Overcoming therapeutic resistance in glioblastoma: the way forward.
Ontology highlight
ABSTRACT:
SUBMITTER: Osuka S
PROVIDER: S-EPMC5272196 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
Overcoming therapeutic resistance in glioblastoma: the way forward.
Osuka Satoru S Van Meir Erwin G EG
The Journal of clinical investigation 20170201 2
Glioblastoma is the most common and lethal primary malignant brain tumor in adults. Patients die from recurrent tumors that have become resistant to therapy. New strategies are needed to design future therapies that target resistant cells. Recent genomic studies have unveiled the complexity of tumor heterogeneity in glioblastoma and provide new insights into the genomic landscape of tumor cells that survive and initiate tumor recurrence. Resistant cells also co-opt developmental pathways and dis ...[more]
Similar Datasets
Project description:Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells-including M2-type macrophages and myeloid-derived suppressor cells-that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.
| S-EPMC7409093 | biostudies-literature
Project description:The Institute of Epidemiology, Disease Control and Research (IEDCR) conducts active, case-based national antimicrobial resistance (AMR) surveillance in Bangladesh. The Capturing Data on Antimicrobial Resistance Patterns and Trends in Use in Regions of Asia (CAPTURA) project accessed aggregated retrospective data from non-IEDCR study sites and 9 IEDCR sites to understand the pattern and extent of AMR and to use analyzed data to guide ongoing and future national AMR surveillance in both public and private laboratories. Record-keeping practices, data completeness, quality control, and antimicrobial susceptibility test practices were investigated in all laboratories participating in case-based IEDCR surveillance and laboratory-based CAPTURA sites. All 9 IEDCR laboratories recorded detailed case-based data (n = 16 816) in electronic format for a priority subset of processed laboratory samples. In contrast, most CAPTURA sites (n = 18/33 [54.5%]) used handwritten registers to store data. The CAPTURA sites were characterized by fewer recorded variables (such as patient demographics, clinical history, and laboratory findings) with 1 020 197 individual data, less integration of patient records with the laboratory information system, and nonuniform practice of data recording; however, data were collected from all available clinical samples. The analyses conducted on AMR data collected by IEDCR and CAPTURA in Bangladesh provide current data collection status and highlight opportunities to improve ongoing data collection to strengthen current AMR surveillance system initiatives. We recommend a tailored approach to conduct AMR surveillance in high-burden, resource-limited settings.
| S-EPMC10732563 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial-mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies.
| S-EPMC7311973 | biostudies-literature
Project description:The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.
| S-EPMC4129449 | biostudies-literature
Project description:The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody-drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.
| S-EPMC6425535 | biostudies-literature
Project description:BACKGROUND:With India preparing for the next decennial Census in 2021, we compared the disability estimates and data collection methodology between the Census 2011 and the most recent population-level survey for India and its states, to highlight the issues to be addressed to improve robustness of the disability estimates in the upcoming Census. METHODS:Data from the Census 2011 and from two complementary nationally representative household surveys that covered all Indian states with the same methodology and survey instruments-the District-Level Household Survey-4 (DLHS-4, 2012-2013) and the Annual Health Surveys (AHS three rounds, 2010-11, 2011-12 and 2012-13) were used. Data from DLHS-4 and AHS 2012-13 round were pooled to generate estimates for the year 2012-13. Data collection methodology between the sources was compared, including the review of definitions of each type of disability. The overall, mental, visual, hearing, speech, and movement disability rate (DR) per 100,000 population were compared between the sources for India and for each state, and the percent difference in the respective rates was calculated. We explored the reliability of these estimates comparing yearly data from the AHS for three successive rounds. RESULTS:Survey data were collected through proxy reporting, however, it is not entirely clear whether the data were proxy- or self-reported or a mix of both in the Census. The overall DR was 25.1% higher in the Census (2,242; 95% CI 2,241-2,243) than the survey (1,791; 95% CI 1,786-1,797) per 100,000 population, with the state-level difference ranging from -64% in Tamil Nadu to 107% in Sikkim state. Despite both sources using nearly similar definitions for overall disability and disability by type, the difference in DR was 125.5%, 54.2%, -25.7%, -19.7%, and 21.9% for hearing, speech, mental, movement, and visual DR, respectively. At the state-level, the difference in disability-specific estimates ranged from -84% to 450%. The extent of variations in the disability-specific estimates in AHS successive rounds ranged from -25% to 929% at the state-level. CONCLUSIONS:There is momentum globally towards building disability measurement that is consistent with the data required for monitoring of the Sustainable Development Goals to ensure robust estimation of disability. The current estimates from the Census and surveys seem much lower than would be expected at the population level. We make recommendations that India needs to take serious note of in order to improve the validity and reliability of India's disability estimates.
| S-EPMC6730860 | biostudies-literature
Project description:The Genome 10K Project was established in 2009 by a consortium of biologists and genome scientists determined to facilitate the sequencing and analysis of the complete genomes of 10,000 vertebrate species. Since then the number of selected and initiated species has risen from ?26 to 277 sequenced or ongoing with funding, an approximately tenfold increase in five years. Here we summarize the advances and commitments that have occurred by mid-2014 and outline the achievements and present challenges of reaching the 10,000-species goal. We summarize the status of known vertebrate genome projects, recommend standards for pronouncing a genome as sequenced or completed, and provide our present and future vision of the landscape of Genome 10K. The endeavor is ambitious, bold, expensive, and uncertain, but together the Genome 10K Consortium of Scientists and the worldwide genomics community are moving toward their goal of delivering to the coming generation the gift of genome empowerment for many vertebrate species.
| S-EPMC5837290 | biostudies-literature
Project description:For a number of years it has been widely assumed that measurement of serum 25-hydroxyvitamin D [25(OH)D] concentration is the best approach to assessing an individual's vitamin D status. However, it has also been recognized that there is substantial within-assay variation in 25(OH)D measurement and even greater between-assay variability. Such assay variation clearly confounds attempts to define what constitutes the diagnosis of hypovitaminosis D. Importantly, assay variability makes pooling of 25(OH)D results from different studies in systematic reviews for the specific purpose of determining dose-response and/or clinical cut points at best problematic. Therefore, to develop and implement evidence-based clinical guidelines, it is essential that 25(OH)D measurement be standardized in both clinical and research laboratories. In this Perspective we outline a way forward toward achieving this goal-the Vitamin D Standardization Program (VDSP).
| S-EPMC5443565 | biostudies-literature
Project description:Defects in apoptosis can promote tumorigenesis and impair responses of malignant B cells to chemotherapeutics. Members of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins are key regulators of the intrinsic, mitochondrial apoptotic pathway. Overexpression of antiapoptotic BCL-2 family proteins is associated with treatment resistance and poor prognosis. Thus, inhibition of BCL-2 family proteins is a rational therapeutic option for malignancies that are dependent on antiapoptotic BCL-2 family proteins. Venetoclax (ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor that represents the first approved agent of this class and is currently widely used in the treatment of chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML). Despite impressive clinical activity, venetoclax monotherapy for a prolonged duration can lead to drug resistance or loss of dependence on the targeted protein. In this review, we provide an overview of the mechanism of action of BCL-2 inhibition and the role of this approach in the current treatment paradigm of B-cell malignancies. We summarize the drivers of de novo and acquired resistance to venetoclax that are closely associated with complex clonal shifts, interplay of expression and interactions of BCL-2 family members, transcriptional regulators, and metabolic modulators. We also examine how tumors initially resistant to venetoclax become responsive to it following prior therapies. Here, we summarize preclinical data providing a rationale for efficacious combination strategies of venetoclax to overcome therapeutic resistance by a targeted approach directed against alternative antiapoptotic BCL-2 family proteins (MCL-1, BCL-xL), compensatory prosurvival pathways, epigenetic modifiers, and dysregulated cellular metabolism/energetics for durable clinical remissions.
| S-EPMC7608616 | biostudies-literature
Project description:Cancer is one of the diseases with high morbidity and mortality on a global scale. Chemotherapy remains the primary treatment option for most cancer patients, including patients with progressive, metastatic, and recurrent diseases. To date, hundreds of chemotherapy drugs are used to treat various cancers, however, the anti-cancer efficacy and outcomes are largely hampered by chemotherapy-associated toxicity and acquired therapeutic resistance. The natural product (NP) oridonin has been extensively studied for its anti-cancer efficacy. More recently, oridonin has been shown to overcome drug resistance through multiple mechanisms, with yet-to-be-defined bona fide targets. Hundreds of oridonin derivative analogs (oridonalogs) have been synthesized and screened for improved potency, bioavailability, and other drug properties. Particularly, many of these oridonalogs have been tested against oridonin for tumor growth inhibition, potential for overcoming therapeutic resistance, and immunity modulation. This concise review seeks to summarize the advances in this field in light of identifying clinical-trial level drug candidates with the promise for treating progressive cancers and reversing chemoresistance.
| S-EPMC8209342 | biostudies-literature