# Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression

> **NIH NIH R21** · DANA-FARBER CANCER INST · 2022 · $232,259

## Abstract

Small cell lung cancer (SCLC) is a highly aggressive malignancy that has limited therapeutic options.
Treatment of SCLC with immune checkpoint inhibitors has been associated with response rates of 10-14% and
increases in survival when combined with chemotherapy. Despite these advances, patients diagnosed with
SCLC have a median overall survival of ~1 year, emphasizing the critical need for identifying druggable
targets that contribute to SCLC progression.
 The oncogenic MUC1-C protein appeared in mammals to protect pulmonary and other types of
epithelial cells from loss of homeostasis associated with exposure to the external environment. MUC1-C
activates inflammatory, proliferative and remodeling signaling pathways that contribute to the wound healing
response. Importantly, in settings of chronic inflammation with repetitive cycles of damage and repair,
prolonged MUC1-C activation promotes cancer progression.
 There is no known involvement of MUC1-C in SCLC. Our proposed work addresses the previously
unexplored hypothesis that MUC1-C plays a master role in promoting SCLC progression and is a
druggable target for SCLC treatment. This hypothesis is based in part on preliminary observations that
MUC1-C promotes reprogramming of SCLC cell chromatin architecture, which is necessary for pluripotency
and lineage plasticity, and that targeting MUC1-C abrogates those alterations in chromatin accessibility.
 Our hypothesis is further supported by findings that MUC1-C activates MYC signaling in SCLC cells
and induces the expression of NOTCH2, a marker of pulmonary neuroendocrine (NE) stem cells that initiate
repair after injury and are the proposed cell of SCLC origin. Along these lines, targeting MUC1-C suppresses
MYC and NOTCH2 expression and therefore represents an attractive therapeutic strategy for the inhibition of
SCLC cell self-renewal capacity and tumorigenicity.
 MUC1-C is being targeted with CAR-T cells, antibody-drug conjugates and a direct inhibitor of MUC1-C
function that are under clinical development. Our studies to assess the effects of targeting MUC1-C will be
performed on human SCLC cell lines growing in vitro and as tumor xenografts and on SCLC PDX tumor
models. The studies will be integrated with the impact of targeting MUC1-C on SCLC cell chromatin
remodeling and gene expression patterns in association with the suppression of lineage plasticity, stemness
and tumorigencity.
 The overall objective of the proposed work is to advance our understanding of SCLC pathogenesis by
demonstrating that MUC1-C represents a previously unrecognized effector which plays an important role in the
progression of this highly aggressive malignancy. MUC1-C is a druggable target that, based on our findings,
could provide new opportunities for advancing SCLC treatment.

## Key facts

- **NIH application ID:** 10354347
- **Project number:** 1R21CA267138-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** DONALD W. KUFE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $232,259
- **Award type:** 1
- **Project period:** 2022-02-04 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354347

## Citation

> US National Institutes of Health, RePORTER application 10354347, Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression (1R21CA267138-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10354347. Licensed CC0.

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