Targeting early events in prostate cancer lineage plasticity

Active Project Grant Awarded Last action

Award ID
R01CA270539
Recipient
Awarding agency
Obligated
$6,274,654

Award facts

Assistance listing
93.396 Cancer Biology Research
Completion date 78% complete
Place of performance
Minneapolis, MN 55455, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $45,592
Amendment $410,334
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Amendment $486,808
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Original award $486,808
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Subawards

Subrecipient Amount Awarded
Dana-Farber Cancer Institute, Inc. Targeting early events in prostate cancer lineage plasticity $100,765
Dana-Farber Cancer Institute, Inc. $35,895
BC Cancer Foundation $104,794

Quick answers

Who received award R01CA270539?

R01CA270539 was awarded to Regents Of The University Of Minnesota by National Cancer Institute (National Institutes of Health) on December 1, 2022.

How much is award R01CA270539 worth?

$6,274,654 has been obligated on R01CA270539.

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