Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light and during wound healing or tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans.
Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.
The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.
The Institute of Cancer Research is a public research institute and a member institution of the University of London in London, United Kingdom, specialising in oncology. It was founded in 1909 as a research department of the Royal Marsden Hospital and joined the University of London in 2003. It has been responsible for a number of breakthrough discoveries, including that the basic cause of cancer is damage to DNA.
Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.
Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.
Vernalis Research develops and applies fragment and structure-based methods to drug discovery, and has generated cell active lead compounds and development candidates against biological targets in oncology, neurodegeneration, anti-infectives and inflammation.
Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007, and was also approved by the European Medicines Agency (EMA) in November 2007. It is a derivative and prodrug of sirolimus.
Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.
TopoTarget was a Copenhagen-based biotechnology company focused on the discovery and development of drugs and therapies to treat cancer. In 2014, it merged with BioAlliance Pharma and is now part of Onxeo.
A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.
An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG).
Luminespib is an experimental drug candidate for the treatment of cancer. It was discovered through a collaboration between The Institute of Cancer Research and the pharmaceutical company Vernalis and licensed to Novartis. From 2011 to 2014 it was in Phase II clinical trials. Chemically it is a resorcinylic isoxazole amide
Molecular oncology is an interdisciplinary medical specialty at the interface of medicinal chemistry and oncology that refers to the investigation of the chemistry of cancer and tumors at the molecular scale. Also the development and application of molecularly targeted therapies.
Laurence Harris Pearl FRS FMedSci is a British biochemist and structural biologist who is currently Professor of Structural Biology in the Genome Damage and Stability Centre and was Head of the School of Life Sciences at the University of Sussex.
18F-FMISO or fluoromisonidazole is a radiopharmaceutical used for PET imaging of hypoxia. It consists of a 2-nitroimidazole molecule labelled with the positron-emitter fluorine-18.
PR-104 is a drug from the class of hypoxia-activated prodrugs (HAPs), which is being researched as a potential anti-cancer therapeutic agent. It is a phosphate ester “pre-prodrug” that is rapidly converted to the HAP PR-104A in the body. PR-104A is in turn metabolised to reactive nitrogen mustard DNA crosslinking agents in hypoxic tissues such as found in solid tumours. Following initial clinical studies, it was discovered that PR-104A is also activated by the enzyme AKR1C3, independently of hypoxia. Hypoxia in the bone marrow of patients with leukaemia, and high activity of AKR1C3 in some leukaemia subtypes has led to interest in clinical trials of PR-104 in relapsed refractory acute leukaemias.
Chaperome refers to the ensemble of all cellular molecular chaperone and co-chaperone proteins that assist protein folding of misfolded proteins or folding intermediates in order to ensure native protein folding and function, to antagonize aggregation-related proteotoxicity and ensuing protein loss-of-function or protein misfolding-diseases such as the neurodegenerative diseases Alzheimer's, Huntington's or Parkinson's disease, as well as to safeguard cellular proteostasis and proteome balance.
Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. Across different cancer types, tumor-associated blood vessels have been discovered to differ significantly from normal blood vessels in morphology, gene expression, and functionality in ways that promote cancer progression. There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors.
