TS Overexpression in SCLC: Mechanism and Therapeutic Targeting

February 3, 2020 updated by: Wake Forest University Health Sciences
The purpose of this research study is to determine the amount of a protein named thymidine synthase that is being made by cancer and to develop laboratory models called PDX (patient derived xenografts) to learn more about SCLC (small cell lung cancer) and to begin testing new treatments.

Study Overview

Status

Completed

Conditions

Detailed Description

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

Enrollment (Actual)

12

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Health Sciences

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

  • Women and men of all races and ethnicity who meet the above-described eligibility criteria are eligible for this trial.
  • The study consent form will also be provided in Spanish for Spanish-speaking participants.

Description

Inclusion Criteria:

  • Patients undergoing a diagnostic FNA by the following diagnostic modalities utilizing FNA: Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS- TBNA) or conventional transbronchial FNA.
  • Patients must have radiographic evidence for presumed lung cancer or have a previously diagnosed SCLC with clinical evidence of recurrence. Patients undergoing FNA of potential SCLC metastates to lymph nodes are also included (e.g., patients with abnormal mediastinal lymphadenopathy). FNA biopsies from separate locations in the same patient will be considered separate specimens.
  • Age >18 years. Used to define adult age that can independently provide consent.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients whose FNA biopsy is unable to provide classification by pathology or is non-diagnostic.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Samples from transbronchial Biopsy
Samples from participants with SCLC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
After biopsy collection, up to 1 year
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.
After biopsy collection, up to 1 year

Other Outcome Measures

Outcome Measure
Time Frame
Survival of mice at 60 days implanted with tumor and treated with CF10
Time Frame: 60 days
60 days
Number of samples with PDX model development
Time Frame: After biopsy collection, up to 1 year
After biopsy collection, up to 1 year
Levels of TS activity
Time Frame: After biopsy collection, up to 1 year
After biopsy collection, up to 1 year
Levels of Top1cc
Time Frame: After biopsy collection, up to 1 year
After biopsy collection, up to 1 year
Levels of DNA double strand breaks
Time Frame: After biopsy collection, up to 1 year
After biopsy collection, up to 1 year
Tumor volume
Time Frame: After biopsy collection, up to 1 year
After biopsy collection, up to 1 year
Number of apoptotic cells.
Time Frame: After biopsy collection, up to 1 year
After biopsy collection, up to 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Wake Forest University Health Sciences

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: William Gmeiner, Ph.D, MBA, Wake Forest University Health Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 14, 2017

Primary Completion (ACTUAL)

January 3, 2020

Study Completion (ACTUAL)

January 3, 2020

Study Registration Dates

First Submitted

November 12, 2018

First Submitted That Met QC Criteria

November 12, 2018

First Posted (ACTUAL)

November 15, 2018

Study Record Updates

Last Update Posted (ACTUAL)

February 5, 2020

Last Update Submitted That Met QC Criteria

February 3, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB00043264
  • P30CA012197 (U.S. NIH Grant/Contract)
  • Pilot Funds 11347 (OTHER_GRANT: Comprehensive Cancer Center of Wake Forest University)
  • CCCWFU 62A17 (OTHER: NCI)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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