The genomic and proteomic content of cancer cell-derived exosomes.

Exosomes are secreted membrane vesicles that have been proposed as an effective means to detect a variety of disease states, including cancer. The properties of exosomes, including stability in biological fluids, allow for their efficient isolation and make them an ideal vehicle for studies on early disease detection and evaluation. Much data has been collected over recent years regarding the messenger RNA, microRNA, and protein contents of exosomes.

Molecular Characterization of a Patient's Small Cell Carcinoma of the Ovary of the Hypercalcemic Type.

Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a very rare tumor type that mainly affects young women. We report a 21-year old woman with SCCOHT. The patient initially presented with stage T3AN1MX disease and treated with surgery.

Targeted therapies for adrenocortical carcinoma: IGF and beyond.

Standard chemotherapy for adrenocortical cancer currently is under evaluation in the context of the recently completed FIRM-ACT evaluating the combination of mitotane with either streptozocin or etoposide, cisplatin, and doxorubicin. New agents are eagerly sought by the ACC community that hopes to make progress against this deadly disease. Investigators have begun to dissect the molecular and genomic context of ACC with a goal of identifying potential novel therapeutic agents.

Kinome-wide siRNA screening identifies molecular targets mediating the sensitivity of pancreatic cancer cells to Aurora kinase inhibitors.

Aurora kinases are a family of mitotic kinases that play important roles in the tumorigenesis of a variety of cancers including pancreatic cancer. A number of Aurora kinase inhibitors (AKIs) are currently being tested in preclinical and clinical settings as anti-cancer therapies. However, the antitumor activity of AKIs in clinical trials has been modest.

Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look.

Increased extracellular matrix (ECM) deposition is a characteristic observed in many solid tumors. Increased levels of one ECM component-namely, hyaluronan (HA)-leads to reduced elasticity of tumor tissue and increased interstitial fluid pressure. Multiple initial reports showed that the addition of hyaluronidase (HYAL) to chemotherapeutic regimens could greatly improve efficacy.

Perineural invasion and associated pain in pancreatic cancer.

Perineural invasion (PNI) is a prominent characteristic of pancreatic cancer. PNI is a process whereby cancer cells invade the surrounding nerves, thus providing an alternative route for metastatic spread and pain generation. PNI is thought to be an indicator of aggressive tumour behaviour and has been shown to correlate with poor prognosis of patients with pancreatic cancer.

Mechanistic modeling to investigate signaling by oncogenic Ras mutants.

Mathematical models based on biochemical reaction mechanisms can be a powerful complement to experimental investigations of cell signaling networks. In principle, such models have the potential to find the behaviors that result from well-understood component interactions and their measurable properties, such as concentrations and rate constants. As cancer results from the acquisition of mutations that alter the expression level and/or the biochemistry of proteins encoded by mutated genes, mathematical models of cell signaling networks would also seem to have the potential to predict how these changes alter cell signaling to produce a cancer phenotype.

Advancing a clinically relevant perspective of the clonal nature of cancer.

Cancers frequently arise as a result of an acquired genomic instability and the subsequent clonal evolution of neoplastic cells with variable patterns of genetic aberrations. Thus, the presence and behaviors of distinct clonal populations in each patient's tumor may underlie multiple clinical phenotypes in cancers. We applied DNA content-based flow sorting to identify and isolate the nuclei of clonal populations from tumor biopsies, which was coupled with array CGH and targeted resequencing.

High-throughput RNAi screening identifies a role for TNK1 in growth and survival of pancreatic cancer cells.

To identify novel targets in pancreatic cancer cells, we used high-throughput RNAi (HT-RNAi) to select genes that, when silenced, would decrease viability of pancreatic cancer cells. The HT-RNAi screen involved reverse transfecting the pancreatic cancer cell line BxPC3 with a siRNA library targeting 572 kinases. From replicate screens, approximately 32 kinases were designated as hits, of which 22 kinase targets were selected for confirmation and validation.

Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells.

Purpose: The combination of erlotinib and gemcitabine has shown a small but statistically significant survival advantage when compared with gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study, we sought to identify gene targets that, when inhibited, would enhance the activity of epidermal growth factor receptor (EGFR)-targeted therapies in pancreatic cancer cells.

Toward a pathway-centered approach for the treatment of adrenocortical carcinoma.

Purpose Of Review: Adrenocortical carcinoma is an aggressive, lethal malignancy of the adrenal cortex. The rarity of the disease has stymied therapeutic development. Recent work toward understanding the molecular pathogenesis of the disease has identified several potential new diagnostic and therapeutic targets.

RuleMonkey: software for stochastic simulation of rule-based models.

Background: The system-level dynamics of many molecular interactions, particularly protein-protein interactions, can be conveniently represented using reaction rules, which can be specified using model-specification languages, such as the BioNetGen language (BNGL). A set of rules implicitly defines a (bio)chemical reaction network. The reaction network implied by a set of rules is often very large, and as a result, generation of the network implied by rules tends to be computationally expensive.

Validation of TPX2 as a potential therapeutic target in pancreatic cancer cells.

Purpose: The targeting protein for Xklp2 (TPX2) has recently gained attention as a putative oncogene possibly amplified in several human malignancies, including pancreatic adenocarcinoma. In this work, we sought to evaluate the copy number and expression of TPX2 in pancreatic cancer cell lines and tumor tissues and to further explore the potential of TPX2 as a therapeutic target.

Experimental Design: The DNA copy number and expression of the TPX2 gene were surveyed in pancreatic cancer cell lines and tumor tissues and compared with those of immortalized normal pancreatic ductal cells and normal pancreatic tissues.

Genomic and expression profiling of adrenocortical carcinoma: application to diagnosis, prognosis and treatment.

Adrenocortical carcinoma (ACC) is an aggressive endocrine tumor with a poor 5-year survival rate of 10-20%. Current therapy is often ineffective and may be associated with intolerable side effects. Although ACC is extremely rare, recent advances in genomic and expression profiling, coupled with knowledge gained from the study of the inherited syndromes that increase ACC risk, are beginning to bring together a picture of a tumor type dependent on p53, the G2/M cell cycle transition and IGF2 stimulation.

Identification and characterization of a novel anticancer agent with selectivity against deleted in pancreatic cancer locus 4 (DPC4)-deficient pancreatic and colon cancer cells.

Objectives: The deleted in pancreatic cancer locus 4 (DPC4)/SMAD4 tumor suppressor gene is frequently inactivated in pancreatic (approximately 55%) and colorectal cancers (approximately 30%). Like other tumor suppressor genes, the loss-of-function mutations found in the DPC4 gene are specific to cancer cells. This provides an attractive and unique opportunity for therapeutic intervention.

Identification of an agent selectively targeting DPC4 (deleted in pancreatic cancer locus 4)-deficient pancreatic cancer cells.

One of the most common types of genetic alterations in cancer is the loss-of-function mutations in tumor-suppressor genes. Such mutations are usually very specific to cancer cells and present attractive and unique opportunities for therapeutic interventions. However, for various reasons, antitumor agents that target loss-of-function mutations have not been readily identified.