White fat cells secrete adipokines that induce inflammation and obesity has been reported to be characterized by high serum levels of inflammatory cytokines such as IL-6 and TNF-α. Rheumatoid arthritis (RA) is a prototype of inflammatory arthritis, but the relationship between RA and obesity is controversial. We made an obese inflammatory arthritis model: obese collagen-induced arthritis (CIA). C57BL/6 mice were fed a 60-kcal high fat diet (HFD) from the age of 4 weeks and they were immunized twice with type II collagen (CII). After immunization, the obese CIA mice showed higher arthritis index scores and histology scores and a more increased incidence of developing arthritis than did the lean CIA mice. After treatment with CII, mixed lymphocyte reaction also showed CII-specific response more intensely in the obese CIA mice than lean CIA. The anti-CII IgG and anti-CII IgG2a levels in the sera of the obese CIA mice were higher than those of the lean CIA mice. The number of Th17 cells was higher and the IL-17 mRNA expression of the splenocytes in the obese CIA mice was higher than that of the lean CIA mice. Obese CIA mice also showed high IL-17 expression on synovium in immunohistochemistry. Although obesity may not play a pathogenic role in initiating arthritis, it could play an important role in amplifying the inflammation of arthritis through the Th1/Th17 response. The obese CIA murine model will be an important tool when we investigate the effect of several therapeutic target molecules to treat RA.

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BACKGROUND: c-MET and PI3K pathways are dysregulated in GBM and can drive cancer growth in pre-clinical models. INC280 is a small molecule inhibitor of c-MET; BKM120 is a pan-class I PI3K inhibitor. A phase Ib/ II study was designed to evaluate INC280+BKM120 in patients with recurrent GBM (NCT01870726). METHODS: Key objectives were to estimate the MTD/RP2D of INC280+BKM120 and to characterize safety/tolerability, pharmacokinetics (PK), and anti-tumor activity of INC280+BKM120 and INC280 alone. Key eligibility criteria were: age ≥ 18 years; ECOG PS ≤ 2, and recurrent GBM (RANO criteria) following ≤ 2 prior systemic therapies, including VEGF inhibitors. For inclusion in phase Ib, mutation/homozygous deletion of PTEN, a suppressor of PI3K signals, was required (irrespective of c-MET status). For phase II with INC280 alone, c-MET amplification (GCN > 5) was required. Blood and tumor specimens were collected for PK and molecular analyses. RESULTS: Thirty-three patients were enrolled in six phase Ib dose cohorts of INC280+BKM120. DLTs were nausea, personality change, and elevated transaminases. MTD was identified at INC280 300 mg BID + BKM120 80 mg QD. RP2D was not declared due to: poor tolerability; a drug-drug interaction resulting in low BKM120 exposure; and no strong evidence of activity. The INC280+BKM120 phase II arm was not opened. In the INC280 monotherapy arm, 10 patients (median age 48 years; 70% women, 90% Caucasian) were enrolled. The most common INC280related AEs (all grades) were nausea and fatigue. Three patients had stable disease as best response (RANO). Molecular analyses are ongoing. CON-CLUSIONS: The MTD of INC280 300 mg BID + BKM120 80 mg QD was identified, with both doses below the single agent RP2Ds. Limited efficacy was observed with the combination in PTEN altered GBM. INC280 alone was well-tolerated but displayed no clear evidence of anti-tumor activity in heavily pre-treated GBM with c-MET alteration.