# Investigating Max as a tumor suppressor gene in small cell lung cancer and other neuroendocrine tumors

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $407,812

## Abstract

SUMMARY
Dysregulated expression of the MYC family of transcriptional regulators is a common denominator in a wide
spectrum of human cancers, including small cell lung carcinoma (SCLC), a highly aggressive neuroendocrine-
type tumor that is among the leading causes of US cancer mortality. MYC family proteins specifically
heterodimerize with MAX in order to bind genomic DNA and stimulate widespread transcription. Surprisingly,
recent reports show that MAX is inactivated through deletions and truncating mutations in a significant subset of
SCLC and other neuroendocrine cancers. The paradox that MAX may act as a tumor suppressor, but yet be
crucial for MYC oncogenicity in SCLC, has important implications for our understanding of the etiology of these
tumors but has not been systematically investigated. This proposal is based on the findings from our two
laboratories that (i) a whole-genome CRISPR inactivation screen in pre-neoplastic SCLC (preSCs) revealed
MAX-targeting sgRNAs to be highly growth promoting; and (ii) deletion of MAX dramatically accelerates SCLC
in an autochthonous mouse model. These results provide, for the first time, highly relevant biological systems to
elucidate MAX's tumor suppressor function.
In Aim 1 we will characterize the biological properties of MAX-deleted SCLC including proliferation, apoptosis
and genomic stability. Moreover, we will use ChIP-Seq and RNA-Seq to determine the genomic landscape of
MYC/MYCL and MAX binding and target gene expression in SCLC and MAX-deleted SCLC. We will functionally
interrogate the importance of key MAX target genes identified through integrative genomic analyses. Targets to
be studied will include MAX-dependent regulators of one carbon metabolism already identified. Aim 2 is based
on the hypothesis that MAX deletion not only alters MYC activity but disrupts the broader MYC- MAX
transcriptional network of activators and repressors. We will determine if MYC/MYCL have MAX independent
oncogenic functions in our SCLC models and in human SCLC cell lines, and examine whether network members
that antagonize or cooperate with MYC (such as MXD/MNT, MLX, and MondoA), act to influence SCLC
progression. In Aim 3 we propose to determine core MAX-regulated genes and pathways common to
neuroendocrine tumor suppression by MAX. This will entail molecular and genetic characterization of our new
models of thyroid medullary carcinomas and pheochromocytomas resulting from MAX loss (in an Rb/p53
deficient background) and identification of pathways shared with MAX-null SCLC. This research will extend the
breadth of our studies to uncover how MAX suppresses neuroendocrine cancers. We anticipate that these
studies will deepen our understanding of the complex role of the MYC network in both driving and suppressing
neoplasia and identify novel tumorigenic pathways that may have the potential to serve as therapeutic targets.

## Key facts

- **NIH application ID:** 10135882
- **Project number:** 5R01CA248762-02
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Robert Neil Eisenman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $407,812
- **Award type:** 5
- **Project period:** 2020-05-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135882

## Citation

> US National Institutes of Health, RePORTER application 10135882, Investigating Max as a tumor suppressor gene in small cell lung cancer and other neuroendocrine tumors (5R01CA248762-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135882. Licensed CC0.

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