Many US medical schools have added a scholarly or research requirement as a potential intervention to increase the number of medical students choosing to become academic physicians and physician scientists. We designed a retrospective qualitative survey study to evaluate the impact of medical school research at the University of Alabama at Birmingham (UAB) on career choices. A survey tool was developed consisting of 74 possible questions with built-in skip patterns to customize the survey to each participant. The survey was administered using the web-based program Qualtrics to UAB School of Medicine alumni graduating between 2000 and 2014. Alumni were contacted 3 times at 2-week intervals during the year 2015, resulting in 168 completed surveys (11.5% response rate). MD/PhD graduates were excluded from the study. Most respondents completed elective research, typically for reasons relating to career advancement. 24 per cent said medical school research increased their desire for research involvement in the future, a response that positively correlated with mentorship level and publication success. Although completion of medical school research was positively correlated with current research involvement, the strongest predictor for a physician scientist career was pre-existing passion for research (p=0.008). In contrast, students motivated primarily by curricular requirement were less likely to pursue additional research opportunities. Positive medical school research experiences were associated with increased postgraduate research in our study. However, we also identified a strong relationship between current research activity and passion for research, which may predate medical school.
Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem‐like cell differentiation and apoptosis, while also impairing epithelial‐to‐mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor‐intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch‐dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. Implications for Practice The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.
Histone deacetylase inhibitors possess a broad array of antitumor activities; however, their net impact on the evolving antitumor immune response is highly dependent on the inhibitors used and the histone deacetylases they target. Herein, we sequentially focus on each stage of the antitumor immune response - from dendritic cell activation and migration, antigen uptake and presentation, T-cell activation and differentiation and the enactment of antitumor effector functions within the tumor microenvironment. In particular, we will discuss how various inhibitors have different effects depending on cellular activation, experimental design and specific histone deacetylases being targeted - and how these changes impact the outcome of an antitumor immune response. At last, we consider the impact these inhibitors may have on T-cell exhaustion and implications for combination with other immunomodulating therapies.
Background: Ovarian cancer is poorly immunogenic; however, increased major histocompatibility complex class II (MHCII) expression correlates with improved immune response and prolonged survival in ovarian cancer patients. We previously demonstrated that the histone deacetylase inhibitor entinostat increases MHCII expression on ovarian cancer cells. This study evaluated whether entinostat treatment and resultant MHCII expression enhanced beneficial immune responses and impaired tumor growth in mice with ovarian cancer. Methods: C57BL/6 mice bearing i.p. ID8 tumors were randomized to treatment with entinostat 20 mg/kg/day versus control. Changes in mRNA expression of 46 genes important for anti-tumor immunity were evaluated using NanoString®, and multi-color flow cytometry was used to measure changes in protein expression and tumor-infiltrating immune cells. Results: Entinostat treatment decreased growth of both s.c. and omental ID8 tumors and prolonged survival in immunocompetent C57BL/6 mice. NanoString® analysis showed significant changes in mRNA expression in 21 of 46 genes, including increased expression of the MHCI pathway, CIITA, interferon gamma, and granzyme B. C57BL/6 mice treated with entinostat had increased MHCII expression on omental tumor cells and higher frequency of tumor-infiltrating CD8+ T cells by flow cytometry. In immunocompromised mice, treatment with entinostat had no effect on tumor size and did not increase MHCII expression. Conclusions: In this murine ovarian cancer model, entinostat treatment enhances beneficial immune responses. Moreover, these anti-tumor effects of entinostat are dependent on an intact immune system. Future studies combining entinostat with checkpoint inhibitors or other immunomodulatory agents may achieve more durable anti-tumor responses in ovarian cancer patients.
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