CCSG Pilot: Targeting L-Tryptophan-5-Hydroxylase 1 (TPH1) in Small Cell Lung Cancer

Grants and Contracts Details

Description

Abstract: Small cell lung cancer (SCLC) is the most aggressive form of lung cancer due to its exceptionally high proliferative rate and strong metastatic ability. Current standard of care first-line treatment for extensive-stage SCLC patients is combined use of platinum and topoisomerase inhibitors, but the majority of patients become refractory within nine months. Addition of immune checkpoint inhibitors to first-line treatment improves overall or progression-free survival for few months at the best. Overall, less than 15% of patients with extensive-stage SCLC may survive longer than two years after diagnosis, and novel treatment option is in dire need. The Appalachian region of Kentucky has significantly higher rate of SCLC incidence compared with everywhere else, therefore the Markey Cancer Center is geographically convenient to recruit SCLC patients to clinical trials. We have established a team of basic & clinical scientists to identify novel therapeutic targets for SCLC, and found that L-Tryptophan-5-Hydroxylase 1 (TPH1), together with a unique receptor subunit HTR3A, are aberrantly high expressed in SCLC specimens and tumor cell lines. In this project, we will demonstrate that: (1) HTR3A is the downstream mediator of the TPH1-serotonin signaling to stimulate proliferation of SCLC cells; (2) disruption of the TPH1-Serotonin-HTR3A axis in SCLC cells inhibits tumor xenograft growth and reduces tumor metastasis in mouse models; (3) Xermelo (an FDA-approved drug widely used in clinic) alone or in combination with first- line chemotherapy effectively kills SCLC cells in culture and inhibits tumor development in patient-derived xenograft (PDX) models. This project is a collaboration between MCO and TO programs, and is supported by BB (Dr. Chen), BPTP, FCIM, OG SRFs and the outside pharmaceutical company TerSera Therapeutics, LLC. Data from this study will be used to apply for external funding such as an NCI R01 grant, and to secure further collaboration with TerSera Therapeutics LLC on applying an investigator-initiated Phase II clinical trial entitled “Repurposing Xermelo for treatment of SCLC”. Lay Summary: Small cell lung cancer (SCLC) is the deadliest type of lung cancer and very commonly found in Appalachian Kentucky. The tumor grows very fast but patient usually has a normal life before they know they have the cancer. In most cases, the cancer is already growing outside of its primary site in the lung and present in other organs when patients are diagnosed with SCLC. This widely spread tumors cannot be surgically cleaned like other types of cancer. Doctors have only limited options of drugs to treat SCLC and usually not very effective, thus most patients died within two years of diagnosis. This project is trying to understand why SCLC tumor cells grow so fast in human body, and we found that a secreted factor called serotonin from tumor cells stimulates their proliferation. By studying how serotonin is produced and how they work on tumor cells using laboratory cells and mice, we hope to better understand the process of tumor growing and spreading in humans. We also found that a widely used non-cancer treatment drug, namely Xermelo, has the potential to block the production of serotonin in tumor cells. We will test whether Xermelo can treat SCLC in mice. If we have promising results, we will work with pharmaceutical company to test this drug on SCLC patients. 2
StatusFinished
Effective start/end date7/1/226/30/23

Funding

  • National Cancer Institute

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