combined pik3ca and fgfr inhibition with alpelisib and infigratinib in patients with pik3ca mutant solid tumors with or without fgfr alterations

PURPOSE Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor–positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed

Efficacy of BGJ398, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations

We report the activity of BGJ398, a potent and selective pan-fibroblast growth factor receptor (FGFR) antagonist, in patients with metastatic urothelial carcinoma bearing relevant genomic alterations. Patients (N = 67) who had received prior platinum chemotherapy with a diverse array of FGFR3 alterations were enrolled. The majority (70.1%) had ≥2 prior antineoplastic therapies. BGJ398 was administered at 125 mg oral daily on a 3 week on, 1 week off schedule until the time of unacceptable toxicity or progression. The primary endpoint was response rate (RR). Amongst 67 evaluable patients, an overall RR of 25.4% was observed and an additional 39% of patients had disease stabilization, translating to a clinical benefit rate of 64.2%. The most common treatment-emergent toxicities encountered with therapy included hyperphosphatemia, elevated creatinine, fatigue and constipation. Further examination of BGJ398 in this disease setting is therefore warranted

ErbB-1 and ErbB-2 Acquire Distinct Signaling Properties Dependent upon Their Dimerization Partner

The different epidermal growth factor (EGF)-related peptides elicit a diverse array of biological responses as the result of their ability to activate distinct subsets of ErbB receptor dimers, leading to the recruitment of different intracellular signaling networks. To specifically examine dimerization-dependent modulation of receptor signaling, we constructed NIH 3T3 cell lines expressing ErbB-1 and ErbB-2 singly and in pairwise combinations with each other ErbB family member. This model system allowed the comparison of EGF-activated ErbB-1 with ErbB-1 activated by Neu differentiation factor (NDF)-induced heterodimerization with ErbB-4. In both cases, ErbB-1 coupled to the adaptor protein Shc, but only when activated by EGF was it able to interact with Grb2. Compared to the rapid internalization of EGF-activated ErbB-1, NDF-activated ErbB-1 showed delayed internalization characteristics. Furthermore, the p85 subunit of phosphatidylinositol kinase (PI3-K) associated with EGF-activated ErbB-1 in a biphasic manner, whereas association with ErbB-1 transactivated by ErbB-4 was monophasic. The signaling properties of ErbB-2 following heterodimerization with the other ErbB receptors or homodimerization induced by point mutation or monoclonal antibody treatment were also analyzed. ErbB-2 binding to peptides containing the Src homology 2 domain of Grb2 or p85 and the phosphotyrosine binding domain of Shc varied according to the mode of receptor activation. Finally, tryptic phosphopeptide mapping of both ErbB-1 and ErbB-2 revealed that receptor phosphorylation is dependent on the dimerization partner. Differential receptor phosphorylation may, therefore, be the basis for the differences in the signaling properties observed

energy [r]evolution - A sustainable world energy outlook

Der Bericht stellt die Neuauflage der Weltenergie-Szenarien dar, die das Institut für Technische Thermodynamik des Deutschen Zentrums für Luft- und Raumfahrt (DLR) zusammen mit über 30 weiteren Experten im Auftrag von Greenpeace International und dem European Renewable Energy Council (EREC) erarbeitet haben. Die Weltenergie-Szenarien „Energy [R]evolution 2010“ zeigen, wie die globalen CO2-Emissionen von heute 30 Milliarden Tonnen pro Jahr bis zur Mitte des Jahrhunderts auf rund zehn Milliarden Tonnen pro Jahr gesenkt werden können. Diese drastische Reduktion der Treibhausgase ist notwendig, um den Anstieg der globalen Durchschnittstemperatur auf zwei Grad Celsius gegenüber dem vorindustriellen Niveau zu beschränken. Gegenüber der letzten Studie geht ein zweites Advanced Energy [R]evolution Szenario noch einen Schritt weiter: Sollte diese CO2-Minderung aufgrund bisher nicht berücksichtigter langfristiger Klimaeffekte die Klimaerwärmung nicht aufhalten, so können zusätzliche Reduktionspotenziale den CO2-Ausstoß schon 10 Jahre früher und bis 2050 sogar bis auf 3,8 Milliarden Tonnen pro Jahr senken. Die Studie, veröffentlicht von Greenpeace International und EREC, beinhaltet u. a. eine umfangreiche Darstellung der Szenarienannahmen sowie der berechneten Kennwerte des Energiesystems je Weltregion

2-Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4

As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity