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Published on: June 9, 2023
Short-term PI3K Inhibition Prevents Breast Cancer in Preclinical Models
Amy T Ku1, Adelaide I J Young1, Ahmed Atef Ibrahim1
1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
Abstract:
Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.
Prevention Relevance:
PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.
Insights
A short course of alpelisib, a PI3K inhibitor, effectively prevented breast cancer development in preclinical models. This targeted approach offers a promising new strategy for breast cancer chemoprevention in high-risk women.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Prevention
Background:
- Antiestrogen therapy is the sole chemoprevention for high-risk women but has limitations.
- Phosphatidylinositol 3-kinase (PI3K) signaling is crucial in breast atypical hyperplasia, a precancerous lesion.
- Developing short-course chemoprevention strategies is essential.
Purpose of the Study:
- To investigate PI3K signaling as a target for breast cancer chemoprevention.
- To evaluate the efficacy of a PI3K inhibitor, alpelisib, in preventing breast cancer progression.
Main Methods:
- Established a mouse model for breast cancer progression from precancerous lesions.
- Administered a short-course prophylactic treatment with alpelisib.
- Assessed alpelisib's effect on lesion expansion and cancer formation in vivo.
- Evaluated alpelisib's impact on patient-derived atypical hyperplasia ex vivo.
Main Results:
- Alpelisib treatment slowed the expansion of early precancerous lesions in the mouse model.
- Prophylactic alpelisib administration prevented breast cancer formation in the established model.
- Alpelisib suppressed the ex vivo expansion of patient-derived atypical hyperplasia.
Conclusions:
- Breast cancer progression from precancerous lesions is dependent on PI3K signaling.
- Targeting PI3K activity with alpelisib represents a viable prophylactic strategy for breast cancer prevention.
- These findings support further clinical trials of alpelisib in high-risk women.
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