Simultaneous inhibition of PARP/AKT to intercept nascent BRCA1/2 breast tumors.
1/5 보강
We utilized the K14-Cre Brca1Tp53 mouse model to investigate whether a pulse of PARP inhibitor (PARPi) ± an AKT inhibitor (AKTi) can prevent Brca1-related breast cancer.
APA
Wang L, Sardella BR, et al. (2026). Simultaneous inhibition of PARP/AKT to intercept nascent BRCA1/2 breast tumors.. NPJ breast cancer, 12(1), 27. https://doi.org/10.1038/s41523-026-00892-6
MLA
Wang L, et al.. "Simultaneous inhibition of PARP/AKT to intercept nascent BRCA1/2 breast tumors.." NPJ breast cancer, vol. 12, no. 1, 2026, pp. 27.
PMID
41545354 ↗
Abstract 한글 요약
We utilized the K14-Cre Brca1Tp53 mouse model to investigate whether a pulse of PARP inhibitor (PARPi) ± an AKT inhibitor (AKTi) can prevent Brca1-related breast cancer. PARPi alone did not intercept or prevent tumor development. PARPi+AKTi intercepted tumors but did not prevent new tumors. These data confirm the efficacy of a PARPi and an inhibitor of PI3K signaling in treating BRCA1/2-related tumors, but this combination is not sufficient to prevent carcinogenesis.
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Methods
Methods
Animal experiments
All animal experiments were conducted in accordance with Institutional Animal Care and Use Committee (IACUC)-approved protocol at Beth Israel Deaconess Medical Center (#052-2020-23). Animals were euthanized using CO2 inhalation in a “Smartbox” device.
Cancer interception study
K14-Cre Brca1f/fTp53f/f tumor fragments of 1 to 2 mm were implanted into the fourth mammary fat pad of 30 female FVB/NJ mice (strain#:001800; Day 0). Tumors were measured twice weekly. To determine the duration of the pulse treatment to achieve best response, we used an independent set of data and the power law relationship equation: ln(t)=ln(k)+α⋅ln(V) (Suppl 1). The time to best response for a 2 mm tumor was 4.43 days, hence the pulse treatment was given for 5 days. For this interception study, the endpoint was when a tumor reached 10 mm, or 211 days after the initiation of primary treatment. Our IACUC uses tumor size in its largest extension as euthanasia and endpoint criteria. The absence of a tumor was confirmed during necropsy. Cancer interception was evaluated as a means of primary treatment efficacy. Kaplan-Meier curves evaluated the median time from the start of primary treatment to the tumors reaching 10 mm. Mice with poor body condition or not reach endpoint were euthanized and censored.
PARPi resistance study
Tumors from the interception study that reached 10 mm were given a secondary treatment of daily olaparib (50 mg/kg i.p). Mice were euthanized when their tumors reached 20 mm or 211 days after initiating primary treatment.
Cancer prevention study
To study the effect of a preventative treatment on spontaneously developed tumors, we generated K14-cre Brca1f/fTp53f/f mice by crossing K14-Cre+
Brca1f/fTp53f/f males and K14-Cre-
Brca1f/fTp53f/f females and confirmed Cre+ genotype by PCR. PARPi and AKTi doses were the same as the cancer interception study. Tumor incidence or mouse health conditions were monitored. When a tumor arose, it was measured twice a week. These mice develop multiple synchronous tumors. Our IACUC stipulates that the combined largest diameter of the sum of the emergent may not exceed 20 mm. Therefore, the endpoint of this study was defined as when the largest tumor reached 8 mm in longest diameter to be safe to not exceed the IACUC-stipulated maximum tumor burden or, if multiple tumors arise, when the combined tumor burden reaches 20 mm.
Data analysis
Pair-wise comparisons of cancer interception was performed using Fisher’s exact test in GraphPad prism v10.5.0. Tumor-specific survival was evaluated using Kaplan-Meier curves and log rank test. Tumor doubling time was calculated using the formula: (t x log10(2))/(log10(Vt/V0)), where Vt is the volume at time t and V0 is the volume at t = 0. One-way ANOVA was used to compare tumor doubling times between the groups. Statistical significance was achieved when p < 0.05. Flowcharts were created using BioRender. Heng, J. (2026) https://BioRender.com/qd2eib5. Graphs were created using GraphPad prism.
Animal experiments
All animal experiments were conducted in accordance with Institutional Animal Care and Use Committee (IACUC)-approved protocol at Beth Israel Deaconess Medical Center (#052-2020-23). Animals were euthanized using CO2 inhalation in a “Smartbox” device.
Cancer interception study
K14-Cre Brca1f/fTp53f/f tumor fragments of 1 to 2 mm were implanted into the fourth mammary fat pad of 30 female FVB/NJ mice (strain#:001800; Day 0). Tumors were measured twice weekly. To determine the duration of the pulse treatment to achieve best response, we used an independent set of data and the power law relationship equation: ln(t)=ln(k)+α⋅ln(V) (Suppl 1). The time to best response for a 2 mm tumor was 4.43 days, hence the pulse treatment was given for 5 days. For this interception study, the endpoint was when a tumor reached 10 mm, or 211 days after the initiation of primary treatment. Our IACUC uses tumor size in its largest extension as euthanasia and endpoint criteria. The absence of a tumor was confirmed during necropsy. Cancer interception was evaluated as a means of primary treatment efficacy. Kaplan-Meier curves evaluated the median time from the start of primary treatment to the tumors reaching 10 mm. Mice with poor body condition or not reach endpoint were euthanized and censored.
PARPi resistance study
Tumors from the interception study that reached 10 mm were given a secondary treatment of daily olaparib (50 mg/kg i.p). Mice were euthanized when their tumors reached 20 mm or 211 days after initiating primary treatment.
Cancer prevention study
To study the effect of a preventative treatment on spontaneously developed tumors, we generated K14-cre Brca1f/fTp53f/f mice by crossing K14-Cre+
Brca1f/fTp53f/f males and K14-Cre-
Brca1f/fTp53f/f females and confirmed Cre+ genotype by PCR. PARPi and AKTi doses were the same as the cancer interception study. Tumor incidence or mouse health conditions were monitored. When a tumor arose, it was measured twice a week. These mice develop multiple synchronous tumors. Our IACUC stipulates that the combined largest diameter of the sum of the emergent may not exceed 20 mm. Therefore, the endpoint of this study was defined as when the largest tumor reached 8 mm in longest diameter to be safe to not exceed the IACUC-stipulated maximum tumor burden or, if multiple tumors arise, when the combined tumor burden reaches 20 mm.
Data analysis
Pair-wise comparisons of cancer interception was performed using Fisher’s exact test in GraphPad prism v10.5.0. Tumor-specific survival was evaluated using Kaplan-Meier curves and log rank test. Tumor doubling time was calculated using the formula: (t x log10(2))/(log10(Vt/V0)), where Vt is the volume at time t and V0 is the volume at t = 0. One-way ANOVA was used to compare tumor doubling times between the groups. Statistical significance was achieved when p < 0.05. Flowcharts were created using BioRender. Heng, J. (2026) https://BioRender.com/qd2eib5. Graphs were created using GraphPad prism.
Supplementary information
Supplementary information
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