ANN ARBOR, Mich. - Just like the smallest flaw in Achilles' strength led to his downfall, the smallest proteins produced by cancer cells may someday give doctors new ways to find tumors earlier than ever, determine quickly how malignant they are and target them with customized therapies.
Now, a five-year, $10 million effort at the University of Michigan Comprehensive Cancer Center will take aim at this potential vulnerability using the latest technology and biomedical knowledge.
The multidisciplinary research effort is among the first in the world to go after cancer in this new way. It will systematically study the proteins that tumors make, the genes that instruct the cells to make them, and the subtle differences among proteins made by different types of tumors.
The U-M research will focus at first on colon, lung and ovarian cancers, which have defied scientists' efforts to find characteristics that can distinguish deadly forms from less malignant varieties. Eventually, the approach should be applicable to other kinds of cancer, notably breast, prostate and childhood tumors.
The effort will be led by U-M pediatric oncology professor Samir Hanash, M.D., Ph.D., and funded by two grants from the National Cancer Institute.
The funding will allow a U-M team and their U.S. and international partners - including medical, computer, chemistry and information specialists - to develop specialized rapid-analysis technology that can look at all the genes and proteins in tumor cells taken from cancer patients.
The project will build on work in the U-M's Medical School and Chemistry Department to identify proteins released by tumors or found on their surfaces. Some of these proteins are candidates to become biomarkers, early indicators or Achilles' heels for different types of tumors.
"This cutting-edge technology has the potential to yield real breakthroughs in cancer research," says Hanash. "We hope to further understand the molecular character of tumors so we can detect them while they are small and predict their behavior, including the likelihood that they'll respond to various treatments."
Adds U-M Medical School Dean Allen Lichter, "This research will lead to dramatic new ways to approach cancer. By detecting the chemical signatures of cancers, we will be able to make diagnoses much earlier and be able to tell which cancers are likely to act aggressively and need early treatment. We are proud to use our research strength to help speed the pace of discovery in the important research area."
The molecular approach to cancer research has become possible in recent years due to advances in the study of proteins and DNA, the development of new computerized technology for medical research, and the cooperation of hospitals to save and study tumor tissue from cancer patients.
The wide search for biomarkers is a new concept made possible only through the increased understanding of how proteins function in the body, and how genes control the production of those proteins in both normal and cancerous cells. In turn, the understanding of human genes has accelerated in recent years due to the efforts of the federal government's Human Genome Project to find and sequence every bit of DNA in the human body.
The U-M protein-gene project will look at tumor genes and their proteins simultaneously, starting with advanced-stage colon tumors, a type of ovarian cancer and two kinds of lung cancer.
The researchers expect to analyze more than 1,000 different proteins from each kind of tumor, both by finding their distinguishing physical characteristics and establishing how abundant they are. Simultaneously, they will use genetic analysis tools known as DNA microarrays, as welll as other DNA analysis technology and highly sensitive, high-speed software previously developed by Hanash's group to determine which genes in a tumor cell are altered, and which have been switched "on", or expressed, to create proteins.
All of this information about proteins and genes will help establish a better way to classify tumors and predict which ones will be most dangerous. That kind of knowledge can help doctors plan treatment, and allow researchers to develop treatments that attack specific kinds of tumors.
The biomarker portion of the project, meanwhile, will look for those tumor proteins - or leftover immune responses to them - in blood. Past research has shown that the body can react to new cancer cells as if they were invading organisms, and that this immune response leaves behind tumor-specific antibodies that can be detected in the bloodstream long before a tumor has grown large enough to be found. Or, the blood might contain proteins that tumor cells have secreted, or released, as part of their growth.
The U-M researchers will search for these biomarkers and develop tests for them. Their effort could give doctors a head start in finding cancer while it can still be treated effectively, and in determining exactly what kind of cancer a patient has so that they can plan for treatment.
The research will rely in part on the Michigan-Ohio Community Clinical Oncology
Program, directed by U-M Medical School professor Dean Brenner, M.D., which
develops innovative strategies for cancer prevention.
With Hanash and Brenner, other U-M researchers on the project include:
- Co-principal investigators David Beer, Ph.D., associate professor, Medical School; Kathleen Cho, M.D., associate professor, Medical School; Eric Fearon, M.D., Ph.D., professor, Medical School; Thomas Giordano, M.D., associate professor, Medical School; Jeremy Taylor, M.D., professor, School of Public Health and Medical School
- Co-investigators Vicki Baker, M.D., professor, Medical School; Laura Beretta, Ph.D., assistant professor, Medical School; Stephen Gruber, M.D., assistant professor, Medical School and School of Public Health; Sharon Kardia, Ph.D., assistant professor, School of Public Health; Rork Kuick, project coordinator, Medical School; David Lubman, Ph.D., professor, College of Literature, Science & the Arts
- Co-investigative collaboratorThomas Glover, Ph.D., associate professor, Medical School