# Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer

> **NIH NIH U01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $656,426

## Abstract

Summary
Small cell lung cancer (SCLC) is characterized by aggressive growth, genomic heterogeneity, and rapid
development of resistance to chemotherapy. SCLC patients frequently demonstrate initial clinical response to
chemotherapy, including the clinical standard of care cisplatin-etoposide regimen, but eventually succumb to
chemo-refractory disease. Recent sequencing studies have demonstrated that SCLC is one of the most highly
mutated cancers, but these efforts have yet to identify targetable `driver' mutations in both chemo-sensitive and
chemo-refractory disease. Using an unbiased, high-throughput cellular screen of a diverse chemical library, we
have identified that SCLC chemo-sensitive and chemo-refractory tumor cells are highly sensitive to inhibitors of
the general transcription apparatus. In particular, we observed that SCLC tumor cells were highly sensitive to
THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7) that functions as a co-factor for
RNA polymerase II (Pol II). We found that this transcriptional vulnerability is conferred, in part, by the exquisite
sensitivity of key super-enhancer (SE) -driven SCLC oncogenes to transcriptional inhibition. We therefore
hypothesize that the inhibition of other transcriptional CDKs found at SEs and their associated genes could
provide additional therapeutic avenues. For this purpose we have developed structure-inspired approaches for
the design of covalent inhibitors targeting various transcriptional CDKs. We further hypothesize that
comparative analysis of enhancer landscapes and gene expression profiles from chemo-naïve and chemo-
refractory primary tumors will 1) identify transcriptional and epigenetic features specific to chemo-refractory
disease, 2) enable grouping into clinically relevant subtypes, and 3) identify transcriptional and epigenetic
dependencies specific to chemo-refractory disease that can be `drugged' using transcriptional CDK inhibitors.
As changes to tumor oncogene expression and chemo-resistance have been shown to impact the immune
compartment, we anticipate that chemo-refractory tumors will also exhibit changes in immune cell activation
and infiltration. By extending our classification of clinical subtypes to the tumor microenvironment, we hope to
find both tumor and immune cell gene expression programs that amenable to small molecule targeting with the
goal of enhancing tumor immune surveillance capabilities. Lastly, as many transcription CDKs are known to
transcriptionally regulate key pathways that modulate the response to DNA-damaging agents and
immunotherapies we will investigate whether transcriptional CDK inhibitors may also be combined with other
investigational SCLC therapies.

## Key facts

- **NIH application ID:** 10174856
- **Project number:** 5U01CA213333-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** NATHANAEL Schiander GRAY
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $656,426
- **Award type:** 5
- **Project period:** 2017-06-09 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174856

## Citation

> US National Institutes of Health, RePORTER application 10174856, Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer (5U01CA213333-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10174856. Licensed CC0.

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