metastatic cancer are also
resistant to the therapies. Thus, developing novel and targeted therapies for inhibiting CRC
progression and metastasis is essential and urgent.
In this regard, extensive preclinical and clinical studies from our laboratory, and of other
laboratories, have now validated a causal role for the upregulated claudin-1 expression in
promoting CRC metastasis. In a comprehensive analysis examining a large CRC-patient cohort,
cell lines and mouse models, we have reported a highly significant association of the deregulated
claudin-1 expression with CRC metastasis. Mechanistic investigations into these findings
revealed physical binding of claudin-1 with proto-oncogene Src, in promoting CRC metastasis. So
far, no known small molecule inhibitor for claudin-1 exists. Using a rigorous analytical design that
included in vitro and in vivo testing, we identified a claudin-1 specific inhibitor. Further analogs were
synthesized, we now have narrowed down our search to a novel and specific small molecule
inhibitor, PDS-0330, for efficient inhibition of the CLDN1 dependent CRC progression. These data
have led to the central hypothesis of this proposal that PDS-0330 can inhibit CLDN1/Src
association to inhibit CRC progression and metastasis. In this grant proposal, we will optimize the
potency, pharmacokinetic properties of PDS-0330 analogs to develop novel tool compounds. We
will also determine binding specificity and characterize the binding epitope of PDS-0330 to inhibit
colon cancer progression. Finally, we will determine the efficacy of PDS0330 in inhibiting Claudin-
1-dependent phenotypes in mouse and organoid model of aggressive CRC.

## Key facts

- **NIH application ID:** 11291157
- **Project number:** 7R01CA250383-05
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Punita Dhawan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,168
- **Award type:** 7
- **Project period:** 2021-02-12 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11291157

## Citation

> US National Institutes of Health, RePORTER application 11291157, Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer (7R01CA250383-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11291157. Licensed CC0.

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