Multiple Myeloma SPORE Grant
Awarded: September, 2003
Awardees: Dana Farber Cancer Institute in collaboration with Mayo Clinic
Amount: $2.7 million over five years
Mayo Clinic staff are principal investigators for Projects 4 and 5 out of the 5 projects funded by the grant. The SPORE grant also funds a Tissue Core which is led by Mayo Clinic.
Mayo Clinic Cancer Center, in association with Dana Farber Cancer Institute, received the only Specialized Program of Research Excellence (SPORE) grant from the National Institutes of Health for research on multiple myeloma in 2003.
Multiple myeloma is a cancer of plasma cells that affects 3 in 100,000 people each year. Plasma cells are a type of white blood cell present in bone marrow — the soft, blood-producing tissue that fills in the center of most bones. The disease is called multiple myeloma because myeloma cells can occur in multiple bone marrow sites in the body.
Plasma cells usually make up less than 5 percent of the cells in bone marrow. But in multiple myeloma, a group of abnormal plasma cells (myeloma cells) multiplies, raising the percentage of plasma cells to more than 10 percent of the cells in bone marrow.
Uncontrolled plasma cell growth can damage bones and surrounding tissue. It can also cause anemia and kidney problems, and interfere with the immune system's ability to fight infections by inhibiting the body's production of normal antibodies.
The exact cause of multiple myeloma isn't known. Multiple myeloma is not contagious, and it is not inherited. The average age of a person with the disease is about 70.
Mayo Clinic-led SPORE grant projects include:
Project #4: Novel Therapeutics Targeting Genetic Abnormalities in Multiple Myeloma
Project Leader: P. Leif Bergsagel, M.D., hematologist, Mayo Clinic Arizona
Developing targeted therapies for myeloma, based upon the genetic abnormalities present in each patient.
Project #5: Molecular Markers of Evolution from MGUS to Multiple Myeloma
Project leader: Rafael Fonseca, M.D., hematologist, Mayo Clinic Arizona
Award amount: $1,110,142 over 5 years
Gaining a better understanding about genetic and chromosomal abnormalities that place people with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) at higher risk for multiple myeloma.
Tissue Core
Principal Investigator: Philip Greipp, M.D., hematologist, Mayo Clinic Rochester
This component of the SPORE grant receives, processes, stores, archives and distributes serum, bone marrow cells, DNA and RNA for investigators participating in the SPORE. The Tissue Core also provides an independent, current and quickly searchable database of clinical and lab results and archived biospecimens.
Career Development Award
Awarded to: Shaji Kumar, M.D., hematologist, Mayo Clinic Rochester, January, 2006
Endothelial cell - tumor cell interaction in multiple myeloma: A potential therapeutic target
Understanding the biological basis of increased blood vessels (angiogenesis) in the bone marrow of patients with multiple myeloma.
In addition to these research projects, the SPORE grant provides funding for a developmental research program for pilot grants to explore innovative research ideas, and a career development program to nurture the next generation of cancer scientists.
Multiple Myeloma SPORE Grant
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Project #4: Novel therapeutics targeting genetic abnormalities in multiple myeloma
Project Leader: P. Leif Bergsagel, M.D., hematologist, Mayo Clinic Arizona
Previous Mayo research has shown that multiple myeloma (MM) is characterized by frequent (70 percent) chromosome translocations involving the immunoglobulin (Ig) genes. Ig genes provide the code for developing proteins that function as antibodies when the body's immune system is triggered. Translocations (a type of mutation) occur when a segment of DNA from another chromosome is transferred to a new position adjacent to the Ig genes. The genes on this new segment of DNA are inappropriately expressed by antibody producing plasma cells and this leads to the development of multiple myeloma. Researchers have identified the oncogenes (genes that cause the transformation of normal cells into cancer cells) on four recurrent chromosomes that are involved in these translocations.
The central goal of Project #4 is to develop targeted therapies for myeloma, based upon the genetic abnormalities present in each patient. The first phase of this research involves validating the hypothesis that oncogenes activated by chromosome translocations play critical roles in the development of MM and thus represent attractive targets for new drug therapies. Mayo researchers propose to study this process in human myeloma cell lines and to develop testing that will screen for drugs that inhibit the function of these targets.
Within Project #4, Mayo researchers have three specific aims:
Aim 1: Focus on one of the four oncogenes, FGFR3, and tests whether it is an appropriate target in both in cell and animal models. FGF3 is translocated in about 15 percent of patients, who respond very poorly to currently available therapies. FGFR3 functions as a tyrosine kinase, an enzyme that causes cells to grow, multiply and spread. Researchers will screen tyrosine kinase inhibitors for activity against FGFR3.
Aim 2: Use a panel of human myeloma cell lines and mouse models to determine the effects of inhibiting other genetic targets, and identify alternative markers for target inhibition.
Aim 3: Conduct a clinical study enrolling 30 patients. Currently underway, this study targets FGFR3 with an FGFR3 kinase inhibitor called CHIR-258. Researchers will then evaluate the effectiveness of additional agents that specifically target pathways associated with genetic mutations in myeloma.
Collaboration
The Project #4 research team includes: Rafael Fonseca, M.D., Mayo Clinic Arizona; Marta Chesi, Mayo Clinic Arizona; Keith Stewart, M.B.Ch.B., Mayo Clinic Arizona; Philip Greipp, M.D., Mayo Clinic Rochester; and Vincent Rajkumar, M.D., Mayo Clinic Rochester.
CHIR-258, the drug tested in Aim 3 of this project, is an orally administered kinase inhibitor developed by Chiron Corporation.
Multiple Myeloma SPORE grant
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Project #5: Molecular markers of evolution from MGUS to multiple myeloma
Project leader: Rafael Fonseca, M.D., hematologist, Mayo Clinic Arizona
Multiple myeloma (MM) sometimes develops from the pre-cancerous condition called monoclonal gammopathy of undetermined significance (MGUS). This condition, like multiple myeloma, is marked by the presence of an abnormal protein (so called "M protein" or "M spike") produced by abnormal plasma cells in your bone marrow. In MGUS however, the amount of the abnormal cells inside the bone marrow isn't high enough to cause harm, and no damage to the bones occurs.
MGUS and an early form of multiple myeloma (MM) called smoldering multiple myeloma (SMM) are pre-cancerous stages of MM. Most patients do not progress to overt myeloma and can live a symptom-free life. However at least 1 percent of people with MGUS and SMM go on to develop MM each year.
Multiple chromosomal and genetic abnormalities have been described in MGUS, SMM and MM, and may play important roles in this progression. The goals for Project #5 include:
- To better understand which genetic and chromosomal abnormalities place people with MGUS/SMM at higher risk for MM.
- To better understand which specific locations on genes, where a gain or loss of DNA segments has occurred, are most strongly associated with the progression to MM.
Hypothesis 1: Genetic and chromosomal abnormalities present in the plasma cells of MGUS/SMM patients at diagnosis result in different risks for progression to MM. Other clinical laboratory markers (such as PC labeling index (PCLI), bone marrow (BM) plasmacytosis, b 2 microglobulin and concentration of the monoclonal protein) are likely higher in those MGUS patients with abnormalities that put them at higher risk for progression to MM. New markers, such as elevated levels in a test called the serum free light chain, also suggest a higher risk of transformation to myeloma. Mayo researchers hope to refine this model and use it to determine a patient's actual risk for disease progression.
Aim 1: To test MGUS samples for the presence of specific genetic alterations that will result in a higher risk for progression to myeloma. Mayo researches will use a slide-based test (called interphase FISH) that is capable of detecting abnormal fusions (called translocations), deletions or gains of extra copies of abnormal chromosomes (called trisomies).
Hypothesis 2: Chromosomal regions or recurrent gain and loss of DNA segments harbor genes that, when activated or de-activated, are responsible for the progression from MGUS/SMM to MM. Identifying the targets of such alterations will yield clues about the mechanisms that trigger this progression to MM.
Aim 2: To generate a genome-wide profile of regional gains and losses in MGUS and MM to identify the loci that are relevant to MM genesis, progression and prognosis. Using a technique called array based comparative genomic hybridization, Mayo researchers can detect (in one single experiment) whether any one of 40,000 points in genetic information is different or duplicated. In some cases, gains (where three or more copies of DNA segments exist) or losses (one or no copies) will lead to genetic changes that give rise to cancer.
Collaboration
Other members of the Project #5 research team include: P. Leif Bergsagel, M.D., and Keith Stewart, M.B.Ch.B., Mayo Clinic Arizona; and Philip R. Greipp, M.D., Shaji Kumar, M.D., and Vincent Rajkumar, M.D., Mayo Clinic Rochester. In addition to working with Dana Farber Cancer Institute, Mayo Clinic researchers have a very active collaboration with researchers at the Translational Genomics Research Institute (TGen), including Jeffrey Trent, Ph.D., John Carpten, Ph.D., Seungchan Kim, Ph.D., and Michael Bittner, Ph.D; and with Agilent Technologies for the research involving comparative genomic hybridization.
Mayo Clinic Cancer Center is a National Cancer Institute (NCI) -designated Comprehensive Cancer Center, a national recognition of excellence in education, research and treatment of cancer. The Pancreatic Cancer SPORE continues a tradition of cutting-edge research across Mayo's three locations in Arizona, Florida and Minnesota. Mayo Clinic has also been awarded SPOREs in brain, breast and prostate cancer, and shares SPOREs for lymphoma and myeloma with other institutions.
The NCI established the SPORE program in 1992 to promote interdisciplinary research and speed the transition of basic research findings from the laboratory to applied settings involving patients and populations. The program's goal is to bring into clinical care novel ideas that have the potential to reduce cancer incidence and mortality, improve survival and enhance patients' quality of life. Laboratory and clinical scientists work collaboratively to plan, design and implement research programs focused on cancer prevention and control, early detection, diagnosis, treatment and survival.
For more information on SPORE grants, visit the National Cancer Institute at www.nci.nih.gov. To find out more about Mayo Clinic research, visit www.mayo.edu. For more information about multiple myeloma treatment at Mayo Clinic, visit www.mayoclinic.org/multiple-myeloma/index.html.
