NEW YORK (GenomeWeb) – A new research institute at the UK's University of Manchester is looking to establish a regime of proteomics-based drug target and biomarker identification, not only for oncology but also for a range of diseases including lupus, arthritis, and schizophrenia.
The Stoller Biomarker Discovery Centre opened last month, in partnership with Sciex and funded by £18 million ($23.5 million) from the Stoller Charitable Trust and the UK's Medical Research Council.
It's the largest clinical proteomics research institute in Europe, Stoller Centre Director Tony Whetton, also a professor at Manchester, told GenomeWeb. "[The Medical Research Council] looked at our body of work in mass spectrometry as applied to biomedicine and decided on our proposal for industrialization of proteomics in biomedical research," he said.
With more than a dozen mass spectrometers from Sciex, including the TripleTOF 6600 systems with SWATH acquisition, QTRAP 6500+ systems, and the Sciex Lipidyzer Platform, the Stoller Centre will also feature liquid chromatography and automated sample preparation technology from Sciex, Danaher, and Beckman Coulter.
Right before the Stoller Centre officially launched, a team of scientists from Manchester and the University of Glasgow, led by Whetton and Glasgow clinical oncologist Thessa Holyoake, published a study in Nature that exemplifies the pathway from proteomics to clinical trials that many Stoller Centre projects will follow: proteomics, followed by informatics to reveal potentially interesting biology and potential drug targets or biomarkers, recapitulation in a model system, and finally clinical trials.
The study used mass spec-based proteomics to try to discover how chronic myelogenous leukemia (CML) stem cells were able to survive in the face of otherwise successful targeted tyrosine kinase inhibitor therapies for the disease. "By comparing them to normal cells, we hoped to find the Achilles heel of the CML stem cells that maintain the disease even in the face of TKI treatment," Whetton said.
Using proteomic data generated with isobaric tagging tandem mass spectrometers, the scientists were able to find a protein signature that differentiated CML stem cells from normal ones.
Informatics analysis by Glasgow's Lisa Hopcroft helped identify the upstream regulators for the particular proteins. The researchers found two proteins, p53 and c-Myc, that are well known in oncology.
But because they are so-well known, the researchers were afraid that the two of them wouldn't be specific enough to explain the biology of their CML stem cells. "We had to be sure this wasn't a protein signature you saw with every kind of cancer," Whetton said. "So we looked at other data sets and demonstrated to our satisfaction that this particular dual node wasn't commonly found in a whole raft of different cancers."
A further look at transcriptomes in the cells confirmed that the RNA signatures matched the protein signatures. The scientist could then move on to the question of whether they could use this information to selectively kill the CML stem cells. They found that a combination of drugs targeting p53 and c-myc were able to effectively kill cells in an animal model of the disease as well as in xenograft transplants into mice.
Holyoake is developing clinical trials to test these findings "as we speak," Whetton said. If the clinical trials are successful, translating the proteomics research into clinical technology, it would complete a story that the Stoller Centre will hope to replicate many times over in the future.
With funding to purchase 13 mass spectrometers and a mandate to focus on many other kinds of diseases, it could very well succeed.
Other blood cancers are an area of immediate interest. "The stem cells sit at the heart of CML and in order to cure the disease we need to eradicate the cells," Whetton said. "There are other leukemias where you can find at their heart a stem cell," such as some acute myeloid leukemias. He said his lab has also looked at polycythemia vera, a neoplasm where the bone marrow makes an excess of red blood cells.
"In several cases we've found pathways which can be potentially targeted for treatment strategies in the myeloproliferative neoplasms," he said.
But the Stoller Centre is not just about cancer and it's not just about proteomics. Whetton said Stoller projects will be plugged into the informatics and genomics resources at Manchester. The center plans to infuse electronic healthcare records with 'omics data sets.
And the range of diseases will include autoimmune diseases such as psoriasis, arthritis, lupus, and mental health disorders such as schizophrenia.
Whetton has already secured funding to run proteomic analyses on samples from psoriasis, arthritis, and lupus cohorts, work that should start in a couple of months.
In addition to drug targets, Stoller expects to live up to its name and churn out new biomarker signatures.
"As precision med rolls forward, there will be a need for companion diagnostics and signifiers for a response to therapy," Whetton said. "One thing we'll be doing to a great extent is to look in plasma and serum samples for biomarkers for specific diseases. Without biomarkers we won't be able to identify which people will benefit from certain medicines, so this new center underpins everything we're doing in precision medicine in Manchester and beyond."