# Targeting the RNA Exosome for Cancer Therapeutics

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $489,405

## Abstract

The RNA exosome is a RNA degradation machinery that plays a critical role in RNA quality control by
degrading erroneous or incorrectly spliced RNAs. In many cancers, such as pancreatic cancer, the splicing
process is compromised, resulting in the generation of large amounts of aberrant transcripts. We hypothesize
that cancer cells are uniquely dependent on RNA exosome activity to remove excess amounts of
aberrant transcripts and that the RNA exosome therefore may be an impactful new target for
therapeutic intervention for pancreatic cancer. We have developed a set of first-in-class small molecule
inhibitors of the RNA exosome and will in this proposal refine these compounds and assess their tumor-
targeting efficacy for pancreatic cancer in three specific Aims. In Aim 1 a lead optimization campaign will be
initiated of our first-in-class RNA exosome inhibitors. The refined compounds will be evaluated for their RNA
exosome-targeting activities using both in vitro and cell-based RNA exosome activity assays and we will
identify their cellular targets. In Aim 2, the potencies of the 10 top RNA exosome inhibitors will be assessed by
MTT and clonogenic survival assays to select the top three compounds for in vivo studies. These top three
compounds will then be used in combination with either ionizing radiation or gemcitabine to assess synergy.
Inducible shRNA and auxin-inducible protein degradation technologies will be used to inactivate the RNA
exosome and these systems will be compared with the top three inhibitors to explore fundamental mechanisms
of action of the RNA exosome in transcriptional and post-transcriptional events. In Aim 3, we will test the 3
most promising compounds in a PDX orthotopic model for pancreatic cancer either alone or in combination
regimens with gemcitabine and nab-paclitaxel. This is a very innovative proposal exploring a novel cancer
therapeutic target and highly focused on the development of new impactful treatments for pancreatic cancer.
Upon the successful completion of this grant period, we intend to perform IND-enabling studies of the best
candidate compounds.

## Key facts

- **NIH application ID:** 9986705
- **Project number:** 5R01CA213214-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Mats Ljungman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,405
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986705

## Citation

> US National Institutes of Health, RePORTER application 9986705, Targeting the RNA Exosome for Cancer Therapeutics (5R01CA213214-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986705. Licensed CC0.

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