Targeting the PI3K pathway in the brain - Efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier

Laurent Salphati, Timothy P. Heffron, Bruno Alicke, Merry Nishimura, Kai Barck, Richard A. Carano, Jonathan Cheong, Kyle A. Edgar, Joan Greve, Samir Kharbanda, Hartmut Koeppen, Shari Lau, Leslie B. Lee, Jodie Pang, Emile G. Plise, Jenny L. Pokorny, Hani Bou Reslan, Jann N Sarkaria, Jeffrey J. Wallin, Xiaolin ZhangStephen E. Gould, Alan G. Olivero, Heidi S. Phillips

Research output: Contribution to journalArticle

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Abstract

Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM. Experimental Design: Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM. Results: GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively. Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.

Original languageEnglish (US)
Pages (from-to)6239-6248
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number22
DOIs
StatePublished - Nov 15 2012

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Blood-Brain Barrier
Phosphatidylinositol 3-Kinases
Glioblastoma
Brain
P-Glycoprotein
Breast Neoplasms
Madin Darby Canine Kidney Cells
GNE-317
Heterografts
Brain Neoplasms
Computer Simulation
Proteins
Research Design
Biomarkers
Growth
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Salphati, L., Heffron, T. P., Alicke, B., Nishimura, M., Barck, K., Carano, R. A., ... Phillips, H. S. (2012). Targeting the PI3K pathway in the brain - Efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. Clinical Cancer Research, 18(22), 6239-6248. https://doi.org/10.1158/1078-0432.CCR-12-0720

Targeting the PI3K pathway in the brain - Efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. / Salphati, Laurent; Heffron, Timothy P.; Alicke, Bruno; Nishimura, Merry; Barck, Kai; Carano, Richard A.; Cheong, Jonathan; Edgar, Kyle A.; Greve, Joan; Kharbanda, Samir; Koeppen, Hartmut; Lau, Shari; Lee, Leslie B.; Pang, Jodie; Plise, Emile G.; Pokorny, Jenny L.; Reslan, Hani Bou; Sarkaria, Jann N; Wallin, Jeffrey J.; Zhang, Xiaolin; Gould, Stephen E.; Olivero, Alan G.; Phillips, Heidi S.

In: Clinical Cancer Research, Vol. 18, No. 22, 15.11.2012, p. 6239-6248.

Research output: Contribution to journalArticle

Salphati, L, Heffron, TP, Alicke, B, Nishimura, M, Barck, K, Carano, RA, Cheong, J, Edgar, KA, Greve, J, Kharbanda, S, Koeppen, H, Lau, S, Lee, LB, Pang, J, Plise, EG, Pokorny, JL, Reslan, HB, Sarkaria, JN, Wallin, JJ, Zhang, X, Gould, SE, Olivero, AG & Phillips, HS 2012, 'Targeting the PI3K pathway in the brain - Efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier', Clinical Cancer Research, vol. 18, no. 22, pp. 6239-6248. https://doi.org/10.1158/1078-0432.CCR-12-0720
Salphati, Laurent ; Heffron, Timothy P. ; Alicke, Bruno ; Nishimura, Merry ; Barck, Kai ; Carano, Richard A. ; Cheong, Jonathan ; Edgar, Kyle A. ; Greve, Joan ; Kharbanda, Samir ; Koeppen, Hartmut ; Lau, Shari ; Lee, Leslie B. ; Pang, Jodie ; Plise, Emile G. ; Pokorny, Jenny L. ; Reslan, Hani Bou ; Sarkaria, Jann N ; Wallin, Jeffrey J. ; Zhang, Xiaolin ; Gould, Stephen E. ; Olivero, Alan G. ; Phillips, Heidi S. / Targeting the PI3K pathway in the brain - Efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 22. pp. 6239-6248.
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T1 - Targeting the PI3K pathway in the brain - Efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier

AU - Salphati, Laurent

AU - Heffron, Timothy P.

AU - Alicke, Bruno

AU - Nishimura, Merry

AU - Barck, Kai

AU - Carano, Richard A.

AU - Cheong, Jonathan

AU - Edgar, Kyle A.

AU - Greve, Joan

AU - Kharbanda, Samir

AU - Koeppen, Hartmut

AU - Lau, Shari

AU - Lee, Leslie B.

AU - Pang, Jodie

AU - Plise, Emile G.

AU - Pokorny, Jenny L.

AU - Reslan, Hani Bou

AU - Sarkaria, Jann N

AU - Wallin, Jeffrey J.

AU - Zhang, Xiaolin

AU - Gould, Stephen E.

AU - Olivero, Alan G.

AU - Phillips, Heidi S.

PY - 2012/11/15

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N2 - Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM. Experimental Design: Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM. Results: GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively. Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.

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