👤 Nagi G Ayad

Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM. Show less

The collagens of bovine vitreous-humour and nasal-septum cartilage have been extracted, fractionated and compared. Both tissues show the same heterogeneity of collagen types, consisting of type II, 1 alpha, 2 alpha, 3 alpha and C-PS collagens. The type II collagen of the vitreous humour was significantly more hydroxylated both in the lysine and proline residues than was that of cartilage. C-PS1 collagen, together with higher-Mr forms were present in the vitreous humour, but the higher-Mr forms were not seen in cartilage. Both C-PS1 and C-PS2 were present in vitreous humour and cartilage, but vitreous humour contained three times more of these collagens than did cartilage. Despite the difference in amount, the molar ratio C-PS1/C-PS2 was approx. 1 in both tissues, suggesting that they are components of a larger molecule. The 1 alpha, 2 alpha, 3 alpha collagens were present in the same concentration in both tissues. These three chains co-precipitated on dialysis against phosphate-buffered saline, pH 7.2, in a manner analogous to type V collagen. Show less