SPORE Grant Boosts Leukemia Research
The National Cancer Institute (NCI) has awarded The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute a five-year, $11.5 million Specialized Program of Research Excellence (SPORE) grant to study and treat leukemia.
The SPORE grant represents a milestone for the leukemia program at Ohio State, which is only the
second recipient of such an NCI grant directed at leukemia research. Titled “Experimental Therapeutics of Leukemia,” the grant focuses on translational research to improve the understanding of leukemia cause, risk stratification and therapy.
Principal investigator John Byrd, MD, (above left) and co-principal investigators Clara D. Bloomfield, MD, (above center) and Guido Marcucci, MD, (above right) helped plan and apply for this award, which encompasses laboratory and clinical investigation in acute myeloid leukemia, acute lymphoid leukemia and chronic lymphocytic leukemia. The grant team includes several prominent senior investigators at Ohio State who have worked
together for years to improve
prognostic factors and treatments for acute and chronic leukemias.
“This award will help a team of accomplished cancer researchers engage in bedside and laboratory translational research of adult
leukemia with the goal of improving clinical outcomes for patients,” says Michael A. Caligiuri, MD, director of Ohio State’s Comprehensive Cancer Center and CEO of The James. The grant supports five research projects, each led by Ohio State cancer center researchers, including Byrd, Bloomfield, Caligiuri and Marcucci, along with Albert de la Chapelle, MD, PhD, William Blum, MD, Michael Grever, MD, and Robert Lee, PhD.
Accompanying these five projects are five cores that provide a SPORE leukemia tissue bank and services for biostatistics, biomedical informatics, medicinal chemistry and administration and operations.
The grant also supports a career development program geared toward young women and minority researchers, and a developmental research program to recruit innovative pilot projects that, if successful,
may later become part of the SPORE.
Ohio State Cancer Drug Begins Clinical Testing
A targeted, oral, anticancer drug developed by cancer researchers at The Ohio State University is being tested in a phase I clinical trial to assess its safety and early evidence of activity. The drug, AR-12, has inhibited solid tumors and lymphoma in animal studies.
Patients with advanced or recurrent breast, colon, lung or prostate cancers or lymphoma who have not responded to previous chemotherapy are eligible for the trial, says principal investigator James Thomas, MD, PhD, director of the Clinical Trials Office at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC-James). Ohio State is one of three sites accepting patients to this trial.
Michael A. Caligiuri, MD, director of the OSUCCC and CEO of The James, says Ohio State researchers worked almost a decade to refine this novel treatment mechanism. “This is a ground-breaking achievement for cancer research at Ohio State because it marks the first time a therapeutic drug developed by our scientists will be tested in cancer patients,” says Caligiuri.
OSUCCC-James researcher Ching-Shih Chen, PhD, worked with cancer and pharmacy colleagues at Ohio State to develop the small-molecule agent, originally called OSU-03012. The agent is being developed as AR-12 by Arno Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on oncology therapeutics.
“The new agent inhibits PDK-1 and PI3k/Akt pathways, a funda-mental signaling point in cancer cells, making AR-12 potentially effective in a wide range of cancer types,” says Chen, a professor of Pharmacy and Internal Medicine.
Chen and colleagues used celecoxib (Celebrex), a nonsteroidal anti-inflammatory drug, to construct AR-12, which triggers cancer cells to self-destruct. In 2004, the agent was accepted by the National Cancer Institute’s Rapid Access to Intervention and Development program, which facilitates the development of promising experimental drugs.
BY THE NUMBERS
Mathematics taking guesswork out of tissue transfer
Plastic surgeons at The Ohio State University are turning to mathematics to ensure that live tissue selected to restore damaged body parts has enough blood and oxygen to survive the surgical transfer.
In the world’s first published mathematical model of tissue transfer, mathematicians have used differential equations to determine which tissue segments selected for transfer from one part of the body to another will receive enough
oxygen to survive.
The most common transfers are used to restore body parts destroyed by cancer and trauma. Researchers say reliable mathematical modeling of the blood supply and oxygen in tissue segments will reduce failures in reconstructive surgery.
To obtain tissue for reconstructive surgery, surgeons cut away a tissue flap fed by a set of perforator vessels –an artery and vein that travel through underlying muscle to support skin and fat. Surgeons generally agree that vessels at least 1.5 millimeters in diameter are required to sustain oxygen flow in the flap.
“That guideline is based on experience, trial and error. We need a more precise ability to determine the necessary blood vessel size,” says Michael Miller, MD, professor of Surgery CCC-James and director of the Division of Plastic Surgery at Ohio State. “I’m convinced there’s a relationship that’s probably very predictive between diameter and blood flow in the vessel and the ability of the tissue to survive based on that.”
The mathematicians have shown that, under certain relationships between flap size and perforator vessel diameter, the oxygen level in the flap remains above 15 percent of normal, ensuring a successful transfer.
“This is still just a concept, but this initial system of five differential equations gives us a range between flap size and the required diameter of the supporting artery that would ensure survival,” says Avner Friedman, PhD, a Distinguished University Professor of Mathematical and Physical Sciences at Ohio State.
Published in the July 21, 2009 issue of the Proceedings of the National Academy of Sciences.
Oxygen distribution in artery blood (A) and in tissue (B) after 4 hours of tissue reperfusion in the case of the small tissue flap (dimensions: 3 cm × 15/8 cm × 1 cm). In this case, the perforator artery is successful in oxygenating the flap, as no fat necrosis develops.
UNDER THE INFLUENCE
Normal cells aid tumor progression
A study led by Ohio State University cancer researchers is the first to show that gene alterations in stromal fibroblasts can foster tumor growth. This work provides the first mouse model that accurately represents the tumor microenvironment found in human breast cancer.
Co-principal investigators Michael Ostrowski, PhD, and Gustavo Leone, PhD, both of The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and their colleagues eliminated the Pten tumor suppressor gene from stromal fibroblasts present in a mouse epithelial mammary tumor.
Pten is a key regulator of cell metabolism that is lost in the malignant cells of many human cancers, this study revealed that it also influences the tumor microenvironment.
The loss of Pten led to over-expression of a second fibroblast gene, Ets2. That resulted in gene expression changes and led to extensive remodeling of the extra-cellular matrix, as well as increased inflammation and angiogenesis, all of which favor tumor growth.
Remarkably, altering the Pten-Ets2 alignment in the mouse model accurately mimicked histological and molecular changes that occur in human breast cancer.
The findings demonstrate that stromal fibroblasts play an important role in suppressing cancer develop-ment and may explain why some human breast cancer patients respond to a standard therapy while others with apparently identical disease don’t.
In addition, the studies identify new stromal-specific biomarkers that may help guide treatment and identify molecular targets for developing new therapies aimed at tumor stromal cells. They could also improve the understanding of other pathological conditions that are influenced by the tissue microenvironment, such as autoimmune disease, lung fibrosis and neurodegenerative diseases.
Published in the Oct. 22, 2009, issue of Nature
Virus linked to common skin cancer
A virus discovered in a rare skin cancer also has been found in people with the second most common form of skin cancer among Americans.
Researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute examined tissue samples from 58 people with squamous cell carci-noma (SCC) and identified the virus in more than a third of them and in 15 percent of the tumors tested. All of the virus in tumor cells had a mutation that could enable viral DNA to integrate into host cell DNA.
“This is indirect evidence that the virus might play a role in causing some cases of SCC,” says principal investigator Amanda Toland, PhD, an OSUCCC-James researcher.
The virus was first discovered in patients with Merkel cell carcinoma, a rare, aggressive skin cancer that occurs mainly in the elderly and people with suppressed immune systems. “Originally we thought this virus caused only this rare skin cancer, but our findings indicate it is more prevalent than that,” Toland says.
To learn if people with SCC harbored the virus, Toland and colleagues examined DNA samples from SCC tumors, normal skin adjacent to the tumor, white blood cells and cells washed from the mouth.
They detected the virus in 26 of 177 SCC samples, 11 of 63 skin samples, and one mouthwash sample. They found no viral DNA in blood samples from 57 patients. In all, 36 percent of SCC patients tested positive for the virus. Sequencing viral DNA from 31 samples revealed that the same mutation was present in all the viruses from tumors and in 60 percent of the viruses from adjacent healthy-looking tissue.
Published in the June 25, 2009 issue of the Journal of Investigative Dermatology.
RECEPTOR ROLE REVEALED
Scientists Discover Key Event in Prostate Cancer Progression
A study led by researchers at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute (OSUCCC-James), and Dana-Farber Cancer Institute, reveals how malignant prostate tumors gain the ability to progress in the absence of androgen.
The onset of hormone-independent growth marks an advanced and currently incurable stage of prostate cancer. In hormone-dependent disease, androgen receptors regulate an early phase of the cell cycle.
In hormone-independent prostate cancer, the research shows, epigenetic changes reprogram the receptors to selectively regulate genes involved in mitosis.
One of those upregulated genes is UBE2C. This causes the cell to skip a mitotic check point, and it accelerates cell division.
“Some late-phase prostate cancers do not require androgen hormones for tumor growth, but they do require androgen receptors,” says first author and co-corresponding author Qianben Wang, PhD, assistant professor of Molecular and Cellular Biochemistry and a researcher with the OSUCCC-James. “Our study reveals that androgen-independent cancer cells aren’t directing androgen-dependent gene expression without androgen, but rather that they activate an entirely different pathway that results in androgen-independent growth.”
Wang, working with corresponding author Myles Brown, MD, professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute, and colleagues conducted the study using prostate cancer cell lines, gene expression data and human tumor tissue.
Wang says the findings could identify new therapeutic targets and lead to new treatments for this lethal stage of the disease.
Published in the July 24, 2009, issue of the journal Cell.
In androgen-dependent prostate cancer, androgen binds to androgen receptors (AR), resulting in the regulation of G1-S phase of the cell cycle and normal mitosis. In androgen-independent disease (above), epigenetic changes cause AR to selectively upregulate genes involved in mitosis, such as UBE2C. Dividing cells skip a mitotic check point, and this accelerates cell division.