# Project 3

> **NIH NIH P01** · H. LEE MOFFITT CANCER CTR & RES INST · 2022 · $339,774

## Abstract

PROJECT 3 SUMMARY
ROLES AND MECHANISMS OF ACTION OF METABOLIC VULNERABILITIES OF SCLC
Small cell lung cancer (SCLC) lacks targeted therapies, and with only 7% overall survival on standard-of-care
cisplatin/etoposide chemotherapy, and only 10% survival on immune checkpoint therapy, NCI has classified
SCLC as a recalcitrant malignancy. Thus, there is an urgent need to identify new and effective targeted therapies
for SCLC. In non-small cell lung cancer (NSCLC) genomic studies led to effective targeted therapies directed at
drivers such as mutant EGFR. Unfortunately, drivers of SCLC are undruggable, where there are loss-of-function
mutations in the tumor suppressors retinoblastoma protein (RB1), p53 (TP53) and p73, as well as amplification
and/or overexpression of MYC oncogenic transcription factors. To identify vulnerabilities for SCLC, we performed
unbiased mass spectrometry-based screens for SCLC-specific changes in the ATP-binding proteome via
activity-based proteome profiling (ABPP), and in the metabolome (metabolomics and lipidomics) using a large
bank of SCLC and NSCLC cell lines, patient-derived xenografts (PDX) and primary tumor tissue. Further, we
performed screens with compounds that inhibit different aspects of metabolism. Integrating these data revealed
SCLC has highly elevated levels of glycolysis, 1-carbon and purine and lipid metabolism, and that combined
treatment with inhibitors of two metabolic regulators – MCT lactate transporters (MCTi) and the glycolytic enzyme
PFKFB3 (PFKFB3i) – triggers SCLC cell line metabolic collapse, growth arrest and cell death. Genetic studies
validated these findings, and confirmed the paradoxical observation that PFKFB3 inhibition provokes a collapse
in oxidative phosphorylation (OxPhos). Given these findings, we will assess the roles of MCTs and PFKFB3 in
the metabolism, development and maintenance of SCLC using established (from Project 1) and new (from Core
2) genetically engineered SCLC mouse models (GEMM), SCLC PDX, and circulating SCLC xenografts (CDX)
(Aim 1). These SCLC models will also be used to test the safety and efficacy of the MCTi/PFKB3i combination
as a therapeutic strategy for SCLC, and we will also assess effects of targeting MCTs and/or PFKB3 on the
repertoire and activity of intratumoral immune cells using SCLC GEMM (with Project 4). Further, we will use
ABPP, in vivo tracing (with Project 2), metabolic flux, and metabolomics studies (with Core 3) to identify and then
target adaptive metabolic changes provoked by the loss or inhibition of MCTs and/or PFKFB3. These studies
will define the mechanism by which PFKFB3 inhibition impairs OxPhos, and how combined MCTi/PFKFB3i
treatment provokes SCLC metabolic collapse (Aim 2). Importantly, our metabolomic studies of paired sensitive
and cisplatin/etoposide-resistant SCLC PDX supports the hypothesis that MCTi/PFKB3i therapy represents an
opportunity to treat and prevent emergence of chemoresistant disease, which we will test using these SC...

## Key facts

- **NIH application ID:** 10438715
- **Project number:** 5P01CA250984-02
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** John L. Cleveland
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,774
- **Award type:** 5
- **Project period:** 2021-06-25 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438715

## Citation

> US National Institutes of Health, RePORTER application 10438715, Project 3 (5P01CA250984-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438715. Licensed CC0.

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