Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy?

Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.

Determinants of physician's office visits and potential effects of co-payments: evidence from Austria.

OBJECTIVE: The objective of this study is to analyse determinants of physician office visits and potential effects of co-payments in Austria. METHODS: Based on survey data, the number of annual physician office visits is regressed on a set of explanatory variable such as income, communication behaviour in waiting room, travel time, gender, age, presence of chronic diseases and connectedness to family members. It was then examined how those determinants are affected by hypothetical co-payments in the range of €5 to €200. RESULTS: Our results suggest a negative impact of income and family connectedness on doctor's visits. On the other hand, age, morbidity and active communication behaviour in the waiting room are positively associated with office visits. The significant impact of both income and active communication behaviour on the number of doctor's visits disappears when significant co-payments greater than €50 are introduced. CONCLUSIONS: Higher co-payments would reduce healthcare service utilization in Austria mainly because of a demand reduction of poorer patients. Another key finding of our study is that the desire to chat with peers in the waiting room is another significant driver of physician office visits. Copyright © 2015 John Wiley & Sons, Ltd.