A phase I trial in patients with malignant glioma combining gefitinib with rapamycin unveiled that daily administration of the agents is possible, and that rapamycin doesn’t dramatically affect buy FK228 drug levels. Out of 34 pretreated individuals with refractory disease, stable disease was achieved by 2 attained a partial radiographic response 13. Based on these results, numerous phase II trials applying different mixtures of EGFR TKIs and mTOR inhibitors in malignant glioma are underway. Partial responses were yielded by a phase I trial combining gefitinib and RAD 001 in patients with advanced NSCLC patients who hadn’t previously been treated with an EGFRTKI in two out of eight evaluable patients. The researchers have started a II clinical trial to further assess the effectiveness with this mixture. mTOR inhibitors will also be being examined due to their ability to over come secondary resistance to EGFR TKI therapy in NSCLC. In NSCLC patients who developed after initially giving an answer to EGFR TKI treatment and were extended on the EGFR TKI with subsequent addition of RAD 001, no objective responses were seen 3 weeks after the addition of RAD 001. In spite of those bad initial findings, the addition of mTOR inhibitors to EGFR inhibitors as a way of eliminating Eumycetoma systems of secondary resistance is not associated with unnecessary accumulation and could possibly be further investigated in clinical trials. A number of clinical trials are examining the mix of mTOR inhibitors with multiple targeted tyrosine kinase inhibitors besides EGFR TKIs, such as imatinib, sunitinib and sorafenib in a variety of malignancies. Preliminary data from the phase I/II medical trial combining RAD 001 with imatinib in 31 patients with GI stromal tumors refractory to imatinib resulted in stabilization of disease for greater than 4 months in nine patients. Two clients subsequently achieved partial responses, indicating that mTOR inhibition might re sensitize tumors to imatinib. Considering that mTOR inhibitors have strong anti angiogenic effects through regulation of HIF 1_, dual angiogenic inhibition may be a rational method. Encouraging efficacy data have already been described from a phase I trial, which combined RAD 001 with the anti VEGF monoclonal Pemirolast BMY 26517 antibody bevacizumab in various solid tumors. In a preliminary analysis, partial responses were reported by the investigators in 2 out of 16 evaluable patients, by having an additional 8 out of 16 patients obtaining minor responses or stability of disease. The combination seemed well tolerated with little overlapping toxicities and no dose limiting toxicities. Centered on solid preclinical in vivo data, a number of stage II and III randomized, controlled clinical trials are underway to determine the efficacy and safety of aromatase inhibitors and mTOR inhibitors in hormone receptor positive breast cancer.