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Updated: Jan 25, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Loss of Notch1 Activity Inhibits Prostate Cancer Growth and Metastasis and Sensitizes Prostate Cancer Cells to
Meghan A Rice1, En-Chi Hsu1, Merve Aslan1
1Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California.
Abstract:
Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of NOTCH1 in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of NOTCH1 and treatment of immunocompromised mice bearing prostate cancer xenografts with RO4929097 display significantly impaired tumor growth. Loss of NOTCH1 additionally decreased metastatic potential of prostate cancer cells in invasion assays in vitro as well as in vivo experiments. Moreover, treatment with gamma secretase inhibitors or NOTCH1 gene deletion synergized with antiandrogen therapies, enzalutamide or abiraterone, to decrease the growth of prostate cancer cells. Combination of gamma secretase inhibitors with abiraterone significantly inhibited cell migration and invasion, while combination with enzalutamide reversed enzalutamide-induced migration and invasion. These collective findings suggest loss of NOTCH1 delays growth of CRPC and inhibits metastasis, and inhibition of Notch1 activation in conjunction with second-generation antiandrogen therapies could delay growth and progression of prostate cancer.
Insights
Targeting Notch1 shows promise for aggressive prostate cancer. Inhibiting Notch1 slows tumor growth and metastasis, offering new therapeutic strategies for castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Prostate cancer is a leading cause of male cancer deaths.
- Aggressive prostate cancer often progresses to lethal castration-resistant prostate cancer (CRPC).
- Current CRPC therapies offer limited lifespan extension.
Purpose of the Study:
- To identify novel therapeutic targets for aggressive prostate cancer.
- To investigate the role of Notch1 in prostate cancer progression and metastasis.
- To evaluate Notch1 inhibition as a potential treatment strategy for CRPC.
Main Methods:
- Assessed the impact of NOTCH1 loss on prostate cancer cell proliferation, invasion, and tumorsphere formation.
- Utilized gamma secretase inhibitors (RO4929097, DAPT) to inhibit Notch1 activity in vitro.
- Evaluated the efficacy of Notch1 inhibition and NOTCH1 gene deletion in mouse xenograft models.
- Investigated the synergistic effects of Notch1 inhibition with antiandrogen therapies (enzalutamide, abiraterone).
Main Results:
- Loss of NOTCH1 significantly decreased prostate cancer cell proliferation, invasion, and tumorsphere formation.
- Therapeutic inhibition of Notch1 reduced cancer cell proliferation and impaired tumor growth in vivo.
- NOTCH1 loss and gamma secretase inhibitors reduced prostate cancer metastasis in vitro and in vivo.
- Notch1 inhibition synergized with enzalutamide and abiraterone to inhibit cancer cell growth.
- Combination therapy with gamma secretase inhibitors and abiraterone inhibited migration and invasion.
Conclusions:
- Loss of NOTCH1 delays CRPC growth and inhibits metastasis.
- Notch1 is a viable therapeutic target for aggressive prostate cancer.
- Inhibiting Notch1 activation alongside second-generation antiandrogens may delay prostate cancer progression.
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