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Targeting early events in prostate cancer lineage plasticity

Award Number: R01CA270539
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Targeting early events in prostate cancer lineage plasticity - PROJECT SUMMARY/ABSTRACT Prostate cancer is the most common non-cutaneous cancer in males. Prostate cancer cells are dependent on a transcription factor called the androgen receptor (AR), which is activated by the androgens testosterone and dihydrotestosterone. Accordingly, an effective treatment for patients with advanced prostate cancer is androgen deprivation therapy, which blocks the effects of androgens, inhibits the AR, and halts the growth of prostate cancer cells. Although this form of treatment is very effective for advanced prostate cancer, the stress of this therapy will eventually lead to the prostate cancer cells developing resistance. In approximately 25-30% of cases, the stress of prostate cancer therapy will cause the prostate cancer cells to transform into cellular states where they no longer resemble the original disease. These prostate cancer cells take on features of alternative cell types through a process called lineage plasticity. These lineage plastic prostate cancers are very difficult to treat because they do not contain AR and there are no effective therapeutics available. Additionally, the processes by which standard prostate cancer therapies can cause prostate cancer lineage plasticity is poorly understood. This proposal seeks to understand the biology of prostate cancer lineage plasticity and develop new therapeutic strategies to treat, prevent, or reverse this disease stage. Our preliminary data demonstrates the stem cell transcription factor KLF5 is up-regulated by standard prostate cancer therapies that inhibit the AR. Up-regulation of KLF5 enhances androgen-independent growth of prostate cancer cells, as well as migration and colony formation phenotypes. Functionally, the transcriptional program initiated by up-regulated KLF5 clashes with the transcriptional program activated by the AR. Because the AR transcriptional program controls prostate cancer cell identity, KLF5 up-regulation breaks down this identity and promotes very early steps in lineage plasticity of prostate cancer cells. We hypothesize that targeting this early step in therapy-induced prostate cancer lineage plasticity will block later events that lead to very aggressive, treatment-resistant manifestations of the disease. We have identified ERBB2 as a focal point of this tug-of-war between AR and KLF5, and shown that ERBB2 inhibitors can block the oncogenic effects of KLF5. To advance these findings and identify additional therapeutic vulnerabilities in this pathway, we propose 2 Specific Aims. In Aim 1, we will study induction of KLF5 and lineage plasticity phenotypes in CRPC. In Aim 2, we will test therapeutic potential of blocking early steps in CRPC lineage plasticity. A successful outcome can lead to rapid development of clinical trials testing these therapeutic strategies for treatment or prevention of lineage plastic prostate cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $455,926 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	3	11/27/2024	NON-COMPETING CONTINUATION	$410,334
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	001	3	6/12/2025	NON-COMPETING CONTINUATION	$45,592
														Subtotal = $455,926

Issue Date FY: 2024 ( Subtotal = $437,922 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$23,046
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	2	11/30/2023	NON-COMPETING CONTINUATION	$414,876
														Subtotal = $437,922

Issue Date FY: 2023 ( Subtotal = $486,808 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	1	11/28/2022	NEW	$486,808
														Subtotal = $486,808

Grand Total All Awards = $1,380,656

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Targeting early events in prostate cancer lineage plasticity

Award Number: R01CA270539

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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