LBA4 Background: Temsirolimus (TEMSR, CCI-779) is a specific inhibitor of mTOR, a signaling protein that regulates cell growth and angiogenesis. In a single-agent, phase 2 study, TEMSR administration to heavily pretreated patients (pts, n = 111) with adv RCC resulted in a median overall survival (OS) of 15.0 mos (Atkins et al, J Clin Oncol 2004). Retrospectively, 49 pts were categorized in a poor-risk group (Motzer et al, J Clin Oncol 2002). The TEMSR-treated pts in this group had a 1.7-fold longer median OS than the first-line, IFN-treated, poor-risk group reported by Motzer et al. In a phase 1 study, the maximum tolerated dose of the combination of TEMSR + IFN in adv RCC pts was TEMSR 15 mg intravenously (IV) once/wk + IFN 6 million units (MU) subcutaneously (SC) 3 times weekly (TIW) (Smith et al, Proc ASCO 2004). Thus, this phase 3 study in first-line, poor-risk adv RCC pts was initiated in July 2003. Methods: Pts with adv RCC and no prior systemic therapy were enrolled in this open-label study if they had ≥3 of 6 risk factors (the 5 Motzer criteria and >1 metastatic disease site). Pts were randomized (1:1:1) to arm 1, IFN up to 18 MU SC TIW; arm 2, TEMSR 25 mg IV once/wk; or arm 3, TEMSR 15 mg IV once/wk + IFN 6 MU SC TIW. The primary study endpoint was OS; the study was powered to compare the TEMSR arms with the IFN arm. Results: We report 20 Mar 2006 preliminary data from an interim analysis performed by the IDMC. Of the 626 pts enrolled, 442 deaths occurred. Patients treated with TEMSR had a statistically longer survival than those treated with IFN (Table). OS of patients treated with IFN and TEMSR + IFN were not statistically different. The 3 most frequently occurring adverse events ≥gr 3 were asthenia (arm 1: arm 2: arm 3, 27%: 12%: 30% pts), anemia (24%: 21%: 39% pts), and dyspnea (8%: 9%: 11% pts). Conclusions: Single-agent TEMSR significantly increases the OS of first-line, poor-risk adv RCC pts compared with IFN, with an acceptable safety profile. [Table: see text] [Table: see text]

No abstract

We reported previously that geniposide showed neurotrophic and neuroprotective activities with the activation of glucagons-like peptide 1 receptor (GLP-1R) in neurons. The current study was designed to further investigate the protective effect of geniposide on β-amyloid (Aβ)-induced cytotoxicity. Our results showed that pre-incubation with geniposide prevented Aβ₁₋₄₂-induced cell injury in primary cultured cortical neurons. Geniposide also induced the expression of insulin-degrading enzyme (IDE), a major degrading protease of Aβ, in a dose-dependent manner. Moreover, bacitracin, an inhibitor of IDE, and RNAi on Glp-1r gene decreased the neuroprotection of geniposide in Aβ₁₋₄₂-treated cortical neurons. Our findings indicated that geniposide activating GLP-1R to against Aβ-induced neurotoxicity involved in its regulation on the expression of IDE in cortical neurons, which provided an additional mechanistic insight into the role of GLP-1R in neuroprotection.