Found in Translation

A new approach to research speeds the flow of data between basic-science bench and patient bedside

Ching Shih ChenIn August 2009, cancer researchers at The Ohio State University began recruiting patients to a landmark phase I clinical trial for an experimental agent called AR-12, which inhibited solid tumors and lymphoma in preclinical studies.

“That trial marked the first time a therapeutic drug developed by Ohio State cancer researchers entered clinical testing in cancer patients,” says John Byrd, MD, associate director for translational research at Ohio State’s Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

AR-12 was discovered in the laboratory of Ching-Shih Chen, PhD, of the OSUCCC-James Molecular Carcinogenesis and Chemoprevention program, and its development involved a nearly decade-long collaboration among Ohio State researchers who refined its novel mechanism of action.

“We were very excited about the trial,” Chen says. “As bench scientists, our goal is to see our research translated into the clinic.”

A second agent designed and developed in Chen’s laboratory, AR-42, will enter clinical testing in mid-2010. And more agents are in the pipeline.

“AR-12 and AR-42 are both fantastic examples of translational research,” Byrd says. “A biological target relevant to cancer was identified through basic research, a drug was designed to interfere with it, preclinical validation was performed, and efforts were transitioned to the National Cancer Institute (NCI) to bring a new class of drugs into the clinic.”

Translational research is a process of scientific investigation in which research findings cyclically move from laboratory bench to clinical application and back to the laboratory bench. “The goal is to rapidly and efficiently move the most promising scientific discoveries from the basic-science laboratory into early-phase clinical testing, and to improve that therapy through research back in the laboratory,” Byrd says.

The NCI views translational research as essential for transforming scientific discoveries from laboratory, clinical and population studies into applications that reduce cancer incidence, morbidity and mortality.

Byrd sees another important benefit of translational research. “As medicine becomes more specialized, it’s harder for people to be involved in both laboratory-based work and clinical practice. A strong translational research program creates a fertile research environment that helps attract and retain outstanding investigators.”

Carefully Contrived Compounds

Chen and his colleagues used the anti-infl ammatory drug celecoxib as a starting point to construct AR-12 (OSU-0312), which is in clinical testing at two other centers as well as at Ohio State.

“AR-12 works by inhibiting the PDK-1 and PI3k/Akt pathways, which are fundamental signaling points in cancer cells, making AR-12 potentially effective in a range of cancer types,” says Chen, a professor of Medicinal Chemistry, of Internal Medicine, and of Urology. Patients with advanced or recurrent breast, colon, lung or prostate cancers or lymphoma who haven’t responded to chemotherapy are eligible for the trial.

Chen’s second drug, AR-42 (OSU-HDAC42) is a histone deacetylase inhibitor, an agent that reactivates silenced tumor-suppressor genes by reversing aberrant epigenetic changes. In a 2008 transgenic mouse study published in the journal Cancer Research, HDAC42 prevented precancerous prostatic intraepithelial neoplasia from progressing to advanced prostate cancer in 100 percent of treated animals compared with 74-percent incidence of poorly differentiated carcinoma that developed in control animals. The drug both kept the animals cancer-free
and prolonged their survival.

“This study shows that an agent  with a molecular target can dramatically inhibit prostate cancer development in an aggressive model of the disease,” says medical oncologist and co-author Steven Clinton, MD, PhD, who leads the Molecular Carcinogenesis and Chemoprevention Program.

The NCI’s Rapid Access to Intervention and Development (RAID) Program helped further the development of both agents for clinical testing.

Verging on a Vaccine

Pravin KaumayaTranslational research is designed to expedite medical advances, but it still takes time. “Translating basic knowledge to the clinic is not a straightforward process; it is a continuous process of rational design and execution using emerging concepts and advances in several scientific fields, such as immunology, protein and structural chemistry, molecular biology and others,” says Pravin Kaumaya, PhD, director of the Division of Vaccine Development in the Department of Obstetrics and Gynecology. Kaumaya also directs the OB/GYN Peptide and Protein Engineering Laboratory in Ohio State’s College of Medicine.

Kaumaya and colleagues have produced one of Ohio State’s first “homegrown” anticancer vaccines to move from the lab to the clinic. “It has taken us two decades to reach this point,” he says.

The vaccine targets HER-2, a protein that is aberrantly expressed in about a third of breast cancers and in other cancer types. HER-2 generally signals a poor response to therapy and a high likelihood of recurrence. A phase I trial involving 24 women and men with metastatic or recurrent solid tumors showed that the vaccine was safe, but there was also evidence of effectiveness.

“Six of the patients showed clinical benefit—one had tumor shrinkage and five had stable disease,” says Kaumaya, who says this was the first male-female trial involving a vaccine strategy using two B-cell epitopes (published in the Journal of Clinical Oncology, November 2008).

The trial also produced a surprise. “We were developing a vaccine for breast cancer that targets HER-2, but because this was a phase I trial we also enrolled patients with other forms of cancer. As it turned out, only one of the six who showed clinical benefit was HER-2 positive. Patients who were not HER-2 positive benefited the most,” Kaumaya says. “That’s because a component of the vaccine also interferes with epithelial growth factor receptor (EGFR). So what we have here is the possibility of a solid tumor universal vaccine that targets both HER-2 and EGFR-overexpressing cancers. I didn’t know that when we started.”

The findings suggest that the vaccine may be effective in brain, lung, pancreatic, colon and ovarian cancers.

Kaumaya and his students have produced a second-generation vaccine that will begin phase I testing later this year (see sidebar). Currently, his team has engineered a third-generation combination peptide vaccine and therapy involving HER-2 and vascular endothelial growth factor (VEGF) that have shown synergistic and additive efficacy in preclinical studies in animals.

Bedside to Bench

For Carlo Croce, MD, director of Ohio State’s Human Cancer Genetics Program, translational research starts with patients.

“The most common view is that research findings in the lab are exploited to develop novel approaches to diagnosis, prognosis and treatment of cancer at the bedside,” Croce says. “But I see translational research as the bi-directional flow from observation at the bedside to the lab, where we make discoveries that we can convert to the clinic. It can go both ways, depending on the circumstances, but in my work we always start with bedside samples of the disease and apply basic science to make discoveries for improving patient care.”

For example, nearly a decade ago, Croce and colleagues were searching for a tumor-suppressor gene located at 13q14, a chromosome site that is deleted in more than half of B-cell chronic lymphocytic leukemia (CLL) cases. Then they read in the journal Science that microRNA—a family of RNA molecules too small to code for a protein—is widely found in worms, flies and humans.

This seemingly unrelated basic finding gave them an idea. “I was convinced there was a gene on 13q14 that is involved in cancer, but no protein-coding genes were found there that could be linked to the disease,” Croce says. “So I knew a different kind of gene must be involved. When we heard about microRNA, we wanted to find out if it could be involved in CLL, and it turned out we were right.”

Croce and colleagues discovered two microRNA genes at the deletion site. They also analyzed CLL cells from 60 patients and showed that the genes were absent in 68 percent of the cases. Their 2002 findings, published in the journal Proceedings of the National Academy of Sciences, made Croce’s lab the first to link microRNA to cancer.

His group and others have since shown that microRNAs are involved in all human cancers and can be used to improve diagnosis and prognosis.

“Our next big challenge,” Croce says, “will be finding ways to use microRNA and anti-microRNA (antisense molecules) for treating CLL—in short, replacing microRNA genes that are underexpressed, or inserting anti-microRNAs to destroy microRNA genes that are overexpressed. We’re doing preclinical toxicology studies now in animals to test the safety of such treatments.

“This is a wonderful example of how you apply observations of disease in the clinic to basic laboratory science that leads to a discovery.”

Reason to Hope

William CarsonWilliam Carson III, MD, values translational research because it can lead to clinical options even for patients with advanced, metastatic or recurrent cancer.

“One of the loneliest feelings in the world is talking to a cancer patient and not having a good treatment to offer,” says Carson, a surgical oncologist at the OSUCCC – James who also is associate director for clinical research and, with Byrd, co-leads the Innate Immunity research program.

“Advanced or metastatic melanoma is resistant to most chemotherapy drugs, and average survival is about six to nine months, so there is a serious need for new therapies that involve drug combinations,” says Carson, whose specialties include this disease.

Carson and his colleagues are refining immune-based treatments that take advantage of the body’s strong immunological response to melanoma. They combined interferon-alpha (INF-a) with the targeted agent bortezomib and showed in animal studies that the two agents worked better together than either one alone, prolonging survival and reducing the growth of melanoma xenografts by half.

“The two drugs synergistically activate complementary cell-death pathways and overcome the usual mechanisms that make melanoma cells resistant to standard therapies,” says Greg Lesinski, PhD, a researcher with the Innate Immunity program and first author on a 2008 paper published in the journal Cancer Research.

These results led to a phase I clinical trial—the first to test this combination against melanoma— involving 15 patients with metastatic disease who had no other treatment options. The combination was well-tolerated and showed anticancer activity, including partial shrinkage of a tumor in one patient and disease stabilization in others, says investigator and melanoma specialist Kari Kendra, MD, PhD.

The question now is whether to pursue a phase II trial or to attempt new phase I trials testing combinations of other agents that Carson and his colleagues are studying. He notes that the translational process often involves intuition along with science.

“Clinical observation is also important when making these determinations; knowing what’s going on with your patients is key,” Carson says. “In a way, deciding to try the INF-a and bortezomib combination was an educated hunch along with a little serendipity.”

But he adds, “We don’t simply guess at what might work. We pre-test these therapies in the lab and gather experimental evidence indicating a high probability that they will benefit patients. Patients who volunteer for clinical trials can know there’s a good chance these therapies will help. The more we can back up our therapies with science, the better it is for patients who are taking a chance with their life.”

Translational research is a means to progress, Byrd says.

“We seek to discover new knowledge and apply it to patients. This is a strength of our cancer center. Translational research enables us to leverage our research dollars to maximally use everything we learn,” he explains. “Patients with cancer want hope that there is something new and better that might allow them to move on with their lives without illness. We need to develop new medicines to get us there, and the best way to do that is through translational research.”

Rational Vaccine Design

Pravin Kaumaya, PhD, and his Ohio State colleagues are using new data about the molecular structure of their original HER-2- and EGFR-targeted anticancer vaccine to develop a second-generation vaccine that could be effective against a range of malignancies, and they may begin phase I testing this autumn.

While the original vaccine was based on predictive models and animal studies, the newer version is based on the crystal structure of HER-2 bound with its antibodies. “It’s rationally engineered to mimic the 3-dimensional structure of the HER-2 oncogene, so we hope it will be more efficacious,” Kaumaya says.

The National Cancer Institute (NCI) has awarded $750,000, and the OSUCCC – James will contribute $100,000 for the new trial, which Kaumaya hopes to complete in less than a year. Meanwhile, his team is working on a third-generation vaccine.

“We have filed patent applications for a combination vaccine that uses technology relating to our HER-2-targeting drug plus an angiogenesis inhibitor that we designed from scratch,” Kaumaya says. “Our preclinical studies have shown that this combination vaccine works.” Next, the researchers will apply to the NCI for funding for a phase I trial.

“This could be a major breakthrough that may one day cure patients and not just treat them,” he says, noting that it’s been an arduous journey involving much time, money and work.

“With translational research, you have to believe in what you’re doing and keep at it even if some people don’t recognize it as important,” Kaumaya says. “It takes unabated perseverance.”

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