The Experts below are selected from a list of 454527 Experts worldwide ranked by ideXlab platform
William R. Wilson - One of the best experts on this subject based on the ideXlab platform.
-
Targeting Hypoxia in cancer therapy
Nature Reviews Cancer, 2011Co-Authors: William R. WilsonAbstract:Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour Hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on Hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour Hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting Hypoxia. Hypoxia is common in developing and advanced tumours and could therefore provide a means for drug selectivity. As discussed in this Review, this can be achieved either by using prodrugs that are activated in hypoxic regions, or by directly targeting Hypoxia-induced signalling pathways that confer survival to tumour cells. Hypoxia represents a compelling therapeutic target, given that it has a major role in tumour development and resistance to therapy, and that the levels of Hypoxia are more severe in most tumours than normal tissues. One approach to targeting Hypoxia seeks to develop bioreductive prodrugs that are activated by enzymatic reduction in hypoxic tissue. These prodrugs are chemically diverse and represent two distinct strategies: activation under moderate Hypoxia (as exemplified by tirapazamine) or only under severe Hypoxia (as exemplified by PR-104). In the latter case, diffusion of the active drug to less hypoxic cells is essential. A second approach seeks small molecule inhibitors against molecular targets involved in the survival of hypoxic cells. Current interest focuses on the inhibition of the Hypoxia-inducible factor 1 (HIF1), the unfolded protein response (UPR) and mTOR pathways, but the most important vulnerabilities in hypoxic cells are not well defined. Most molecularly targeted agents have been 'repurposed' from other applications, and have low selectivity as hypoxic cytotoxins. Both approaches face substantial challenges in relation to off-target effects, which, ironically, also present opportunities. For bioreductive prodrugs, activation by aerobic reductases can contribute to normal tissue toxicity, but this is exploitable in tumours that highly express these enzymes. For molecularly targeted agents, Hypoxia-independent signalling through the same pathways may provide opportunities for additional antitumour activity. Both bioreductive prodrugs and molecularly targeted agents also need to overcome the problem of drug penetration through poorly perfused hypoxic tissue; strategies for addressing this requirement are being developed. The current generation of bioreductive prodrugs generate DNA-reactive cytotoxins, making them difficult to combine with conventional chemotherapy because of overlapping toxicity. This challenge is stimulating the development of bioreductive prodrugs that release molecularly targeted agents as their effectors, potentially combining the best features of both approaches. Given the marked heterogeneity in Hypoxia between tumours of the same type, the clinical exploitation of Hypoxia using all of these approaches will require their co-development with companion diagnostics for Hypoxia (and for other determinants of sensitivity).
-
Exploiting tumour Hypoxia in cancer treatment
Nature Reviews Cancer, 2004Co-Authors: J. Martin Brown, William R. WilsonAbstract:Solid tumours contain regions at very low oxygen concentrations (Hypoxia), often surrounding areas of necrosis. The cells in these hypoxic regions are resistant to both radiotherapy and chemotherapy. However, the existence of Hypoxia and necrosis also provides an opportunity for tumour-selective therapy, including prodrugs activated by Hypoxia, Hypoxia-specific gene therapy, targeting the Hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria. These strategies could turn what is now an impediment into a significant advantage for cancer therapy. A characteristic feature of solid tumours is the presence of cells at very low oxygen tensions. These hypoxic cells confer radiotherapy and chemotherapy resistance to the tumours, as well as selecting for a more malignant phenotype. These hypoxic cells, however, provide a tumour-specific targeting strategy for therapy, and four approaches are being investigated: prodrugs activated by Hypoxia; Hypoxia-selective gene therapy; targeting the Hypoxia-inducible factor 1 (HIF-1) transcription factor; and the use of recombinant obligate anaerobic bacteria. Tirapazamine is the prototype Hypoxia-activated prodrug. Its toxic metabolite, a highly reactive radical that is present at higher concentrations under Hypoxia, selectively kills the resistant hypoxic cells in tumours. This makes the tumours much more sensitive to treatment with conventional chemotherapy and radiotherapy. Several other Hypoxia-activated prodrugs, including AQ4N, NLCQ-1 and dinitrobenzamide mustards, are in preclinical or early clinical development. Hypoxia-activated gene therapy using Hypoxia-specific promoters provides selective transcription of enzymes that can convert prodrugs into toxic drugs. The efficacy of this approach has been shown in animal models, but clinical testing must await better systemic delivery of vectors to hypoxic cells. Targeting HIF-1 is a third strategy. This protein is stabilized under hypoxic conditions and promotes the survival of tumour cells under hypoxic conditions. Several strategies to inactivate or to exploit this unique protein in tumours are being investigated at the preclinical level. Finally, using recombinant non-pathogenic clostridia — an obligate anaerobe that colonizes tumour necrosis after systemic administration — is another strategy to exploit the unique physiology of solid tumours. This approach has demonstrated considerable preclinical efficacy.
Marianne Koritzinsky - One of the best experts on this subject based on the ideXlab platform.
-
Hypoxia signalling through mTOR and the unfolded protein response in cancer
Nature Reviews Cancer, 2008Co-Authors: Bradly G. Wouters, Marianne KoritzinskyAbstract:Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to Hypoxia are orchestrated in part through activation of the Hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O_2-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to Hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth. Responses to Hypoxia are orchestrated not only through activation of the Hypoxia–inducible factor family of transcription factors (HIFs), but also through HIF–independent signalling pathways. How are these pathways integrated? Cellular responses to Hypoxia are mediated by both Hypoxia-inducible factor (HIF)-dependent and HIF-independent pathways. Each of these O_2-sensitive signalling pathways exhibits unique sensitivity to the severity and duration of O_2 deprivation. Hypoxia inhibits signalling downstream of the kinase mammalian target of rapamycin (mTOR) and mRNA translation initiation through multiple independent mechanisms. Signalling through this pathway appears to influence both tumour progression and Hypoxia tolerance in advanced tumours. Severe hypoxic exposure causes endoplasmic reticulum (ER) stress and leads to rapid activation of the unfolded protein response (UPR). The UPR regulates several downstream effector pathways that together function to promote Hypoxia tolerance. Hypoxic signalling through mTOR and the UPR results in significant changes in mRNA translation that influence gene expression and cellular behaviour in hypoxic cells. Targeting these pathways can reduce or slow tumour growth. Many of the cellular consequences of Hypoxia are jointly influenced by overlapping O_2-sensitive pathways. HIF, mTOR and UPR signalling during Hypoxia influence tumour metabolism, autophagy and ER homeostasis. Many current and experimental anticancer agents cause ER stress and activate the UPR, and may thus show selective toxicity to hypoxic cells. Conversely, hypoxic signalling through the mTOR pathway is likely to influence the efficacy of many of the new drugs targeting this pathway.
Amato J Giaccia - One of the best experts on this subject based on the ideXlab platform.
-
suppressing mitochondrial respiration is critical for Hypoxia tolerance in the fetal growth plate
Developmental Cell, 2019Co-Authors: Mohd Parvez Khan, Christophe Merceron, Edward L Lagory, Zachary Tata, L Mangiavini, Jiarui Hu, Krishna Vemulapalli, Navdeep S Chandel, Amato J Giaccia, Ernestina SchipaniAbstract:Summary Oxygen (O2) is both an indispensable metabolic substrate and a regulatory signal that controls the activity of Hypoxia-Inducible Factor 1α (Hif1a), a mediator of the cellular adaptation to low O2 tension (Hypoxia). Hypoxic cells require Hif1a to survive. Additionally, Hif1a is an inhibitor of mitochondrial respiration. Hence, we hypothesized that enhancing mitochondrial respiration is detrimental to the survival of hypoxic cells in vivo. We tested this hypothesis in the fetal growth plate, which is hypoxic. Our findings show that mitochondrial respiration is dispensable for survival of growth plate chondrocytes. Furthermore, its impairment prevents the extreme Hypoxia and the massive chondrocyte death observed in growth plates lacking Hif1a. Consequently, augmenting mitochondrial respiration affects the survival of hypoxic chondrocytes by, at least in part, increasing intracellular Hypoxia. We thus propose that partial suppression of mitochondrial respiration is crucial during development to protect the tissues that are physiologically hypoxic from lethal intracellular anoxia.
-
tumor microenvironment and cellular stress signaling metabolism imaging and therapeutic targets preface
Advances in Experimental Medicine and Biology, 2014Co-Authors: Constantinos Koumenis, Ester M Hammond, Amato J GiacciaAbstract:Introduction.- Hypoxia and metabolism in cancer.- Hypoxia and Regulation of Cancer Cell Stemness.- Hypoxia-mediated metastasis.- Escape Mechanisms from Antiangiogenic Therapy: An Immune Cell's Perspective.- Hypoxic VDAC1: a potential mitochondrial marker for cancer therapy.- Hypoxia directed drug strategies to target the tumor microenvironment.- Radiotherapy and the Tumor Microenvironment: Mutual Influence and Clinical Implications.- Autophagy and cell death to target cancer cells: exploiting synthetic lethality as cancer therapeutic.- Intratumoral Hypoxia as the Genesis of Genetic Instability and Clinical Prognosis in Prostate Cancer.- miR-210: Fine-Tuning the Hypoxic Response.- The role of complement in tumor growth.- Imaging angiogenesis, inflammation and metastasis in the tumor microenvironment with magnetic resonance imaging.- Index.
Timothy E Essington - One of the best experts on this subject based on the ideXlab platform.
-
evaluating Hypoxia inducible factor 1α mrna expression in a pelagic fish pacific herring clupea pallasii as a biomarker for Hypoxia exposure
Comparative Biochemistry and Physiology A-molecular & Integrative Physiology, 2015Co-Authors: Halley E Froehlich, Steven B Roberts, Timothy E EssingtonAbstract:Abstract Hypoxia [dissolved oxygen (DO) − 1 ] is a major environmental perturbation for many aquatic ecosystems, particularly highly productive estuaries. Most research attention and understanding about the impacts of Hypoxia on estuarine species has focused on the benthos, where Hypoxia is most common. Although the pelagic zone is also susceptible to the effects of Hypoxia, the biological interactions and consequences are not as well understood in marine environments because documenting exposure or avoidance of Hypoxia is often difficult. Physiological biomarkers may provide a way to gain more detailed spatiotemporal information regarding species' exposure to Hypoxia. Here, we identified and tested a Hypoxia-specific responsive gene, Hypoxia-inducible factor-1α (hif-1α), to evaluate its potential as a biomarker for Hypoxia exposure in Pacific herring ( Clupea pallasii ). We conducted controlled laboratory experiments to establish the level of hepatic hif-1α elevated gene expression (> 1 sd normoxic mean), exposure amplification (≥ 2 hours), reduction rate (ca. 24 hours), and some evidence of a lethal hypoxic limit (ca. 2 mg L − 1 , ≥ 4 hours). We then used these findings to evaluate the spatiotemporal patterns of hif-1α for Pacific herring in a seasonally Hypoxia estuary, Hood Canal, Washington, USA. Although expression did not parallel the local hypoxic conditions in the estuary, herring from the more severe hypoxic year (2013) had a higher probability of having elevated mRNA levels. These patterns indicate that hepatic hif-1α levels may not be directly indicative of local DO levels for pelagic marine fish, but rather provide insight into Hypoxia exposure over broader scales.
-
Quantifying Hypoxia Impacts on an Estuarine Demersal Community Using a Hierarchical Ensemble Approach
Ecosystems, 2010Co-Authors: Timothy E Essington, Caroline E PaulsenAbstract:In coastal marine ecosystems, Hypoxia and anoxia are emerging as growing threats whose ecological impacts are difficult to ascertain because of the frequent lack of adequate references for comparison. We applied conventional and hierarchical ensemble analyses to evaluate the weight of evidence in support of Hypoxia impacts on local densities of individual and groups of demersal fish and invertebrate species in Hood Canal, WA, which is subject to seasonal Hypoxia in its southern reaches. Central to our approach was a sample design and analysis scheme that was designed specifically to consider multiple alternative hypotheses regarding factors that dictate local species’ densities. We anticipated persistent effects of Hypoxia (felt even when seasonal Hypoxia was absent) on species densities would be most pronounced for sessile species, but that immediate effects (felt only when seasonal Hypoxia was present) would dominate for mobile species. Conventional analysis provided strong evidence that densities of sessile species were persistently reduced in the hypoxic-impacted site, but did not indicate widespread immediate density responses during hypoxic events among mobile species. The absence of strong weights of evidence for Hypoxia effects was partly a consequence of alternative hypotheses that better explained spatial-temporal variation in species’ densities. The hierarchical ensemble analysis improved the precision of species-specific effect sizes, and also allowed us to make inferences about the response of aggregated groups of species. The estimated mean density reductions during hypoxic events (dissolved oxygen ~2 mg/l) ranged from 73 to 98% among mobile invertebrates, benthic, and benthopelagic fishes. The large reduction in benthic and benthopelagic species suggests substantial effects of Hypoxia in Hood Canal even at oxygen levels that were marginally hypoxic. Understanding the full ecological consequence of Hypoxia will require a greater knowledge on the spatial extent of distributional shifts and their effects on competitive and predator–prey interactions.
Lorenz Poellinger - One of the best experts on this subject based on the ideXlab platform.
-
Generating specificity and diversity in the transcriptional response to Hypoxia
Nature Reviews Genetics, 2009Co-Authors: Urban Lendahl, Henry Yang, Lorenz PoellingerAbstract:Hypoxia and the cellular hypoxic response have key roles in homeostasis and physiological adaptations, as well as in pathophysiological conditions. The cellular hypoxic response can generate both diversity and specificity in the downstream signalling output, despite a relatively simple core signalling pathway. Hypoxia-inducible factor-α proteins constitute key transcriptional regulators in the cellular hypoxic response, and are subject to various different post-translational modifications. Analysis of the Hypoxia transcriptional response has begun to reveal a core hypoxic transcriptional signature in addition to cell type-specific gene activation events. The transcriptional responses to acute and chronic Hypoxia are distinct. Likewise, Hypoxia-mimicking chemical compounds have a substantially broader transcriptional output than Hypoxia. Intersections with other signalling mechanisms, such as Myc and Notch signalling, contribute to modulation of the hypoxic response. The sensing of oxygen levels and maintenance of oxygen homeostasis is crucial for cells. The hypoxic-sensitive regulation of gene expression allows information about the oxygen status to be converted into appropriate cellular responses. Although there is a core transcriptional pathway, the signalling cascade can be modified to allow diversity and specificity in the transcriptional output. In this Review, we discuss recent advances in our understanding of the mechanisms and factors that contribute to the observed diversity and specificity. A deeper knowledge about how hypoxic signalling is tuned will further our understanding of the cellular hypoxic response in normal physiology and how it becomes derailed in disease. In addition to the core hypoxic transcriptional pathway, several mechanisms exist to allow transcriptional diversity and specificity. This Review highlights recent advances in our understanding of the mechanisms and factors that contribute to the tailoring of the appropriate hypoxic transcriptional response.
