TS Overexpression in SCLC: Mechanism and Therapeutic Targeting
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|ClinicalTrials.gov Identifier: NCT03741829|
Recruitment Status : Active, not recruiting
First Posted : November 15, 2018
Last Update Posted : March 6, 2019
|Condition or disease|
|Small Cell Lung Cancer|
Small cell lung cancer (SCLC) is a highly lethal malignancy that is not treatable with targeted therapies and that does not respond long-term to treatment with cytotoxic chemotherapy1. One distinguishing molecular characteristic of SCLC is very high expression levels of thymidylate synthase (TS). TS plays an important role in de novo nucleotide biosynthesis and the very high TS levels expressed in SCLC cells indicate that these cells require the de novo nucleotide biosynthetic pathway to proliferate. Thus, complete TS inhibition could result in highly favorable outcomes in SCLC patients. TS inhibitors have been evaluated in SCLC clinical trials and have anti-tumoral activity when combined with a second chemotherapeutic agent. However, treatment with TS inhibitors has not been shown to surpass other combination chemotherapy regimens. An important point regarding these clinical studies is that TS activity levels were not monitored as an endpoint of drug response, thus it is not known whether TS activity was efficiently inhibited.Investigators predict that complete TS inhibition will result in favorable outcomes.
With support from Wake Innovations, Investigators are developing a novel fluoropyrimidine polymer, CF10, which strongly inhibits TS. CF10 is a second generation fluoropyrimidine polymer. The first generation polymer, F10, showed excellent anti-cancer activity in animal models of acute myeloid leukemia, glioblastoma, and prostate cancer. CF10 is designed to have improved tumor penetration and better in vivo stability than F10. Investigators hypothesize that CF10 will be highly effective for treating SCLC both as a single agent and in combination with TS inhibitors that target alternative sites of the TS enzyme.
After establishing CF10 has activity as a single agent and in combination with folate-based TS inhibitors (e.g. pemetrexed) in SCLC cell lines and xenograft models, Investigators will test CF10 in patient-derived xenograft (PDX) models and in organoids derived from SCLC patient samples. Investigators will develop PDX models of SCLC and SCLC organoids using transbronchial fine needle aspiration (FNA) from SCLC patients at Baptist/WFBCCC collected by co-I's Bellinger, Dotson, and Thomas. Non-malignant cells will be collected using a brush biopsy to enable comparison of malignant and non-malignant tissue from the same patient with regard to mechanistic endpoints.
|Study Type :||Observational|
|Actual Enrollment :||12 participants|
|Official Title:||TS Overexpression in SCLC: Mechanism and Therapeutic Targeting|
|Actual Study Start Date :||June 14, 2017|
|Actual Primary Completion Date :||January 7, 2019|
|Estimated Study Completion Date :||February 2020|
Samples from transbronchial Biopsy
Samples from participants with SCLC.
- TYMS (Thymidylate Synthetase) expression levels [ Time Frame: After biopsy collection, up to 1 year ]TYMS (Thymidylate Synthetase) expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.
- miRNA expression levels [ Time Frame: After biopsy collection, up to 1 year ]miRNA expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.
- Survival of mice at 60 days implanted with tumor and treated with CF10 [ Time Frame: 60 days ]
- Number of samples with PDX model development [ Time Frame: After biopsy collection, up to 1 year ]
- Levels of TS activity [ Time Frame: After biopsy collection, up to 1 year ]
- Levels of Top1cc [ Time Frame: After biopsy collection, up to 1 year ]
- Levels of DNA double strand breaks [ Time Frame: After biopsy collection, up to 1 year ]
- Tumor volume [ Time Frame: After biopsy collection, up to 1 year ]
- Number of apoptotic cells. [ Time Frame: After biopsy collection, up to 1 year ]
Biospecimen Retention: Samples With DNA
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03741829
|United States, North Carolina|
|Wake Forest University Health Sciences|
|Winston-Salem, North Carolina, United States, 27157|
|Principal Investigator:||William Gmeiner, Ph.D, MBA||Wake Forest University Health Sciences|