Figure 7.

Efficacy of BEZ235 alone and in combination with trastuzumab in HER2+/trastuzumab-sensitive, BT474 (A), HER2+/trastuzumab-resistant, BT474HerR (B) and HER2+/PIK3CA mutated, HCC1954 (C) human tumor xenograft models: A pilot study was conducted with HCC1954 cells to determine 1) the number of cells required to inject for the establishment of tumors and their maintenance in animals throughout the period of drug administration and 2) the maximum tolerable dose of drugs in animals with tumor burden. The number of cells injected was adjusted on the basis of the tolerable tumor burden in untreated animals (following IACUC guidelines). On the basis of the results of the pilot study, cells were injected in matrigel subcutaneously into the flank of immunocompromised female nude (nu/nu) mice. Established xenograft tumors were treated with BEZ235 (45 mg/kg, oral, every other day) alone and in combination with trastuzumab (10 mg/kg i.p., twice weekly for 3 weeks). The table [(lower panel of (Aa), (Ba) & (Ca)] shows the change in volumes of xenograft tumors and body weights of the mice in response to drug combinations. PD data of BT474 tumor (Ab), BT474HerR (Bb) and HCC1954 (Cb) for cell proliferation marker (Ki67), tumor-induced angiogenic markers (CD31 & pVEGFR and cell signaling markers (pAKT & pS6RP) were presented. (D) A dual PI3K/mTOR inhibitor (BEZ235) plus trastuzumab showed in vivo efficacy in mouse xenograft models. Quantification of the mean changes (relative values) in tumor volume of xenografts after 3 weeks treatment, negative values indicate tumor regression.