The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy.

Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. Mocetinostat upregulated PD-L1 and antigen presentation genes including class I and II human leukocyte antigen (HLA) family members in a panel of NSCLC cell lines in vitro. Mocetinostat target gene promoters were occupied by a class I HDAC and exhibited increased active histone marks after mocetinostat treatment. Mocetinostat synergized with interferon γ (IFN-γ) in regulating class II transactivator (CIITA), a master regulator of class II HLA gene expression. In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. In ex vivo assays, patient-derived, mocetinostat-treated Tregs also showed significant down regulation of FOXP3 and HELIOS. The combination of mocetinostat and a murine PD-L1 antibody antagonist demonstrated increased anti-tumor activity compared to either therapy alone in two syngeneic tumor models. Together, these data provide evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy.

Report of Cholangiocarcinoma With Transheterozygous BRCA1 and BRCA2 Co-mutation.

Cholangiocarcinoma is an aggressive malignancy involving the epithelial cells of the intrahepatic, perihilar, or extrahepatic biliary tree. It is a disease that is often diagnosed late in its course and progresses quickly. Identifying genomic mutations may provide an important utility in predicting disease course and individualizing therapy for these patients. Mutations in BRCA1 or BCRCA2 genes have been increasingly documented in hepatobiliary malignancies, but they remain a relatively uncommon occurrence. Co-mutations in both BRCA1 and BRCA2 genes are even rarer, with no previously documented reports to our knowledge of BRCA co-positivity in a patient with a hepatobiliary malignancy. We present a case of a patient with cholangiocarcinoma found to have mutations in both BRCA1 and BRCA2 genes.

T-Cell Lymphoproliferative Disorders Following Allogeneic Bone Marrow Transplant: A Report of Two Cases and a Literature Review.

Post-transplantation lymphoproliferative disorders (PTLD) are a commonly occurring condition following solid organ transplantation (SOT) and, rarely, hematopoietic stem cell transplantation (HSCT). As the name suggests, a PTLD is a condition where there is a clonal proliferation of lymphoid cells that occurs as a complication after transplantation. Though the clonal origin cell is primarily associated with the B-cell lineage, there are existing cases in the literature describing PTLD from the T-cell lineage. Large granulocytic leukemia (LGL) is one rare T-cell lineage subtype that typically progresses with a passive clinical course and is discovered with leukocytosis and peripheral blood smears demonstrating large granules in lymphocytes. In this study, we describe two patients initially diagnosed with acute myeloid leukemia (AML) who were both found to have T-cell PTLD after undergoing allogeneic hematopoietic stem cell transplant. One was found with a clonal expansion of T-cells on flow cytometry and the other with LGL on peripheral blood and flow cytometry. This discovery was made at 16 and 20 months after their transplant respectively. Distinguishing factors for these two patients are demonstrated by the derivation of lymphoproliferative disorder from graft vs. host disease (GVHD) or viral etiology, which is significant as both of which have been shown to be associated with PTLD. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) positivity have been shown to be associated with PTLD, and both our patients were EBV-negative but had harbored prior CMV infections. Additionally, they had a benign course with no development of cytopenias or symptoms since the time of diagnosis. These two cases add to the growing literature that is working to better characterize the rare development of LGL and, in general, T-cell PTLD following allogeneic bone marrow transplantation.

Simulating Early Clinical Experiences With Surgical Procedures in the Anatomy Laboratory.

Background There is evidence to suggest that early exposure to clinical experiences could bolster a medical student's education and prepare them to tackle the problem-based learning encountered during clinical rotations. We hypothesized that incorporating common surgical procedures into the gross anatomy laboratory during preclinical years would enhance the anatomical learning experience for students. The incorporation of these procedures would not be disruptive to the normal conduct of the anatomy laboratory, nor result in exorbitant costs. Objectives The goal of a more integrated curriculum is to better enable medical students by providing them a unique learning experience, so that they may more readily recall the knowledge needed to deal with the complex problems of clinical work. Recognizing the importance of this concept, we have incorporated multiple common clinical procedures into our anatomy curriculum as a pilot program. Methods Seven common surgical procedures, including intraosseous needle insertion, venous cut-down, chest tube insertion, surgical cricothyroidotomy, core needle liver biopsy, appendectomy, and hysterectomy, were taught as a part of this study. Video instructions on each of the surgical procedures were provided before each corresponding laboratory. Surveys were distributed to study participants to measure their satisfaction with the procedures and whether or not it was disruptive to the allotted laboratory time. Results Both students and faculty who were sampled in the study reported that they were satisfied with the procedures (96.5% and 100%, respectively), that the procedures did not interfere with laboratory times (96% and 100%), and that the procedures facilitated clinical learning (98% and 100%). Conclusion This study demonstrated that providing a novel surgical teaching program to medical students was beneficial to their education and non-disruptive to the conventional anatomy curriculum. This exercise further facilitates osteopathic education by demonstrating how structure and function organize surgical practice. The integration of Edward Via College of Osteopathic Medicine, Auburn Campus's (VCOM-AC's) surgical procedures into other medical school anatomy courses can yield more prepared and confident students as they venture into their clinical rotations.

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity.

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models.

Purpose:MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661-72. ©2017 AACR.