Preclinical therapeutic efficacy of a novel blood-brain barrier-penetrant dual PI3K/mTOR inhibitor with preferential response in PI3K/PTEN mutant glioma
Metrics: PDF 1826 views | HTML 1982 views | ?
Dimpy Koul1, Shuzhen Wang1, Shaofang Wu1, Norihiko Saito1, Siyuan Zheng2, Feng Gao1, Isha Kaul1, Masaki Setoguchi3, Kiyoshi Nakayama3, Kumiko Koyama4, Yoshinobu Shiose5, Erik P. Sulman6, Yasuhide Hirota5, W. K. Alfred Yung1
1Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Brain Tumor Center, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan
4Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan
5Oncology Research Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan
6Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
W. K. Alfred Yung, email: [email protected]
Dimpy Koul, email: [email protected]
Keywords: PI3K/mTOR/ brain penetrant, PI3K mutations and/or PTEN aberrations
Abbrevations: GBM, Glioblastoma; BBB, blood -brain barrier; GIC, glioma-initiating cell; PI3K, phosphoinositide 3-kinase; TMZ, temozolomide
Received: July 20, 2016 Accepted: January 23, 2017 Published: February 21, 2017
Glioblastoma (GBM) is an ideal candidate disease for signal transduction targeted therapy because the majority of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. Loss of heterozygosity of chromosome 10, mutations in the tumor suppressor gene PTEN, and PI3K mutations are molecular hallmarks of GBM and indicate poor prognostic outcomes in many cancers. Consequently, inhibiting the PI3K pathway may provide therapeutic benefit in these cancers. PI3K inhibitors generally block proliferation rather than induce apoptosis. To restore the sensitivity of GBM to apoptosis induction, targeted agents have been combined with conventional therapy. However, the molecular heterogeneity and infiltrative nature of GBM make it resistant to traditional single agent therapy. Our objectives were to test a dual PI3K/mTOR inhibitor that may cross the blood–brain barrier (BBB) and provide the rationale for using this inhibitor in combination regimens to chemotherapy-induced synergism in GBM. Here we report the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor, DS7423 (hereafter DS), in in-vitro and in-vivo studies. DS was tested in mice, and DS plasma and brain concentrations were determined. DS crossed the BBB and led to potent suppression of PI3K pathway biomarkers in the brain. The physiologically relevant concentration of DS was tested in 9 glioma cell lines and 22 glioma-initiating cell (GIC) lines. DS inhibited the growth of glioma tumor cell lines and GICs at mean 50% inhibitory concentration values of less than 250 nmol/L. We found that PI3K mutations and PTEN alterations were associated with cellular response to DS treatment; with preferential inhibition of cell growth in PI3KCA-mutant and PTEN altered cell lines. DS showed efficacy and survival benefit in the U87 and GSC11 orthotopic models of GBM. Furthermore, administration of DS enhanced the antitumor efficacy of temozolomide against GBM in U87 glioma models, which shows that PI3K/mTOR inhibitors may enhance alkylating agent-mediated cytotoxicity, providing a novel regimen for the treatment of GBM. Our present findings establish that DS can specifically be used in patients who have PI3K pathway activation and/or loss of PTEN function. Further studies are warranted to determine the potential of DS for glioma treatment.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.