Connecting the Human Microbiome and Pancreatic Cancer.

Pancreatic cancer is a deadly disease that is increasing in incidence throughout the world. There are no clear causal factors associated with the incidence of pancreatic cancer; however, some correlation to smoking, diabetes and alcohol has been described. Recently, a few studies have linked the human microbiome (oral and gastrointestinal tract) to pancreatic cancer development. A perturbed microbiome has been shown to alter normal cells while promoting cancer-related processes such as increased cell signaling, immune system evasion and invasion. In this article, we will review in detail the alterations within the gut and oral microbiome that have been linked to pancreatic cancer and explore the ability of other microbiomes, such as the lung and skin microbiome, to contribute to disease development. Understanding ways to identify a perturbed microbiome can result in advancements in pancreatic cancer research and allow for prevention, earlier detection and alternative treatment strategies for patients.

Gastric cancer: a comprehensive review of current and future treatment strategies.

Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.

Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells.

Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes BAX, TP53 and CASPASE 9. Mechanistically, KPT-8602-PARPi suppressed AR, ARv7, PSA and AR targets FOXA1 and UBE2C. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including BRCA1, BRCA2, CHEK1, EXO1, BLM, RAD51, LIG1, XRCC3 and RMI2. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.

Ras and exosome signaling.

Ras gene (HRAS, NRAS, and KRAS) has been observed to be mutated and hyper-activated in a significant proportion of cancers. However, mutant Ras remains a challenging therapeutic target. Similarly, inhibition of targets upstream and downstream of Ras has shown limited clinical utility. There have been attempts to develop and deliver mutant K-Ras silencing RNAs either through their encapsulation in liposomes or nanoparticles. However, these approaches show very limited success due to the lack of stability of such carrier molecules alongside associated toxicity. There is a pressing need for the identification of better therapeutic targets for Ras or its associated pathways as well as improvements in the design of superior RNAi delivery systems to suppress mutant K-Ras. More than a decade ago, it was shown that aggregates of palmitoylated Ras isoforms (H-Ras and N-Ras) passage through the cytosol on rapidly moving nanosized particles ("rasosomes"). Fast forward a decade, considerable new knowledge has emerged in the area of small vesicles, microparticles, and exosomes. Exosomes are tiny vesicles and play a significant role in regulating cancer-related signaling pathways. Exosomes have also been studied as delivery vehicles to transport drugs, proteins, and microRNAs of choice for therapeutic purposes. K-Ras pathway proteins have been implicated in exosome biogenesis and extravasation processes. This review provides an update on the current knowledge related to K-Ras signaling and exosomes and also discusses how these tiny vesicles can be harnessed to successfully deliver the K-Ras silencing moieties.

Gastric Cancer Heterogeneity and Clinical Outcomes.

Gastric adenocarcinoma is a highly aggressive disease with poor overall survival. The aggressive nature of this disease is in part due to the high intra and inter tumoral heterogeneity and also due to the late diagnosis at presentation. Once progression occurs, treatment is more difficult due to the adaptation of tumors, which acquires resistance to commonly used chemotherapeutics. In this report, using publicly available data sets and pathway analysis, we highlight the vast heterogeneity of gastric cancer by investigating genes found to be significantly perturbed. We found several upregulated genes in the diffuse gastric cancer subtypes share similarity to gastric cancer as a whole which can be explained by the increase in this subtype of gastric cancer throughout the world. We report significant downregulation of genes that are underrepresented within the literature, such as ADH7, GCNT2, and LIF1, while other genes have not been explored within gastric cancer to the best of our knowledge such as METTL7A, MAL, CWD43, and SLC2A12. We identified gender to be another heterogeneous component of this disease and suggested targeted treatment strategies specific to this heterogeneity. In this study, we provide an in-depth exploration of the molecular landscape of gastric cancer in order to shed light onto novel areas of gastric cancer research and explore potential new therapeutic targets.

Metabotropic glutamate receptor-1 regulates inflammation in triple negative breast cancer.

Breast cancer remains a major cause of death among women. 15% of these cancers are triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which no current effective targeted therapy exists. We have previously demonstrated a role for mGluR1 in mediating tumor cell growth, endothelial cell proliferation, and tumor-induced angiogenesis in TNBC. In this study, we explore a role for mGluR1 in regulating inflammation in TNBC. GRM1 expression was silenced in MDA-MB-231 cells to study changes in expression of inflammatory genes regulated by mGluR1. Results were confirmed by ELISA using GRM1-silenced and overexpressed cells and mGluR1 inhibitors. A functional role for these differentially expressed genes was determined in vitro and in vivo. 131 genes were differentially expressed in GRM1-silenced MDA-MB-231 cells, with some of these falling into four major canonical pathways associated with acute inflammation, specifically leukocyte migration/chemotaxis. Upregulation of three of these genes (CXCL1, IL6, IL8) and their corresponding protein was confirmed by qPCR analysis and ELISA in GRM1-manipulated TNBC cells. Upregulation of these cytokines enhanced endothelial adhesion and transmigration of neutrophils in co-culture assays and in 4T1 mouse tumors. Our results suggest mGluR1 may serve as a novel endogenous regulator of inflammation in TNBC.

Kinetics of nucleotide entry into RNA polymerase active site provides mechanism for efficiency and fidelity.

During transcription, RNA polymerase II elongates RNA by adding nucleotide triphosphates (NTPs) complementary to a DNA template. Structural studies have suggested that NTPs enter and exit the active site via the narrow secondary pore but details have remained unclear. A kinetic model is presented that integrates molecular dynamics simulations with experimental data. Previous simulations of trigger loop dynamics and the dynamics of matched and mismatched NTPs in and near the active site were combined with new simulations describing NTP exit from the active site via the secondary pore. Markov state analysis was applied to identify major states and estimate kinetic rates for transitions between those states. The kinetic model predicts elongation and misincorporation rates in close agreement with experiment and provides mechanistic hypotheses for how NTP entry and exit via the secondary pore is feasible and a key feature for achieving high elongation and low misincorporation rates during RNA elongation.