# Mechanisms of Arginine Deprivation in Small Cell Lung Cancer

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $370,215

## Abstract

Project Summary
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor responsible for over 30,000
deaths each year in the US. SCLC has a two-year survival rate of ~6% with no approved targeted therapies
beyond the recent approval of immunotherapy. SCLC is initially highly responsive to chemotherapy, but rapidly
develops resistance leading to mortality in ~12 months. A major unmet need for SCLC treatment is the
identification of new therapeutic targets and treatment strategies. SCLC has historically been treated as a single
disease without patient stratification. SCLC is driven by distinct MYC family members (MYCL or MYC), which
are notoriously difficult to drug. We and others showed that MYC and MYCL-driven SCLC have distinct molecular
phenotypes with unique vulnerabilities to targeted therapies. We performed unbiased metabolite profiling on
MYC versus MYCL-driven subtypes of SCLC and found that they are metabolically distinct. Using human cell
lines, genetically-engineered mouse models (GEMMs), and human patient-derived xenografts (PDX), we found
that MYC-driven SCLC is uniquely dependent on the amino acid arginine. Arginine depletion with pegylated
arginine deiminase (ADI-PEG20) is the most effective drug we have tested in >25 drug combinations in GEMMs.
Consistently, MYC-driven SCLC has reduced ASS1 expression, the enzyme required to synthesize arginine. In
preliminary data, we discovered that MYC-driven tumor cells treated with ADI-PEG20 undergo autophagy and
ferroptosis. After dramatic initial responses, tumors eventually relapse with re-expression of ASS1 and metabolic
reprogramming with changes in one-carbon, polyamine, and ferroptosis-related pathways. We hypothesize that
arginine deprivation in MYC-driven SCLC promotes autophagy and death by ferroptosis, and that inhibition of
ferroptosis will improve the efficacy of ADI-PEG20. We also hypothesize that during ADI-PEG20 resistance, re-
expression of ASS1 leads to metabolic reprogramming that can be blocked by targeting new metabolic pathways.
To test these hypotheses, our objectives are: 1) Determine the function of autophagy and ferroptosis in response
to arginine deprivation in SCLC. 2) Determine mechanisms of resistance to ADI-PEG20 and test new
combination strategies to increase the efficacy of ADI-PEG20 treatment. This approach is innovative because
we will employ our immune-competent GEMM of MYC-driven SCLC and new human PDX that recapitulate key
features of the human disease. We will integrate state-of-the-art technologies in metabolite profiling and single
cell RNA-seq to understand the mechanisms of resistance to arginine deprivation in vivo. This research is
significant because arginine deprivation is being tested in numerous clinical trials in various cancer types and
we are currently designing new clinical trials for ADI-PEG20 in SCLC. A better understanding of the functions of
arginine deprivation may improve treatment of MYC-driven cancers and lead t...

## Key facts

- **NIH application ID:** 10866365
- **Project number:** 5R01CA251147-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Trudy Gale Oliver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $370,215
- **Award type:** 5
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866365

## Citation

> US National Institutes of Health, RePORTER application 10866365, Mechanisms of Arginine Deprivation in Small Cell Lung Cancer (5R01CA251147-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10866365. Licensed CC0.

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