Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors.

We tested the antitumor efficacy of mTOR catalytic site inhibitor MLN0128 in models with intrinsic or acquired rapamycin-resistance. Cell lines that were intrinsically rapamycin-resistant as well as those that were intrinsically rapamycin-sensitive were sensitive to MLN0128 in vitro. MLN0128 inhibited both mTORC1 and mTORC2 signaling, with more robust inhibition of downstream 4E-BP1 phosphorylation and cap-dependent translation compared to rapamycin in vitro. Rapamycin-sensitive BT474 cell line acquired rapamycin resistance (BT474 RR) with prolonged rapamycin treatment in vitro. This cell line acquired an mTOR mutation (S2035F) in the FKBP12-rapamycin binding domain; mTORC1 signaling was not inhibited by rapalogs but was inhibited by MLN0128. In BT474 RR cells, MLN0128 had significantly higher growth inhibition compared to rapamycin in vitro and in vivo. Our results demonstrate that MLN0128 may be effective in tumors with intrinsic as well as acquired rapalog resistance. mTOR mutations are a mechanism of acquired resistance in vitro; the clinical relevance of this observation needs to be further evaluated.

Targeting the PI3-kinase/Akt/mTOR signaling pathway.

This article presents an overview of the PI3K/Akt/mTOR signaling pathway. As a central regulator of cell growth, protein translation, survival, and metabolism, activation of this signaling pathway contributes to the pathogenesis of many tumor types. Biochemical and genetic aberrations of this pathway observed in various cancer types are explored. Last, pathway inhibitors both in development and already approved by the Food and Drug Administration are discussed.

Career track of Society of University Surgeons Resident Research Award recipients.

BACKGROUND: The Society of University Surgeons (SUS) has an ongoing competitive funding program to support research training for residents. We sought to determine the career track of award recipients. METHODS: We included in the study SUS resident awardees who completed awards from 1989-2007. Characteristics of awardees and their academic productivity were extracted from curriculum vitae provided by awardees (n = 24), or from online sources (n = 7). RESULTS: Awardees spent an average of 2.7 y (range, 1-4 y) of dedicated research time during residency. Awardees averaged 9.8 publications (range, 1-32), with 5.4 as first author (range, 1-17), with their mentor within 3 y of award completion, with an average maximum impact factor of 5.7. A total of 25 residents (81%) pursued fellowships. At an average follow-up of 11.4 y (range, 4-22 y) from the end of the award and 7.2 y (range, 0-18 y) from end of clinical training, awardees had a Hirsch index of 14.5 (range, 2-48). At the time of the study, 26 awardees (84%) were in academic surgery. Of the 23 awardees who had completed surgical training ≥ 3 y earlier, 11 (48%) received independent research funding, seven of whom (30%) received R01 or equivalent funding. CONCLUSIONS: The SUS resident research awardees had a productive research experience. Although our retrospective study cannot determine causation, the SUS award mechanism delivers on its promise of supporting junior surgeon-scientists who pursue academic careers and establish independent research programs. Further studies are needed to determine how rates of subsequent independent research funding can be improved.

In hepatic fibrosis, liver sinusoidal endothelial cells acquire enhanced immunogenicity.

The normal liver is characterized by immunologic tolerance. Primary mediators of hepatic immune tolerance are liver sinusoidal endothelial cells (LSECs). LSECs block adaptive immunogenic responses to Ag and induce the generation of T regulatory cells. Hepatic fibrosis is characterized by both intense intrahepatic inflammation and altered hepatic immunity. We postulated that, in liver fibrosis, a reversal of LSEC function from tolerogenic to proinflammatory and immunogenic may contribute to both the heightened inflammatory milieu and altered intrahepatic immunity. We found that, after fibrotic liver injury from hepatotoxins, LSECs become highly proinflammatory and secrete an array of cytokines and chemokines. In addition, LSECs gain enhanced capacity to capture Ag and induce T cell proliferation. Similarly, unlike LSECs in normal livers, in fibrosis, LSECs do not veto dendritic cell priming of T cells. Furthermore, whereas in normal livers, LSECs are active in the generation of T regulatory cells, in hepatic fibrosis LSECs induce an immunogenic T cell phenotype capable of enhancing endogenous CTLs and generating potent de novo CTL responses. Moreover, depletion of LSECs from fibrotic liver cultures mitigates the proinflammatory milieu characteristic of hepatic fibrosis. Our findings offer a critical understanding of the role of LSECs in modulating intrahepatic immunity and inflammation in fibro-inflammatory liver disease.