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Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.

Reliable estimates of the fluid pressure in the pore space of rocks are critical for different aspects of petroleum exploration and production including injection operations and scenarios of water flooding. Numerous approaches are available for formation pore pressure evaluation, however, these measurements become a challenge inside a cased borehole, and a list of possible options is short: either the casing is to be perforated, or the production tubing needs to be disconnected to perform the pressure tests. We present a method for through-casing evaluation of formation pore pressure without shutting down production. We suggest equipping an observation well with a borehole gravimeter and acquiring time variations of the vertical component of the gravity field. Changes in gravity occur during gas production and are related to time variations of formation pore pressure. Gravity changes obtained in the observation well are supposed to be inverted for time-dependent formation pore pressure variations beyond the casing. Our results and recommendations are based on numerical modeling of pore pressure spatial distribution during gas field exploitation and relevant changes in borehole gravity. Benchmark models were elaborated in order to consider a dynamic process of pressure changes in time and space under conditions similar to those in the Medvezhye gas field (Russia). Different modeling scenarios are considered for early and late stages of gas field exploitation. The sensitivity analysis was performed to estimate quantitatively a sensitivity of borehole temporal gravity changes to variations in formation pore pressure behind the casing. Based on resolution analysis we justify the possibility to extract the gravity measurements directly related to changes in pore pressure from the total changes in the gravity field due to reservoir exploitation. The impact of pore pressure on the gravity field measured in boreholes during the water flooding is also evaluated, and obtained results are discussed.