# PROTACs for pancreatic cancer therapy

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $393,400

## Abstract

Project Summary
 Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with an abysmal 5-year survival rate of <
9% for patients with PDAC. This sobering statistic indicates a need for novel therapeutic options. The vast
majority (~90%) of PDAC patients carry a gain-of-function Kras mutation, which activates downstream signaling
to drive tumorigenesis. One of these signaling molecules activated by Kras is IKKb. The cytokine, TNFa, is a
well characterized molecule that also activates IKKb through phosphorylation of serine residues (S177 and S181)
in its activation loop. Analyses of surgically resected tumor samples revealed the presence of TNFa in the tumor
microenvironment of ~50% of all cancers. Consistently, in the tumor samples, a perfect correlation between the
presence of TNFa and p-IKKb was observed. We analyzed PDAC samples obtained from the UNMC rapid
autopsy pancreatic program and found elevated levels of p-IKKb in the PDAC cells of the primary tumor and liver
mets when compared to adjacent normal tissue. A testable hypothesis derived from these observations was that
p-IKKb exhibits oncogenic function in the presence of tumor associated mutations such as KrasG12D. To test this
hypothesis, we generated mice that expressed constitutively activated IKKb (IKKbS177E,S181E) in the presence of
KrasG12D. We observed that forced expression of IKKbS177E,S181E dramatically accelerated KrasG12D driven
pancreatic cancer (median survival of < 2-weeks). Our cohort of KrasG12D; p53(-/-) mice became moribund ~ 5-6
months of age, which is consistent with reported studies. It is important to note that pancreas-specific IKKb(-/-)
blocks the development of PDAC in KrasG12D mice. These studies suggest that p-IKKb exhibits potent oncogenic
function and selective targeting of p-IKKb is a viable therapeutic option for PDAC. Traditionally, drugs are
designed to bind / occupy their target and inactivate its function. The efficacy of the drug in this scenario
correlates with the occupancy time of the drug on target (occupancy driven model). One of the challenges with
this approach is dose-limiting toxicity, as it continues to be difficult to accurately predict the necessary dose
required to inactivate the target in patients. An emerging event driven approach provides an alternate to the
classical drug discovery approach. In this innovative model the drug functions as a catalyst that brings together
the cellular protein destruction machinery to the target of interest. These catalysts are called PROteolysis
Targeting Chimeras (PROTACs). They are composed of two ligands conjugated through a linker. One ligand of
the PROTAC binds to the target of interest and the other ligand binds to an E3 ligase to facilitate the degradation
of the target protein using the endogenous cellular machinery. The catalytic nature of PROTACs alleviates dose-
limiting toxicity issues observed with traditional drugs. In this project we propose to apply the event driven model
to develop ...

## Key facts

- **NIH application ID:** 10027631
- **Project number:** 1R21CA251151-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Amarnath (Amar) Natarajan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,400
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10027631

## Citation

> US National Institutes of Health, RePORTER application 10027631, PROTACs for pancreatic cancer therapy (1R21CA251151-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10027631. Licensed CC0.

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