The Multiple Myeloma Research Foundation has awarded $2.25 million to three universities to find protein biomarkers leading to possible therapeutics for the disease, making it the foundation’s biggest award yet for proteomics-directed research.
Under the grant, the three schools — the University of Michigan, the University of Arkansas for Medical Sciences, and Indiana University — will each receive $750,000 over three years.
While the foundation, founded in 1998, has funded individual proteomics research, the award announced last week is the largest investment it has made in the field and marks the first time that it has funded such an effort involving multiple collaborators, said Louise Perkins, director of research for the foundation.
The foundation has been providing funds for ongoing genomic work into multiple myeloma using analysis techniques such as gene-expression profiling, comparative genomic hybridization, and single-molecule sequencing, Perkins said. It said it now felt it was time to explore proteomics technologies to complement the genomics research.
“We want [our patients] to be able to have the right drugs at the right time,” Perkins said. “And that’s where we feel that laying the groundwork in the area of genomics and proteomics will help to set a framework for such a personalized medical approach.”
In spite of that, the decision to move into the proteomics field was not met with unanimous approval within the foundation. Because a “robust” protein biomarker, paraprotein, already exists for multiple myeloma, Perkins said there was internal debate within the group about the need to find additional biomarkers.
“’Why do we need a biomarker? We have a perfectly good protein-based biomarker in myeloma,’” she said some at the foundation said. “Yet, I think we all understand that by looking at not just why cells do things, which is, in my mind, one way of looking at genomics, but how they go about doing it, which is proteomics, you get a completely different look at what is important, why certain myeloma patients are responsive to therapies or resistant to therapies.”
Multiple myeloma is cancer of the plasma cell and has no known cure. According to the foundation, an estimated 19,900 Americans were diagnosed with the disease in 2007, and 10,970 died from it. Roughly one in three patients with the disease will survive five years after diagnosis, giving it one of the lowest five-year survival rates of all cancers.
Carole Asher, grants coordinator for MMRF, said the foundation chose the three universities after it performed a general search for leading proteomics researchers. She suspected most of them would not be interested in pursuing a project in multiple myeloma biomarkers, either because they were busy with other work or because multiple myeloma is not an area they study. Those researchers, though, were able to direct the foundation to colleagues who would be interested.
All three universities will be using mass spectrometers for their research. While MMRF didn’t specifically plan it that way, “we wanted to actually avoid lower-throughput technologies that were going to slow things down,” Perkins said.
At the University of Arkansas, two main goals will be driving the work, said Rick Edmondson, associate professor of medicine and coordinator of the school’s work on the grant. His lab was outfitted with a Thermo Fisher Scientific LTQ Orbitrap in September.
“Realistically, when we’re done, we will be satisfied to be able to say, ‘Looking at samples obtained from myeloma patients involved in several clinical studies, we understand the protein profiles of those patients and have at least some initial relationship between those profiles and response and resistance to therapies.’”
One will be to look at protein expressions between healthy patients; patients with multiple myeloma; and patients with monoclonal gammopathy of undetermined significance, or MGUS, who don’t develop the disease. While the presence of MGUS is considered a precursor to developing multiple myeloma, only about 1 percent of patients with MGUS develop multiple myeloma, Edmondson said.
His team is “not just comparing the three, but also taking into account all the clinical information that we have to correlate,” he said. “We’re looking for where we can find correlations with the gene array data, as well as disconnects. Preliminary data shows a very high degree of correlation between protein expression and gene expression … but where we’re interested is where we see a disconnect.
“We think that this can be an area where perhaps microRNA is playing a role in altering transcription from gene expression. We also have array CGH data so we’re looking at chromosomal abnormalities,” Edmondson said.
The second aim of his team’s research is to analyze plasma cells from patients with the disease to profile how protein expression changes from the time a patient is in clinical remission to when a patient relapses. Virtually all patients with multiple myeloma who go into remission eventually relapse, Edmondson said.
“We hope to see changes at the molecular level that will give us some insights into the underlying biology of chemo-resistance,” he said.
At Indiana University, a team led by Mu Wang, director of proteomics at the university’s School of Medicine, will be using a conventional label-free quantification platform for unbiased biomarker discovery followed by targeted validation.
While his lab, equipped with seven mass spectrometers, has done extensive work in cardiovascular diseases and breast and ovarian cancers, this will be the first time it is researching multiple myeloma.
Rather than using plasma, his team will be using sorted myeloma cells and comparing them with normal cells to identify abnormal proteins.
“Our platform is going to mainly deal with quantitative changes, which are expression changes, not post-translational modifications,” Wang said. The IU team will also be working with members from Purdue University during the later stages of its research. Fred Regnier will use his expertise in bioCD, a protein-array technology, for validation work, and Xiang Zhang will provide help with bioinformatics, Wang said.
And at the University of Michigan, in addition to trying to identify proteomic differences between myeloma patients and controls, a goal will be to detect protein signatures that can identify subsets of the disease, in general, and signatures that can predict response, or the lack of, to therapies such as Velcade and Revlimid, specifically, said Andrzej Jakubowiak, associate professor of internal medicine at the University of Michigan Health System, and co-director of the MMRF project at the university with Arun Sreekumar, an assistant professor at the university’s center for translational pathology.
From the gene-expression profiling research, there is evidence of heterogeneity in multiple myeloma, Jakubowiak said.
“An overall goal is to not start a patient on a regimen, which is unlikely to produce good results, [but] rather make directed individualized therapy from the get-go. And we think that a proteomics platform can help in this regard better than anything else, for its potential simplicity,” he said.
All three institutions will start off by validating each other’s analysis on the same cell using their different proteomic platforms. Then, after they have begun doing their own research, the institutions will cross-validate each others’ findings.
The researchers are also expected to eventually publish a paper based on their findings.
“Realistically, when we’re done, we will be satisfied to be able to say, ‘Looking at samples obtained from myeloma patients involved in several clinical studies, we understand the protein profiles of those patients and have at least some initial relationship between those profiles and response and resistance to therapies,’” Perkins said. “That will be certainly the key deliverable.”
This week, the foundation also awarded $200,000 to Jetze Tepe from Michigan State University for a phosphoproteomics study. The award is for two years. Specifically, Tepe’s work will look at the addition of phosphate groups at specific positions on the protein p65 and changes that may occur as a function of disease stage, chemotherapeutic treatment, and treatment resistance.