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Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer
Keisuke Taniguchi1, Tomo Suzuki1, Tomomi Okamura1
1Yakult Central Institute, Yakult Honsha Co., Ltd., Tokyo, Japan.
Abstract:
Metastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain metastases. Here, we established murine models of brain metastasis using cell lines derived from human brain metastatic tumors, and aimed to explore the antitumor efficacy of perifosine, an orally active allosteric Akt inhibitor. We evaluated the effectiveness of perifosine by using it as a single agent in ectopic and orthotopic models created by injecting the DU 145 and NCI-H1915 cell lines into mice. Initially, the injected cells formed distant multifocal lesions in the brains of NCI-H1915 mice, making surgical resection impractical in clinical settings. We determined that perifosine could distribute into the brain and remain localized in that region for a long period. Perifosine significantly prolonged the survival of DU 145 and NCI-H1915 orthotopic brain tumor mice; additionally, complete tumor regression was observed in the NCI-H1915 model. Perifosine also elicited much stronger antitumor responses against subcutaneous NCI-H1915 growth; a similar trend of sensitivity to perifosine was also observed in the orthotopic models. Moreover, the degree of suppression of NCI-H1915 tumor growth was associated with long-term exposure to a high level of perifosine at the tumor site and the resultant blockage of the PI3K/Akt signaling pathway, a decrease in tumor cell proliferation, and increased apoptosis. The results presented here provide a promising approach for the future treatment of patients with metastatic brain cancers and emphasize the importance of enriching a patient population that has a higher probability of responding to perifosine.
Insights
Perifosine, an Akt inhibitor, effectively treats brain metastases in mice by prolonging survival and causing tumor regression. This drug shows promise for treating metastatic brain cancers by blocking key signaling pathways.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Metastatic brain tumors represent advanced cancer stages with limited chemotherapy options.
- Developing effective treatments for brain metastases is a critical unmet need in oncology.
Purpose of the Study:
- To investigate the antitumor efficacy of perifosine, an orally active allosteric Akt inhibitor, in preclinical models of brain metastasis.
- To evaluate perifosine's potential as a therapeutic agent for metastatic brain cancers.
Main Methods:
- Established murine models of brain metastasis using DU 145 and NCI-H1915 cell lines.
- Administered perifosine as a single agent in ectopic and orthotopic models.
- Assessed perifosine's brain distribution, tumor regression, survival rates, and effects on the PI3K/Akt pathway.
Main Results:
- Perifosine distributed into the brain and showed prolonged localization.
- Significant survival prolongation was observed in mice with orthotopic brain tumors.
- Complete tumor regression occurred in the NCI-H1915 model, with strong antitumor responses in both orthotopic and subcutaneous models.
- Tumor growth suppression correlated with sustained perifosine exposure, PI3K/Akt pathway blockage, reduced proliferation, and increased apoptosis.
Conclusions:
- Perifosine demonstrates significant antitumor efficacy against brain metastases in preclinical models.
- The drug's ability to penetrate the brain and inhibit the PI3K/Akt pathway offers a promising therapeutic strategy.
- Further investigation is warranted to identify patient populations likely to respond to perifosine treatment for metastatic brain cancers.
