# Inhibition of castration resistant prostate cancer by targeting of the IKKbeta/AR signaling

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $353,772

## Abstract

Prostate cancer (PCa) is the second leading cause of cancer-related deaths for men in the United
States. Prostatectomy and radiation are standard front line therapies, but a significant portion of these
patients will recur and eventually develop metastatic disease. The primary means of treatment for
patients with recurrent/metastatic PCa is blockade of androgen receptor (AR) or the use of androgen-
deprivation therapy (ADT) through surgical and/or pharmacological depletion of circulating androgens.
Nevertheless, these types of treatment only last for 1 or 2 years. The disease will almost always recur,
even with low levels of circulating androgens in the blood, and progress toward becoming a castration
resistant prostate cancer (CRPC) that usually is fatal. Therapeutic failure of ADT is often accompanied
by molecular alterations of the AR, including AR overexpression and mutation. In addition, the
abnormal activation of other survival pathways through compensatory mechanisms following androgen
depletion and AR inhibition is also essential for CRPC progression and therapeutic resistance. Through
mass spectrometry analysis, we have found that IkappaB kinase beta (IKKbeta), one of the two
catalytic subunits of the IKK complex that controls NF-κB activity, associates with and phosphorylates
androgen receptor in CRPC cells. IKKbeta activity is significantly elevated in CRPC cells and
knockdown of IKKbeta leads to a dramatic decrease in AR signaling. Furthermore, the novel IKKβ
inhibitor, CmpdA, when used as either a single agent or in combination with a FDA approved AR
inhibitor MDV3100, leads to a significant inhibition of CRPC cell proliferation and survival. The overall
objective of this project is to determine the role of IKKβ in regulating CRPC growth and to test the
therapeutic efficacy of the IKKbeta inhibitor CmpdA in CRPC. We hypothesize that IKKbeta is a critical
driver for CRPC and that inhibition of IKKbeta, in combination with AR inhibitors, could lead to
regression of CRPC. To test this, we will determine whether IKKbeta is required for CRPC growth in
vitro and in vivo in established cells, characterize the mechanism and significance of IKKbeta regulation
of AR in CRPC and determine the therapeutic potential of dual targeting of IKKbeta and AR in CRPC.
Completion of this project will provide important insight into how to effectively treat CRPC through a
combination of IKKbeta inhibitor and androgen blockade.

## Key facts

- **NIH application ID:** 9856145
- **Project number:** 5R01CA212094-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Hancai Dan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,772
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856145

## Citation

> US National Institutes of Health, RePORTER application 9856145, Inhibition of castration resistant prostate cancer by targeting of the IKKbeta/AR signaling (5R01CA212094-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856145. Licensed CC0.

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