An NGS-based assay for accurate detection and quantification of immune gene expression in mouse tumor models.

Tumor microenvironment (TME) is a complex dynamic system with many tumor-interacting components including tumor-infiltrating leukocytes (TILs), cancer associated fibroblasts, blood vessels, and other stromal constituents. It intrinsically affects tumor development and pharmacology of oncology therapeutics, particularly immune-oncology (IO) treatments. Accurate measurement of TME is therefore of great importance for understanding the tumor immunity, identifying IO treatment mechanisms, developing predictive biomarkers, and ultimately, improving the treatment of cancer.

Humanized Mouse Models for Immuno-oncology Drug Discovery.

Breakthroughs in cancer treatment with immunotherapeutics have provided long-term patient benefits for many different types of cancer. However, complete response is not achieved in many patients and tumor types, and the mechanisms underlying this lack of response are poorly understood. Despite this, numerous new targets, therapeutics, and drug combinations are being developed and tested in clinical trials.

A living biobank of matched pairs of patient-derived xenografts and organoids for cancer pharmacology.

Patient-derived tumor xenograft (PDX)/organoid (PDO), driven by cancer stem cells (CSC), are considered the most predictive models for translational oncology. Large PDX collections reflective of patient populations have been created and used extensively to test various investigational therapies, including population-trials as surrogate subjects in vivo. PDOs are recognized as in vitro surrogates for patients amenable for high-throughput screening (HTS).

Translational and Clinical Relevance of PDX-Derived Organoid Models in Oncology Drug Discovery and Development.

Patient-derived cancer disease models conserve many key features of the original human cancers, potentially allowing higher predictive power than traditional cell line models. Accordingly, in vivo patient-derived xenografts (PDX) are frequently utilized in preclinical and translational oncology studies as patient surrogates for population-based screens ("mouse clinical trials"), for which large PDX biobanks have been generated over the last decade from various cancer types. In vitro patient-derived organoids (PDO) have recently emerged as a disruptive technology, enabling early "patient in a dish" clinical trials.

Different syngeneic tumors show distinctive intrinsic tumor-immunity and mechanisms of actions (MOA) of anti-PD-1 treatment.

Cancers are immunologically heterogeneous. A range of immunotherapies target abnormal tumor immunity via different mechanisms of actions (MOAs), particularly various tumor-infiltrate leukocytes (TILs). We modeled loss of function (LOF) in four common anti-PD-1 antibody-responsive syngeneic tumors, MC38, Hepa1-6, CT-26 and EMT-6, by systematical depleting a series of TIL lineages to explore the mechanisms of tumor immunity and treatment.

Preclinical pharmacology modeling of chimeric antigen receptor T therapies.

Chimeric antigen receptor (CAR) T cells have largely been successful in treating hematological malignancies in the clinic but have not been as effective in treating solid tumors, in part, owing to poor access and the immunosuppressive tumor microenvironment. In addition, CAR-T therapy can cause potentially life-threatening side effects, including cytokine release syndrome and neurotoxicity. Current preclinical testing of CAR-T therapy efficacy is typically performed in mouse tumor models, which often fails to predict toxicity.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay.

Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin-polyethyleneimine conjugates.

Materials for delivery of oligonucleotides need to be simple to produce yet effective in vivo to be considered for clinical applications. Formulations of biomaterials based on combinations of existing demonstrated polymeric gene carriers with targeted derivatives are potential candidates for rapid translation but have not been fully explored for siRNA applications. Here we investigated formulations based on derivatised PEI for delivery of siRNA to gastrointestinal cancer cells.

Theoretical considerations in using animal models of metastasis and brief methodology for in vivo colorectal cancer models in SCID and nude mice.

Metastatic spread is generally responsible for the mortality of colorectal cancer patients. There are no adequate treatments for advanced colorectal cancer, and novel therapeutic modalities are urgently required. To this end, valid metastatic models, which accurately mimic the disease process, are needed.

Elevated SP-1 transcription factor expression and activity drives basal and hypoxia-induced vascular endothelial growth factor (VEGF) expression in non-small cell lung cancer.

VEGF plays a central role in angiogenesis in cancer. Non-small cell lung cancer (NSCLC) tumors have increased microvascular density, localized hypoxia, and high VEGF expression levels; however, there is a lack of understanding of how oncogenic and tumor microenvironment changes such as hypoxia lead to greater VEGF expression in lung and other cancers. We show that NSCLC cells secreted higher levels of VEGF than normal airway epithelial cells.

MEDLINE-based assessment of animal studies on Chinese herbal medicine.

Unlabelled: ETHNO-PHARMACOLOGICAL RELEVANCE: The scientific proof and clinical validation of Chinese herbal medicine (CHM) require a rigorous approach that includes chemical standardization, biological assays, animal studies and clinical trials.

Aim Of The Study: To assess the experimental design of animal studies on the activity of CHM by selection and scrutinizing of a series of papers in some major disease areas.

Materials And Methods: We have analyzed the English publications reported in MEDLINE (ISI web of knowledge).

Epigenetic reprogramming of breast cancer cells with oocyte extracts.

Background: Breast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis.

Two new protocols to enhance the production and isolation of human induced pluripotent stem cell lines.

There are two critical stages in the retroviral reprogramming of somatic cells to produce human induced pluripotent stem cell (hiPSC) lines. One is the production of high titer virus required to reprogram somatic cells; the other is identification of true hiPSC colonies from heterogeneous cell populations, and their isolation and expansion to generate a sustainable, pluripotent stem cell line. Here we describe simple, time-saving methods to address the current difficulties at these two critical junctures.

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion.

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized.

Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7.

Background And Aims: Helicobacter pylori (H pylori) infection is a major risk factor in the development of distal gastric adenocarcinoma. Development of the invasive phenotype is associated with the phenomenon of epithelial:mesenchymal transition (EMT). Soluble heparin-binding epidermal growth factor (HB-EGF) has been implicated in this process.

Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activity in vitro and in human tumor xenografts.

All four members of the human epidermal growth factor (EGF) receptor (HER) family are implicated in human cancers. Although efficacious in a subset of patients, resistance to single-targeted anti-HER therapy [i.e.

Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells.

Parathyroid-hormone related protein (PTHrP) is the primary factor in humoral hypercalcemia of malignancy and is highly secreted by breast cancers. The pro-hormone undergoes post-translational processing and cleavage to give rise to mature secretory peptides, one of which is midregion PTHrP (38-94/95/101) containing a nuclear localisation sequence (NLS) in amino acids (87-106). The current study investigates whether the NLS in midregion PTHrP is important in breast cancer growth.

ATP and UTP responses of cultured rat aortic smooth muscle cells revisited: dominance of P2Y2 receptors.

1. It has previously been shown that ATP and UTP stimulate P2Y receptors in vascular smooth muscle cells (VSMCs), but the nature of these receptors, in particular the contribution of P2Y2 and P2Y4 subtypes, has not been firmly established. Here we undertake a further pharmacological analysis of [3H]inositol polyphosphate responses to nucleotides in cultured rat VSMCs.