title: Validation and toxicity of PI3K/Akt pathway inhibition by HIV protease inhibitors in humans.
abstract: OBJECTIVE
  Activation of the phosphatidylinositol 3-kinase/Akt pathway in tumors leads to radiation resistance, and inhibition of this pathway radiosensitizes tumors in laboratory models. Several first-generation human immunodeficiency virus (HIV) protease inhibitors (HPIs) inhibit Akt activation and are radiosensitizers. In order to validate a biomarker of Akt activity in anticipation of clinical trials using HPIs combined with radiotherapy, we sought to determine whether Akt activation was inhibited in leukocytes of HIV+ patients that were already taking these agents.
  
  
  RESULTS
  Patients taking these "active" radiosensitizing protease inhibitors had low levels of phospho-Akt compared to HIV+ patients taking either no medications or other anti-retroviral regimens. We found no significant differences in acute toxicities or in the ability to finish radiation treatment between 14 patients taking radiosensitizing HPIs and the 28 controls.
  
  
  METHODS
  Peripheral blood mononuclear cells from HIV+ patients either taking radiosensitizing HPIs (nelfinavir, saquinavir, amprenavir) or not were analyzed by Western blotting for phospho-Akt. In order to determine whether these radiosensitizing HPIs increase the toxicity of radiotherapy, we performed a retrospective cohort study of HIV+ cancer patients treated with radiation and compared patients on radiosensitizing HPIs to controls not taking these agents.
  
  
  CONCLUSIONS
  These results demonstrate the proof of principle that HPIs can inhibit Akt activation in patients taking normally prescribed anti-retroviral doses and are not associated with excessive toxicity. Radiosensitizing HPIs are excellent candidates for Phase I clinical trials as radiation sensitizers, and peripheral blood mononuclear cells can be used as a drug activity biomarker for Akt pathway inhibition.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. plastaras@xrt.upenn.edu
authors.forename: John P
authors.initials: JP
authors.lastname: Plastaras
authors.forename: Neha
authors.initials: N
authors.lastname: Vapiwala
authors.forename: Mona S
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Deborah
authors.initials: D
authors.lastname: Gudonis
authors.forename: George J
authors.initials: GJ
authors.lastname: Cerniglia
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Gupta
mesh_terms: D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000633:toxicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology*; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D017320:HIV Protease Inhibitors; D011838:Radiation-Sensitizing Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019888:Nelfinavir