TS Overexpression in SCLC: Mechanism and Therapeutic Targeting

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.

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.