It is noteworthy that the ability to cross the BBB is not common to all PI3K inhibitors [47, 48]
It is noteworthy that the ability to cross the BBB is not common to all PI3K inhibitors [47, 48]. In a phase I dose-escalation study of buparlisib in advanced solid tumors, the maximum tolerated dose was determined to be 100 mg/day . have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs. (= 0.045), suggesting that lapatinib may be able to delay or prevent metastatic spread to the CNS . In a phase II study of 242 patients with HER2+ CNS metastases whose disease had progressed on trastuzumab and had been treated with cranial radiation (reported by Lin and (a gene encoding the regulatory subunit p85) were identified in 39% and 7% of tumors, respectively, while was also amplified in 29% of tumors. In addition, homozygous or hemizygous deletions of the tumor suppressors and were observed in 16% and 29% of tumors, respectively . In another report, activation of the PI3K/AKT/mTOR pathway (defined as alteration, PTEN loss, or AKT activation) was reported to be as high as 75% . Activation of the pathway has been associated with poor prognosis in patients with HER2+ breast cancer following trastuzumab treatment, and has been implicated in SR 59230A HCl resistance to HER2-targeted therapies, including trastuzumab and lapatinib [30, 31]. Furthermore, in one study of 52 BCBMs, the PI3K/AKT/mTOR pathway was found to be active in approximately 70% of BCBMs . In another study sequencing 110 primary breast tumors and BCBMs, alterations in PTEN were found in a significantly larger fraction of BCBM tumor tissues compared with samples from primary tumors with good prognosis, bone relapse, or other distant metastases . Activation of the pathway in BCBMs validates it as a potential therapeutic target. PI3K/AKT/mTOR pathway inhibitors in HER2+ BCBMs Various drugs targeting key components of the PI3K/AKT/mTOR pathway are currently in development and include PI3K, mTORC1, dual mTORC1/2, AKT, and dual PI3K and mTORC1/2 inhibitors. Here we will review the data for those drugs that have shown preliminary efficacy in the treatment of cancer involving the CNS in clinical or preclinical models (Table 1). Table 1 Inhibitors of the PI3K/AKT/mTOR pathway with preclinical or clinical evidence of activity SR 59230A HCl in the central nervous system mutations when tested in immunodeficient mice bearing HER2+ breast cancer xenografts . Preclinical studies in rodents have demonstrated that buparlisib can penetrate the BBB, and inhibit the PI3K/AKT/mTOR pathway, as evidenced by reduced phosphorylated AKT (pAKT) in the brains of mice treated with buparlisib [47, 48]. Furthermore, in a mouse model recapitulating widely metastatic HER2+ breast cancer, buparlisib effectively controlled metastatic growth in multiple organs, including the brain [47, 48]. In fact, in the brains of mice treated with buparlisib, 90% inhibition in the number of metastatic human cells was found . In the clinic, buparlisib has also been shown to penetrate the BBB in patients with glioblastoma, as evidenced by reduced pAKT levels in biopsies taken before and after treatment . It is noteworthy that the ability to cross the BBB is not common to all PI3K inhibitors [47, 48]. In a phase I dose-escalation study of buparlisib in advanced solid tumors, the maximum tolerated dose was determined to be 100 mg/day . Of 31 evaluable patients, there was one PR (triple-negative breast cancer) and 16 patients (52%) had stable disease, including five patients with breast cancer. Of note, a 28% reduction in a CNS lesion was observed in one patient with metastatic breast cancer . In IMPG1 antibody another phase Ib/II study of buparlisib plus trastuzumab in patients with locally advanced or metastatic HER2+ breast cancer resistant to trastuzumab, two out of four patients with measurable CNS disease had stable disease at the time of study withdrawal . An expansion arm of this study is investigating buparlisib plus trastuzumab, specifically in patients with HER2+ BCBMs (“type”:”clinical-trial”,”attrs”:”text”:”NCT01132664″,”term_id”:”NCT01132664″NCT01132664). Common adverse events reported with buparlisib include rash, hyperglycemia (due to inhibition of SR 59230A HCl PI3K-dependent insulin signaling), diarrhea, anorexia, and nausea. Also of note, altered mood and anxiety.