R01CA250383

Impact of CLDN1 Inhibition on Chemoresistance and Metastasis of Colon Cancer

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 models of aggressive CRC.

University Of Kansas Medical Center Research Institute

NOT APPLICABLE

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Kansas City, Kansas 66160 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the End Date has been extended from 01/31/26 to 03/31/27 and the total obligations have increased 433% from $571,142 to $3,045,997.