# Preventing invasive prostate cancer

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $508,994

## Abstract

Abstract: Cell motility is required for in situ cancer to form invasive primary prostate cancer (PCa). Inhibiting
motility would intercept formation of invasive cancer. Until now it has not been possible to selectively inhibit
motility. We have discovered a precision acting first-in-class agent, KBU2046. It selectively inhibits motility, has
a wide therapeutic window, has led us to uncover heretofore unknown regulatory pathways, targets those
pathways, performs well in GLP grade IND enabling studies, and opens up new high value innovative concepts
for cancer prevention-interception. Studies support the hypothesis that KBU2046 is an effective cancer
interception agent that operates through a novel mechanism, and that it and the pathways it modulates will have
high potential for inhibiting the development of invasive cancer, which in turn has lethal potential.
 Aim 1. Identify and validate KBU2046’s pharmacologic binding site. In silico, biophysical and biochemical
studies suggest that KBU2046 binds at the protein-protein interface between HSP90β and CDC37 and
selectively decreases binding to Raf1. Using KBU2046-based photo-crosslinkable probes and proteolysis
targeting chimeras (PROTACs), coupled to chemo-proteomic approaches and bioinformatic analysis, studies
will identify and validate KBU2046 binding sites in the cellular milieu.
 Aim 2. Characterize the signaling pathway by which Raf1 regulates the motility of human prostate cells. We
show KBU2046 decreases phosphorylation of ser338 on Raf1’s activation motif, that downstream regulation of
motility is mediated through a novel pathway wherein Raf1 forms a complex with the actin binding protein, L-
plastin (LCP1), while mass spectrometer (MS) proteomic / bioinformatic analysis demonstrates primary effects
on cell motility proteins. Studies will examine this pathway in at risk human prostate cells, will use Raf1
active/inactive constructs, similarly engineer LCP1 constructs, probe signaling through orthogonal analytics,
profile effects on protein signature using MS, and will examine the role of individual pathway members on cell
motility and KBU2046 efficacy.
 Aim 3. Evaluate targeting motiliy in clinically relevant models of human disease. In the RapidCaP transgenic
model, codeletion of Pten and p53 induces in situ→invasive→metastatic PCa. It supports treatment before
versus after development of in situ lesions, allowing us to examine prevention and interception efficacy,
respectively, for inhibiting formation of invasive cancer. Using primary cells from our prostate rapid autopsy
program (RAP), we show mechanistically relevant responsiveness to KBU2046. Primary cells and resultant
organoids provide a unique opportunity to examine efficacy in clinically relevant models. RapidCaP and RAP
tissues will be interrogated at molecular and functional levels to examine effects of KBU2046.
 Impact. Investigators seek to advance the innovative concept that cell motility is an important cancer
prevention-in...

## Key facts

- **NIH application ID:** 10931324
- **Project number:** 5R01CA276846-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Raymond C. Bergan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $508,994
- **Award type:** 5
- **Project period:** 2023-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931324

## Citation

> US National Institutes of Health, RePORTER application 10931324, Preventing invasive prostate cancer (5R01CA276846-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10931324. Licensed CC0.

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