# Molecular mechanisms of SCLC initiation and detection in mice and humans

> **NIH NIH U01** · STANFORD UNIVERSITY · 2022 · $533,142

## Abstract

Small cell lung carcinoma (SCLC) is one of the deadliest cancers, a “recalcitrant” cancer for which there
is no effective treatment except when the disease is diagnosed early. However, only a small fraction of patients
are diagnosed early in disease. The greatest challenge to early diagnosis is that SCLC tumor cells typically
acquire an exceptional mutation burden and metastasize early, so for most patients disease has spread
beyond the lung at the time of diagnosis. The key to developing effective early diagnosis and treatment
methods is to elucidate the earliest molecular and cellular events of tumor initiation to uncover ones that can
be detected by screening during the premalignant phase of the disease. The goal of this proposal is to define
the early, premalignant molecular and cellular events of SCLC, so that they can be detected early and
destroyed before they become a deadly, untreatable disease.
 SCLC is a neuroendocrine cancer. The prominent cell of origin is pulmonary neuroendocrine (NE) cells,
neurosensory and neurosecretory epithelial cells that sense and respond to the environment in the lung.
Recently, a minor subpopulation of NE cells was found to have stem cell activity, proliferating, dispersing, and
replenishing the surrounding bronchial epithelium following severe airway injury. Loss of tumor suppressors Rb
and p53 constitutively activates the stem cell program within days of loss of the tumor suppressors, even in the
absence of injury. In this proposal, a combination of genetics, cell culture, and single-cell genomics is used to
systematically interrogate these stem cells at cellular resolution, both in healthy lungs and in the early,
premalignant stage of SCLC. The goal is to define the molecular events immediately following loss of Rb and
p53 that constitutively activate the stem cell program and initiate their transformation into cancer stem cells that
spread, mutate, and escape immune destruction, and to identify the signals they secrete that might allow the
tumors to be detected before they become deadly.

## Key facts

- **NIH application ID:** 10469595
- **Project number:** 5U01CA231851-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MARK A KRASNOW
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $533,142
- **Award type:** 5
- **Project period:** 2018-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469595

## Citation

> US National Institutes of Health, RePORTER application 10469595, Molecular mechanisms of SCLC initiation and detection in mice and humans (5U01CA231851-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469595. Licensed CC0.

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