Perifosine, an oral, anti-cancer agent and inhibitor of the Akt pathway: Mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity

Paul G. Richardson, Cathy Eng, Jill Kolesar, Teru Hideshima, Kenneth C. Anderson

Research output: Contribution to journalReview articlepeer-review

75 Scopus citations

Abstract

Perifosine is a novel targeted oral Akt inhibitor currently in Phase III clinical development for treatment of colorectal cancer (CRC, in combination with capecitabine) and multiple myeloma (MM, in combination with bortezomib and dexamethasone). Areas covered: The mechanism, preclinical testing, and clinical activity of perifosine in CRC and MM are discussed, with supportive pharmacokinetic information presented. Appropriate literature searches were carried out for background and discussion purposes. Expert opinion: In preclinical models, perifosine has been shown to target phosphatidylinositol 3-kinase-Akt signaling. In CRC cell lines, preclinical studies indicate that perifosine may enhance the cytotoxic effects of fluorouracil, likely primarily through the nuclear transcription factorkappa B pathway. A placebo-controlled Phase II randomized trial of capecitabine ± perifosine in previously treated patients with metastatic CRC showed the combination to be superior. In MM, Phase I/II clinical trials have established the optimal dosing schedule for perifosine and bortezomib in combination, and demonstrated that perifosine can sensitize to, or overcome resistance to, bortezomib, associated with prolonged responses and a favorable side effect profile. Ultimately, the favorable tolerability of perifosine will allow for its testing in combination with multiple targeted therapies to improve PFS and OS, which represent an important unmet need in these populations.

Original languageEnglish
Pages (from-to)623-633
Number of pages11
JournalExpert Opinion on Drug Metabolism and Toxicology
Volume8
Issue number5
DOIs
StatePublished - May 2012

Bibliographical note

Funding Information:
This article was supported by Keryx Biopharmaceuticals. PG Richardson is on the advisory board for Millennium, Celgene, Keryx Biopharmaceuticals and Johnson & Johnson. KC Anderson is on the advisory board for Millennium, Merck & Co. Celgene, Bristol-Myers Squibb and Onyx Pharmaceuticals is also the founder of Acetylon Pharmaceuticals and Oncopep. T Hideshima is a consultant for Acetylon Pharmaceuticals. All other authors have nothing to disclose.

Keywords

  • Akt
  • D-21266
  • KRX-0401
  • biomarker
  • colorectal cancer
  • multiple myeloma
  • perifosine
  • targeted agent

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint

Dive into the research topics of 'Perifosine, an oral, anti-cancer agent and inhibitor of the Akt pathway: Mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity'. Together they form a unique fingerprint.

Cite this