Preclinical therapeutic efficacy of a novel blood-brain barrier-penetrant dual PI3K/mTOR inhibitor with preferential response in PI3K/PTEN mutant glioma

Abstract

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.

MSK1-Mediated β-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma

“…In current study, the IHC results showed that pAKT and pS6 was significantly decreased after DS7423 treatment. These results, combining our previous pharmacodynamics study (23), suggested DS7423 can cross BBB to achieve functional concentration to inhibit PI3K/mTOR signaling. While BEZ235 can also cross the BBB in orthotopic glioblastoma models (49), the potential in vivo synergy of BEZ235 and MSK1 knockdown or inhibitor was not tested in current study.…”

“…We used two PI3K/mTOR inhibitors, BEZ235 (22) and DS7423 (Supplemental Figure S1 for structure), to exclude the possibility of non-specific drug toxicity. Both BEZ235 and DS7423 are in clinical trials in patients with advanced solid tumors, and a previous study from our laboratory showed that DS7423 is blood–tumor barrier permeable (23). We report that MSK1 was significantly up-regulated after BEZ235 and DS7423 treatment in all cell lines tested.…”

MicroRNA‑494 promotes the proliferation and migration of human glioma cancer cells through the protein kinase�B/mechanistic target of rapamycin pathway by phosphatase and tensin homolog expression

“…In the pathogenesis of autophagy, the most dominant morphological feature of autophagy is the presence of a large amount of foam-like structures in cells (13). They are the double membrane phagocytic vacuoles that contain cytoplasm and organelles.…”

“…A previous study demonstrated that the PTEN gene is associated with the genesis and development of multiple solid tumors (12). A previous study suggested that abnormal methylation of the PTEN gene promoter may be observed in different types of tumors (11), including breast cancer, esophageal cancer, thyroid carcinoma, renal carcinoma, oral squamous cell carcinoma and ovarian clear cell carcinoma (13). The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway is extensively distributed in cells.…”

Transcription and Translation Inhibitors in Cancer Treatment

“…It has been tested in mouse xenograft models of glioma (Fan et al, 2006). There are also other dual mTOR/PI3K inhibitors which have been tested in animals xenograft models (Koul et al, 2017;Shen et al, 2018;Yu et al, 2018;. There is a good therapeutic potential for dual mTOR/PI3K kinase inhibitors, and there are clinical trials ongoing for many of them, including LY3023414 and gedatolisib.…”