Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor.

Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective RAF inhibitors reported to date.

Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.

Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade.

The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti-PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy. SIGNIFICANCE: The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency-approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.This article is highlighted in the In This Issue feature, p. 1.

Coaching by design: exploring a new approach to faculty development in a competency-based medical education curriculum.

As curricula move from a time-based system to a competency-based medical education system, faculty development will be required. Faculty will be asked to engage in the observation, assessment and feedback of tasks in the form of educational coaching. Faculty development in coaching is necessary, as the processes and tools for coaching learners toward competence are evolving with a novel assessment system. Here, we provide a scoping review of coaching in medical education. Techniques and content that could be included in the curricular design of faculty development programming for coaching (faculty as coach) are discussed based on current educational theory. A novel model of coaching for faculty (faculty as coachee) has been developed and is described by the authors. Its use is proposed for continuing professional development.

Long-term efficacy of insulin pump therapy on glycemic control in adults with type 1 diabetes mellitus.

OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) is an effective method of intensive therapy for patients with type 1 diabetes; however, most studies have not examined long-term glycemic control. We evaluated the long-term efficacy of CSII in a cohort of adult patients with type 1 diabetes. SUBJECTS AND METHODS: This was a retrospective observational study of 200 patients with type 1 diabetes who initiated CSII at a single outpatient clinic in Kingston, ON, Canada between January 1998 and December 2012. Data were collected from 3 months prior to and up to 15 years after initiation of CSII and included glycated hemoglobin (HbA1c) level and demographic factors potentially associated with glycemic control. RESULTS: Mean age and duration of diabetes at CSII initiation were 35.4 years and 22.4 years, respectively. Mean duration of CSII at the time of analysis was 6 years. Mean HbA1c at initiation of CSII was 8.7% and decreased to a nadir of 7.5% 6 months post-initiation (SD = 1.0) (P < 0.001). This increased over time (range, 7.8-8.2%) but remained lower than the pre-CSII HbA1c (P < 0.001). Shorter duration of diabetes prior to CSII initiation, history of missed appointments, mental illness, and active smoking were predictors of higher HbA1c on CSII. Pre-CSII HbA1c predicted long-term HbA1c on CSII. CONCLUSIONS: The data demonstrate that in a clinic setting, patients on CSII maintain lower HbA1c values over a 1-10-year period compared with pre-CSII values. Poor pre-CSII HbA1c, history of missed appointments, mental illness, and active smoking are predictors of those less likely to achieve an HbA1c target of ≤ 7.0%.

CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo.

CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.

Deletion of N-type calcium channels alters ethanol reward and reduces ethanol consumption in mice.

N-type calcium channels are modulated by acute and chronic ethanol exposure in vitro at concentrations known to affect humans, but it is not known whether N-type channels are important for behavioral responses to ethanol in vivo. Here, we show that in mice lacking functional N-type calcium channels, voluntary ethanol consumption is reduced and place preference is developed only at a low dose of ethanol. The hypnotic effects of ethanol are also substantially diminished, whereas ethanol-induced ataxia is mildly increased. These results demonstrate that N-type calcium channels modulate acute responses to ethanol and are important mediators of ethanol reward and preference.