Preclinical Modeling and Therapeutic Avenues for Cancer Metastasis to the Central Nervous System

Metastasis is the dissemination of cells from the primary tumor to other locations within the body, and continues to be the predominant cause of death among cancer patients. Metastatic progression within the adult central nervous system is 10 times more frequent than primary brain tumors. Metastases affecting the brain parenchyma and leptomeninges are associated with grave prognosis, and even after successful control of the primary tumor the median survival is a dismal 2–3 months with treatment options typically limited to palliative care. Current treatment options for brain metastases (BM) and disseminated brain tumors are scarce, and the improvement of novel targeted therapies requires a broader understanding of the biological complexity that characterizes metastatic progression. In this review, we provide insight into patterns of BM progression and leptomeningeal spread, outlining the development of clinically relevant in vivo models and their contribution to the discovery of innovative cancer therapies. In vivo models paired with manipulation of in vitro methods have expanded the tools available for investigators to develop agents that can be used to prevent or treat metastatic disease. The knowledge gained from the use of such models can ultimately lead to the prevention of metastatic dissemination and can extend patient survival by transforming a uniformly fatal systemic disease into a locally controlled and eminently more treatable one

Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing

Assessing poverty alleviation through social protection: School meals and family benefits in a middle-income country

PRIFPRI3; ISI; CRP2PHND; PIMCGIAR Research Program on Policies, Institutions, and Markets (PIM

MicroRNA Regulation of Brain Tumour Initiating Cells in Central Nervous System Tumours

CNS tumours occur in both pediatric and adult patients and many of these tumours are associated with poor clinical outcome. Due to a paradigm shift in thinking for the last several years, these tumours are now considered to originate from a small population of stem-like cells within the bulk tumour tissue. These cells, termed as brain tumour initiating cells (BTICs), are perceived to be regulated by microRNAs at the posttranscriptional/translational levels. Proliferation, stemness, differentiation, invasion, angiogenesis, metastasis, apoptosis, and cell cycle constitute some of the significant processes modulated by microRNAs in cancer initiation and progression. Characterization and functional studies on oncogenic or tumour suppressive microRNAs are made possible because of developments in sequencing and microarray techniques. In the current review, we bring recent knowledge of the role of microRNAs in BTIC formation and therapy. Special attention is paid to two highly aggressive and well-characterized brain tumours: gliomas and medulloblastoma. As microRNA seems to be altered in the pathogenesis of many human diseases, “microRNA therapy” may now have potential to improve outcomes for brain tumour patients. In this rapidly evolving field, further understanding of miRNA biology and its contribution towards cancer can be mined for new therapeutic tools

Evaluation of new technology for intraoperative evoked compound action potential threshold measurements

<div><p></p><p><i>Objective:</i> To determine whether new technology for intraoperative evoked compound action potential (ECAP) threshold measurements—the CR120 Intraoperative Remote Assistant device—is comparable to the existing Custom Sound^® clinical system, as well as assess test-retest accuracy of the systems. <i>Design:</i> Within subject, repeated measures comparative design. <i>Study sample:</i> ECAP data were collected from 81 pediatric subjects (41 females and 40 males). <i>Results:</i> The average ECAP threshold measurement time for the Custom Sound system was 6.2 minutes (SD = 1.0) versus 4.8 minutes (SD = 0.7) for the CR120 device. ECAP thresholds measured with Custom Sound and the CR120 device had an average Pearson product-moment correlation coefficient for all electrodes (N = 1724) of 0.92, p < 0.01; an average mean absolute difference of 6 CLs (SD = 6); and a 95% confidence interval of − 1 to 1 CLs. The test-retest results for Custom Sound and the CR120 device are also included. <i>Conclusion:</i> A significant reduction in the measurement time for ECAP thresholds was noted with the CR120 device. Furthermore, ECAP thresholds measured with the CR120 device are equivalent to Custom Sound within a clinically acceptable range.</p></div