Dr Rajeev Gupta, a Leukaemia Research-funded consultant haematologist, has uncovered that the gene Nephroblastoma Overexpressed ( Nov ) plays a key role in regulating the production of blood from stem cells. The work, which was carried out in the MRC Molecular Haematology Unit, is published in the journal Science.
Stem cells are vital for normal blood production and are used in transplants in patients with leukaemia and other blood cancers.
Dr Gupta said: The Nov gene makes a type of protein similar to a hormone. Such molecules often play important biological roles, and so four years ago when we first found that the gene is active in blood cells, including stem cells, we decided to study it in more detail. Switching off the Nov gene reduces stem cell activity and the production of blood cells falls. Conversely, when we added Nov protein to stem cells we increased the production of blood cells. This implies that the gene plays a key role in the regulation of blood production from stem cells. Professor Tariq Enver, who leads the team at the MRC Molecular Haematology Unit in Oxford, said: Of course genes never work alone and the next step of our work will focus on identifying the genetic pathway through which Nov works, i.e. finding out who Nov's friends are. Once these interactions have been established and we know whether Nov is the best gene to work with, we will be another step closer to devising better therapies for leukaemia patients.It is hoped that the discovery may in the future lead to Nov or a related gene playing a clinical role in stem cell transplants particularly in the context of cord blood.
Cord blood donations contain sufficient numbers of stem cells to treat children but single donations are generally not enough for use in adults. We are actively pursuing whether Nov can amplify stem cells in cord blood. If so, cord blood could potentially be used more widely for the treatment of adult patients, said Professor Enver. Dr Gupta added: Nov and related genes certainly show great potential to play a role in future improvements for cancer patients treated with stem cell-based therapies, such as bone marrow transplants. We are actively working to transfer our laboratory work to the bedside.
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The current study showed that, in some of the resistant cells, ERBB3 is activated by amplification of a different oncogene called MET, in essence bypassing the blockage of EGFR. Analysis of samples from patients whose tumors became resistant after initially responding to Iressa revealed that MET was amplified in resistant samples from 4 of 18 patients. Although treating resistant cell lines with either Iressa or a MET inhibitor did not stop tumor growth, treatment with both agents did induce cell death.
"This method of reactivating the EGFR signalling pathway with MET may be a common resistance mechanism in other therapies that target receptors of the ERBB family, which are used against breast cancer, colon cancer, head and neck cancer, and the brain tumor glioblastoma multiforme," says J'nne, who is an assistant professor of Medicine at Harvard Medical School (HMS). Engelman is an HMS instructor of Medicine.
"Our results suggest that, when patients' tumors become resistant, repeat biopsies to identify which resistance mechanism is involved will be critical and could help us develop effective therapies for those resistant tumors," adds co-author Lewis Cantley, PhD, of the Beth Israel Deaconess Medical Center.
To that end, the investigators are working on a research protocol for combined treatment with FDA-approved EGFR inhibitors and with MET inhibitors, which are in preapproval trials against other types of cancer. They also plan to analyze a larger number of resistant samples to get a clearer idea of the frequency of this resistance mechanism.
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