Four OSUCCC – James researchers receive ‘grand opportunity’ grants to spur research on cancer prevention, prediction and targeted therapies.
BY KENDALL POWELL
When President Barack Obama signed the American Recovery and Reinvestment Act (ARRA) into law on February 17, 2009, it meant an influx of $787 billion to stimulate the U.S. economy. It included $8.2 billion to fund new biomedical research projects, and $1 billion for building new laboratory facilities through the National Institutes of Health.
The NIH designated the ARRA money to fund projects that would stimulate the economy, create new jobs or retain existing jobs, and that had the potential to make scientific progress within two years. To date, Ohio State University researchers have been awarded 174 grants totaling $82 million from the ARRA funds, with $42 million of that going to 42 researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James). The cancer center also received two construction grants from ARRA funds totaling $11.9 million (see “Concrete Results).
Four cancer center investigators received “Grand Opportunity” grants, also known as GO grants, totaling $7.3 million. In the same way that the total ARRA funds are meant to jump-start the economy with new jobs, construction projects and tax breaks, the NIH GO grants are meant to boost research projects that would significantly benefit from a one-time, two-year infusion of cash.
GO grants support large-scale, high-impact projects that are likely to spur growth and investment in biomedical research, public health or healthcare delivery. They must also be projects that researchers can deploy immediately and that have a budget greater than $500,000 per year for two years. They might be projects that require collaboration across laboratories or institutions, that create new research methods or unique data sets or that partner with industry and small businesses to accelerate the testing of new therapies. The OSUCCC – James GO grants exemplify all of these.
Predicting Response to Therapy With microRNA
Total Grant: $4 Million
Carlo Croce’s laboratory studies microRNA, a large family of molecules that regulates gene expression usually by blocking translation. Croce and his colleagues discovered that the microRNA called miR-29 inhibits DNA methyl transferases (DNMTs), enzymes that aberrantly methylate DNA and silence tumor-suppressor genes in cancer cells. The investigators also found that when mutations shut down miR-29, tumor-suppressor genes are also silenced, facilitating tumor progression.
“We speculated that we can reactivate these tumor suppressors by reintroducing miR-29s into cells that had lost them,” says Croce, MD, professor and chair of Molecular Virology, Immunology and Medical Genetics and director of the Human Cancer Genetics Program. His group showed that was true in cell culture.
Targeted agents already exist that work by demethylating tumor-suppressor genes. Examples include 5-azacytidine and decitabine. Croce reasoned that if patients had lost the miR-29s, then their DNMTs were operating without regulation, and these patients would more likely respond to demethylating agents.
Using a test for miR-29, “We can predict the response to the demethylating agents, who should respond to the drugs and who will not,” says Croce. “These are very toxic drugs, so you don’t want to treat a patient with a harmful drug if the patient will not respond to it.”
Croce’s GO grant will fund three small clinical trials to test this idea in three cancer types: acute myelogenous leukemia, lung cancer and the aggressive form of chronic lymphocytic leukemia. Croce says this is critical to find better ways to “stratify” patients as cancer treatments become increasingly targeted to specific genetic problems. This work will also lay the foundation for developing a targeted therapy that would deliver miR-29s to patients whose tumor cells have lost them. “We know how to do this in mice and rats, but not yet how to deliver them to humans,” says Croce.
A Bioadhesive Berry Gel for Oral Cancer
Total Grant: $1.3 Million
As an oral pathologist, Susan Mallery spends much of her time peering down a microscope at the precancerous and cancerous lesions removed from patients’ mouths. It frustrates her that these lesions return in about one-third of patients, and that one-third of these recurring lesions progress to oral squamous cell carcinoma, a malignancy that affects 35,000 Americans per year.
Mallery, DDS, PhD, professor in the Division of Oral Surgery, Pathology and Anesthesia, and her colleague, oral surgeon Peter Larsen, DDS, chair of Oral and Maxillofacial Surgery, Anesthesiology and Pathology, have seen firsthand how debilitating this recurrent disease and its treatment can be. Repeated surgery in the highly sensitive areas of the tongue, lips and floor of the mouth is often necessary. It can be disfiguring, and recovery can be painful.
They would like to offer patients a chemopreventive agent that prevents these lesions from progressing or recurring. Gary Stoner, PhD, an emeritus professor in the College of Medicine, studies natural products that are potential chemopreventive agents. He found that black raspberries contained high levels of four anthocyanins, natural compounds that are antioxidants and have anticancer properties. When he fed the berries to rats as 10 percent of their diet, it inhibited esophageal cancer.
But the investigators knew that patients are unlikely to eat that quantity of berries, and that anthocyanins are absorbed poorly from the digestive tract. They chose a method that delivers a higher dose of the treatment directly to the precancerous cells in the mouth.
“Gary’s very promising animal studies, my interest in local delivery formulation, and Pete’s observations on our patients all came together and we decided on a bioadhesive gel,” says Mallery.
The team developed a gel that is 10 percent freeze-dried black raspberries and tested it in a pilot phase I clinical trial on a small group of patients that included 10 healthy controls and 20 with premalignant lesions. The patients applied the gel four times a day—after meals and before bed—for six weeks. That initial test showed that the gel decreased some genetic markers of progression for some patients.
The GO grant will allow the team to test the gel in a larger, more complex phase I/II trial that will also include the University of Louisville and the University of North Carolina Chapel Hill. That trial will compare the gel’s effects against a placebo, and it will test how patients respond to and metabolize the gel.
“We had some patients with higher-grade lesions who responded extremely well,” says Mallery. “We even had patients where the lesions clinically disappeared.” But some patients seemed to be refractory to the treatment, and she’d like to know what controls those different responses.
“Quality of life for our citizens is worth a lot of money,” says Mallery. “If we find an effective way to prevent progression or induce regression of this cancer, then we’ll have that many more citizens in the workforce, getting more pleasure from life and not facing another surgery on their mouth.”
A Vaccine for EBV Lymphoma
Total Grant: $1 Million
Even though 95 percent of Americans are infected with the Epstein-Barr virus (EBV), the virus that causes mononucleosis, for most of us it amounts to little more than a nuisance infection during our college years. “Patients with intact immune systems can fight it off, and it doesn’t give them as much grief,” explains Robert Baiocchi, MD, PhD, assistant professor in the Division of Hematology and Oncology.
But for Baiocchi’s HIV patients with compromised immune systems, the virus can lead to deadly lymphoma. The good news, he explains, “is that EBV-caused lymphomas are in theory preventable, if we can boost the patient’s immune response.”
Toward that goal, Baiocchi’s group is designing an EBV vaccine including multiple full-length viral proteins that will present multiple antigens. “We believe this will evoke a much more robust immune response,” Baiocchi says.
EBV has more than 90 proteins that could be used in a vaccine. Baiocchi and his colleagues have already identified one protein, called BZLF1, that when detected by a lymphoma patient’s immune system correlates with survival and tumor regression. They are incorporating it into a vaccine that will be tested in a phase I safety trial.
His team will use the GO grant to generate four or five more EBV proteins for use as vaccine components that can be tested in clinical trials. Ultimately, Baiocchi believes it will take a vaccine with multiple components, including viral proteins and adjuvants, to prevent these lymphomas. Funding from the Leukemia & Lymphoma Society of America supported his group as they took the BZLF1 vaccine from the lab to animal models and finally to testing in patients. The GO grant “allows us to discover new targets and put them into that same pathway of development that already exists,” he says.
His group will partner with local biotechnology companies that can produce the different vaccine components. Each viral protein they verify in the lab as immune-boosting will need to be grown, purified, tested for toxicity and manufactured into a vaccine that can be tested in a phase I trial. “Even if we just discover two or three target viral proteins that are attractive, each will need to go into the next phase of development. This is a strategy that needs to be tried because these are preventable cancers."
Sorting Molecular Markers for Glioblastomas
Total Grant: $2.5 Million, OSU Subcontract is $1 Million
In the 1990s, the Radiation Therapy Oncology Group (RTOG), an international oncology cooperative, developed a system for categorizing glioblastoma—one of the most devastating of human tumors—into six prognostic groups, from best to worst survival times. This model, called a recursive partitioning analysis, was largely based on the clinical features of patient tumors and on patient demographics.
But Arnab Chakravarti, MD, professor and chair of Radiation Oncology and co-director of the Brain Tumor Program, wants to update that model, largely because of two recent advances. First, research has uncovered molecular, genetic and epigenetic traits that are important for glioblastoma progression or that play a key role in treatment resistance. Second, the standard of care for these tumors has evolved to include not only surgery and radiation, but also the chemotherapy drug temozolomide (TMZ) during and after radiation treatment, explains Chakravarti, who is also chair of the RTOG Brain Tumor Translational Research Group.
Because of this, Chakravarti and the RTOG believe that including new variables about the particular molecular signatures of each patient’s tumor and their response to radiation-plus-TMZ or other treatments will greatly improve the prognostic model.
In one study, for example, patients whose tumor cells had a methylation mark that silences a DNA repair gene called MGMT had improved outcomes with TMZ treatment. “Patients without this methylation did not appear to reap any extra benefi t from the addition of TMZ,” says Chakravarti. In other words, TMZ is more effective when the MGMT gene is not expressed. Certain other molecules, such as a mutated version of the epidermal growth factor receptor, permit cancer cells to resist the effects of radiation and chemotherapy.
Charting these molecular signatures will improve doctors’ ability to stratify patients. It will help determine which current or experimental therapies will most benefi t individual patients, and it will guide the development of new molecular-based therapies.
To refine the classification model, Chakravarti and his collaborators at MD Anderson Cancer Center in Houston, Texas, will use the GO grant to analyze tissue samples taken from about 2,000 glioblastoma patients from North America, Europe and Asia. The team will assess the samples for a panel of about 30 key molecular, genetic and epigenetic markers and correlate them with patient responses to radiation-plus-TMZ treatments and patient outcomes.
“Our ultimate objective is to identify molecular markers for treatment resistance mechanisms in cancer cells, then take those back to the lab and find ways to overcome those mechanisms,” says Chakravarti. To accomplish this and move potential therapies into the clinic, at the end of the two-year GO grant Chakravarti and the RTOG plan to apply to the NIH for a Specialized Programs of Research Excellence (SPORE) grant to continue this work. At $2.5 million per year for five years, SPORE grants are among the largest grants awarded by the NIH.
A Boon for Ohio and the Nationa
For these OSUCCC – James researchers, calling these “stimulus grants” means something slightly different for each investigator.
Baiocchi sees his grant leading to partnerships with local biotechnology companies and to the workforce needed to support all the steps necessary to produce and test the new vaccines against EBV. Chakravarti’s effort to profi le almost 2,000 cases of glioblastoma—the largest data set to date for brain tumors—will bring many new employment opportunities for scientists.
“This could be a huge benefit to the economy both of Ohio and nationwide. These fi ndings will likely lead to diagnostic and prognostic platforms for brain tumor patients, and that will require hands on deck to manufacture these platforms and get them out to the medical community at large,” he says.
Recently, while discussing experiments, one of Mallery’s postdoctoral fellows slipped in the comment, “I know you don’t like to waste money.” Mallery took the moment to point out that it is the taxpayer money from the cashiers at the local store, from schoolteachers and other workers that ultimately funds medical research.
“They are entrusting their money to us, and we need to use it wisely,” she told her postdoc. “If we can improve just 10 people’s lives, how cool is that? We are lucky to be able to try to do that.”
In addition to research grants, ARRA grants are improving the infrastructure of the OSUCCC – James. An $8 million construction grant will support finishing the fourth floor of Ohio State’s Biomedical Research Tower (BMT) to provide a home base for the Experimental Therapeutics Program. Another construction grant for $3.9 million will fund the renovation of an 8,776-square-foot space within the Goss Laboratory building that houses a group of highly collaborative viral oncology researchers.
Michael Grever, MD, professor and chair of the Department of Internal Medicine and co-leader of the Experimental Therapeutics Program, says, “The OSUCCC – James is one of a limited number of institutions in the country that has National Cancer Institute funding for both phase I and II studies of new drugs.”
Currently, investigators in the Experimental Therapeutics Program are spread out across various departments on campus.
Although the new floor of the BMT will not house all members of the program, it will bring together biologists, chemists, translational scientists and clinicians to develop new therapeutic strategies for cancer, says Grever. The construction project will create lab and office space for about 16 investigators and their groups—part of a plan to accelerate the recruitment of more faculty to the program. In addition, the 24,000-square-foot space will hold core laboratory facilities for medicinal chemists to synthesize new molecules, for pharmacokinetics studies to measure how drugs get distributed in the body, and for pharmacodynamics studies to measure how well drugs hit the targeted tumor cells.
When the Goss Laboratory building was built in 1961, the laboratory spaces were isolated from one another. The renovation will gut the space and install open laboratory benches and office space.
“This allows us to design a modern, interactive space for researchers doing similar things,” says Michael Lairmore, DVM, PhD, associate dean of research for the College of Veterinary Medicine. The new space will house four investigators who have large laboratory groups and collaborate on an NIH Program Project Grant using retroviruses to understand the biology of cancer cells.
The space will also include tissue culture hoods for working with infectious viruses and a state-of-the-art facility for performing necropsies on infected animals. “These facilities, designed around a theme of our groups’ research and equipment we share in common, will provide a real opportunity for us to accelerate our research,” Lairmore notes.
Both the Goss Laboratory and Biomedical Research Tower renovations are expected to begin in spring and summer of 2011. The BRT renovation alone is expected to create 40 new construction jobs and space for 16 new faculty, and produce a demand for 100 support personnel.