# Project 1: Targeting Oncogenic Transcription Factors

> **NIH NIH P01** · COLD SPRING HARBOR LABORATORY · 2024 · $655,771

## Abstract

PROJECT 1 – TARGETING ONCOGENIC TRANSCRIPTION FACTORS
PROJECT SUMMARY
DNA-binding transcription factors have exceptional specificity as cancer drivers and dependencies, but these
targets lack deep hydrophobic cavities that allow for drug discovery. Hence, there is striking lack of pharmacology
for modulating such targets in our arsenal of cancer therapies. The main objective of Project 1 is to reveal
therapeutically-relevant mechanisms involving the oncogenic transcription factors KLF5 and TEAD:YAP/TAZ,
which are strong dependencies in carcinomas of the breast and pancreas while being dispensable for tissue
homeostasis. This Project has applied the latest innovations in genetic screening technology to discover novel
interactions involving these onco-transcription factors. Our objectives will now be to elucidate these mechanisms
with maximum precision and explore how such mechanisms can be leveraged to develop novel pharmacology.
Aim 1 will focus on exploring the link between TEAD:YAP/TAZ and the poorly understood kinases MARK2/3.
Using paralog co-targeting `double knockout' screening, we have discovered that MARK2/3 catalytic function is
selectively essential in YAP/TAZON cancer cells. Our epigenomic and epistasis experiments indicate that the
essential function of MARK2/3 in cancer is to sustain TEAD:YAP/TAZ function. In this aim, we will employ an
organoid biobank to rigorously evaluate the YAP/TAZ activity as a predictive biomarker of sensitivity to catalytic
MARK2/3 inhibition. In addition, we will use `bump-and-hole' chemical-genetic tools, peptide-based inhibitors,
and epistasis experiments to reveal the critical substrates of MARK2/3 in the Hippo-YAP/TAZ pathway that
account for its cancer maintenance function. The mechanistic research outlined in Aim 1 will test the hypothesis
that chemical modulation of MARK2/3 can exploit the addiction of carcinoma cells to the TEAD:YAP/TAZ
complex. Aim 2 focuses on the zinc finger protein KLF5, which is major driver and dependency in pancreatic and
breast cancer. Using an innovative marker-based genetic screening strategy, we have identified several novel
cofactor ligands of KLF5, including both transcriptional coactivators as well as RNA splicing factors. We will
perform rigorous biochemical and genetic experiments to definitively demonstrate whether KLF5 requires direct
binding these cofactors to execute its essential function in cancer. Such interactions might serve as opportunities
for developing orthosteric inhibitors of KLF5 function. In addition, we will collaborate with the other Projects to
identify vulnerabilities of the KLF5 mRNA using antisense oligonucleotides (ASOs). Organoid models will be
employed to evaluate the therapeutic potential of several ASO-based targeting strategies that modulate KLF5
expression or splicing. Collectively, this Project features a unique ensemble of technologies and hypotheses in
pursuit of a major objective in molecular oncology: to overcome `undruggable' targe...

## Key facts

- **NIH application ID:** 10772999
- **Project number:** 5P01CA013106-52
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** CHRISTOPHER VAKOC
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,771
- **Award type:** 5
- **Project period:** 1997-02-10 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772999

## Citation

> US National Institutes of Health, RePORTER application 10772999, Project 1: Targeting Oncogenic Transcription Factors (5P01CA013106-52). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10772999. Licensed CC0.

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