# Studies of the initiation and progression of small cell lung cancer using cells derived by differentiation from human pluripotent stem cells

> **NIH NIH U01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $456,199

## Abstract

PROJECT SUMMARY
 Small cell lung cancer (SCLC) is an especially virulent form of lung cancer that is
only transiently responsive to therapy and kills about 30,000 Americans each year.
Based on a more general interest in understanding why certain kinds of cancers have
characteristic genotypes, we are developing methods for studying the initiation of human
cancers by genetically modifying cells at discrete stages of differentiation after chemical
induction of specific lineages from human embryonic stem cells (hESCs). We have
extended recently published methods for inducing hESCs to form parts of the pulmonary
lineage by perturbing NOTCH signaling and reducing expression of the RB1 gene (one of
the two genes commonly inactivated in SCLC); in this way, we have prepared cultures
with high proportions of pulmonary neuroendocrine cells (PNECs), the putative
precursors of SCLC. Moreover, by also reducing expression of P53, the other gene
commonly inactivated in SCLC, PNEC-containing cultures are able to produce small
tumors resembling SCLC when implanted in immune-deficient mice.
 We now propose to expand our studies of this promising model for studying the
origins of SCLC in several ways: by determining the mechanisms by which interference
with NOTCH and RB1 generates PNECs; by exploring several possible assays for the
SCLC-like phenotype we have recently observed; by defining the similarities between the
genetic and physiological features of the SCLCs derived from hESCs and the SCLCs
arising in human patients; and by making induced pleuropotent stem cells (iPSCs) from
normal and tumor cells from patients with lung cancer, especially SCLC, in an effort to
seek genetic risk factors for SCLC. Through these studies, we expect to generate new
information and ideas about risk assessment, prevention, diagnosis, and treatment for
SCLC.
!

## Key facts

- **NIH application ID:** 10089417
- **Project number:** 5U01CA224326-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** HAROLD E. VARMUS
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $456,199
- **Award type:** 5
- **Project period:** 2018-02-09 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089417

## Citation

> US National Institutes of Health, RePORTER application 10089417, Studies of the initiation and progression of small cell lung cancer using cells derived by differentiation from human pluripotent stem cells (5U01CA224326-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10089417. Licensed CC0.

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