Posted by rob on March 25, 2005 under Uncategorized | 
Myeloproliferative Disorders Associated with Tyrosine Kinase Mutation
Researchers from the UK have identified an acquired single point mutation as the probable cause of more than half the cases of myeloproliferative disorders. The details of this study appeared in the March 19, 2005 issue of the Lancet.
Myeloproliferative disorders currently include polycythemia vera, essential thrombocytosis and idiopathic myelofibrosis. The cause or causes of this group of diseases is unknown. In the past, patients with chronic myeloid leukemia (CML) were included in this group of diseases, but cytogenetic and molecular studies revealed unique cause of CML. Now a similar phenomenon may be occurring with other myeloproliferative disorders.
JAK2 is a tyrosine kinase that has a major role in cell proliferation. The hypothesis of this study was that mutated JAK2 could be responsible for myeloproliferative disorders. Researchers in the study performed molecular genetic studies in 73 patients with polycythemia vera, 51 with essential thrombocytosis, and 16 with idiopathic myelofibrosis. They found that 97% of patients with polycythemia vera had a sincle acquired mutation of JAK2 cytoplasmic tyrosine kinase. The same mutation was present in 57% of patients with essential thrombocytosis and 50% of patients with idiopathic myelofibrosis. They also found this mutation is all erythropoietin-dependent erythroid colonies and present in multipotent cells giving rise to both erythroid and myeloid cells. These authors suggest that identification of mutated JAK2 will assist in classification of myeloproliferative disorders and may provide insight into pathogenesis.
Comments: This study is important, as it could lead to specific therapies for myeloproliferative disorders similar to that observed with the development of Gleevec® for the treatment of CML.
Reference: Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. The Lancet. 2005;365:1054-1061.
Myeloproliferative Disorders Associated with Tyrosine Kinase Mutation
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Genomic cancer therapy to become reality
25/03/2005 – The wealth of new targets identified from genomics and the discoveries made in the molecular pathology of cancer will give rise to a new generation of cancer treatment, moving one step closer to individualised, target therapy.
In a talk given by Paul Workman, of the Cancer Research UK centre for cancer therapeutics he said that scientists were becoming increasingly optimistic about the future of cancer treatment. While no one expects a cure for cancer in the next decade, he thought it would be demoted to the status of a chronic disease that people can live with.
Cancer drug therapy is undergoing a transition from the previous pregenomic cytotoxic era to the new postgenomic era. Workman predicted that future mechanism-based therapeutic agents would be designed to act on molecular targets that are involved in the malignant progression of human cancers. Such agents would show greater therapeutic selectivity for cancer versus normal cells.
Speaking at the Drug Discovery Technology conference in London last week, Workman identified the features and potential advantages of postgenomic cancer drug development.
He focused particularly on new molecular targets driving the molecular pathology and progression of human cancers, providing an intellectual framework for discovering new drugs with improved efficacy and selectivity.
Workman also identified high throughput screening, structural biology, combinatorial chemistry and microarrays as new technology applications set to further accelerate drug discovery and development.
“Target selection for drug discovery is essentially a matter of judgment, involving a large measure of risk assessment. There will be greater confidence in a target for which all the criteria are met, but this may take several years, by which time any competitive position in the field may be lost,” he said.
Use of pharmacokinetic and pharmacodynamic endpoints was a primary advantage singled out. They had the potential to enhance the rationality and hypothesis-testing power of early clinical trials, provides the basis for early go/no go decisions, and reduces the risk of expensive late stage failure.
“The development of diagnostic, prognostic and pharmacogenomic biomarkers will allow the targeting of individualised treatments to patients most likely to benefit,” he commented.
There is already a glut of novel cancer drugs that act on the cancer genome and while these drugs currently remain one of the most potent weapon medicine has against cancer, so much more can be done to reduce the toxic effects that accompany such treatment.
The majority of current cancer drugs are cytotoxic agents that exert its effects on proliferating cells, both normal and cancerous. This is the case even for recently successful drugs such as irinotecan in colorectal cancer, taxanes in breast, ovarian and lung cancer and carboplatin in ovarian cancer. Since cytotoxic agents have a selectively ‘antiproliferative’ action rather than selective ‘anticancer’ properties, the therapeutic window for tumour versus normal tissue is modest at best
In the industrialised world, one in three people develop cancer and one in four still die from it. World-wide cancer incidence is predicted to double from 10 to 20 million per annum and the death rate is predicted to increase from 6 to 10 million by 2020.
Gleevec is a small molecule that is approved in the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours via inhibition of the Bcr-Abl and c-Kit receptor tyrosine kinases respectively.
Herceptin is a humanised antibody approved in ErbB2 positive breast cancers while Iressa is a small molecule inhibitor of the EGF receptor tyrosine kinase approved in non-small cell lung cancer and active in other tumour types.
Workman pointed to 17AAG, a small molecule inhibitor of the Hsp90 molecular chaperone, which showed early promise in phase I clinical trials.
The worldwide market for oncology drugs is predicted to be worth at least $15 billion (€11.6 billion) by 2002. Indeed, as a result of the ageing population and improvements in the treatment of other chronic ailments such as cardiovascular diseases, and in addition taking into account the remarkable breakthroughs in our basic understanding of the disease and the technological revolutions that are accelerating the process of drug discovery.
Genomic cancer therapy to become reality
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A Mute Swan flies above the Djurbrunnsgaards canal in Stockholm as migratory birds are on the move with the arrival of Spring.
