Drugs on Campus

A drug-development pipeline that takes cancer therapies from conception and design to the patient bedside isn’t a pipe dream at The Ohio State University—it’s under construction.


In 2003, a casual conversation between a chemist with a knack for designing new molecules and a physician-scientist treating leukemia patients sparked the development of a potential new cancer therapeutic. The physician, John Byrd, MD, director of the Division of Hematology, was running a clinical trial of a new class of anticancer drugs, called histone deacetylase, or HDAC, inhibitors. He pondered out loud to his colleague Ching-Shih Chen, PhD, professor of Medicinal Chemistry, of Internal Medicine, and of Urology, whether it would be possible to design a more potent version of a well-known HDAC inhibitor, valproic acid, which has a long record as a safe antiseizure medication. Chen took up the question as a challenge and seven years later, the compound he designed, known as AR-42 began being tested in cancer patients with hematologic malignancies (blood or bone marrow cancers) at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Chen, with the help of his clinical colleagues and support of the OSU College of Pharmacy and the OSUCCC – James Experimental Therapeutics Program, has ushered, not one, but two anticancer compounds into Phase I clinical trials. His success shows that the early stages of drug discovery and development can be executed within an academic campus setting, literally moving an idea from the laboratory bench to a pill in a patient’s hand. Leaders at OSU hope to capitalize on the unique resources and expertise available on campus and nearby to create a drug development pipeline that would propel discoveries into the clinic even more efficiently.

“At OSU, we have a really outstanding College of Pharmacy College of Medicine, College of Veterinary Medicine, College of Math and Physical Sciences, along with the OSUCCC – James. And we are right across the street from Battelle Memorial Institute,” an international leader in preclinical therapeutic research including pharmacology and toxicology studies, notes Michael Grever, M.D. chairman of the Department of Internal Medicine and co-leader of the OSUCCC – James Experimental Therapeutics Program. “We started talking and thought there would be some value in putting together a more formal drug development program here.”

A Tale of Two Compunds

Both of the anticancer compounds designed by Chen’s laboratory started with key information about drugs already on the market. AR-42 began as a search to make a structure similar to the short-chain fatty acid valproic acid that would have a more potent HDAC inhibiting activity.

After the conversation with Byrd, Chen’s group started with a scaffold similar to valproic acid and then performed structure-based drug design to arrive at AR-42, which proved to be about four or five times more potent than the leading HDAC inhibitor drugs already in clinical testing. In addition, the new compound had some other advantages, such as inhibiting not just HDAC, but also AKT, an enzyme that helps cancer cells evade programmed cell death.

“I often say that basic scientists have to work closely with clinicians because they can provide us with a good perspective into clinical medicine,” Chen says, who is known for being a very engaged collaborator.

Similarly, the idea for the second compound, called AR-12, started from the observation that patients taking daily doses of the pain medicine celecoxib (Celebrex) may have a generally lower incidence of cancer. Celecoxib’s pain relief is related to its inhibition of the COX2 enzyme, and Chen wondered if the anticancer effect was due to this inhibition or to something else altogether. His laboratory began by dissecting that question and found that the cancer prevention was instead related to celecoxib’s secondary inhibition of PDK1, a kinase that acted upstream of AKT.

“AKT is a holy grail for cancer-drug discovery because it is keyfor cancer cells to survive and proliferate,” Chen says. “As soon as that was identified as the target [of celecoxib], we jumped on this problem.”

His group began designing a molecule that would remove the COX2-inhibiting activity (which is now known to have negative cardiac side effects) and enhance PDK1 inhibition. The result, AR-12, potently inhibited PDK1 kinase and when tested against a panel of cancer cell lines, successfully inhibited many of them, including breast and prostate cancer cell lines.

With encouragement from Grever, Chen submitted applications for both compounds to the National Cancer Institute’s (NCI) Rapid Access to Intervention Development (RAID) program. This program sponsors the preclinical testing of compounds developed in academia, specifically the pharmacology and toxicology studies needed to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA). An IND application typically requires toxicology and pharmacokinetic data from testing in two different animal models as well as evidence of the drug’s in-vivo efficacy.

RAID-program support was essential for the continued development of both AR-12 and AR-42, Chen says, since OSU lacks the resources and facilities to perform the toxicology studies and to manufacture a drug in the quantities and quality needed for first-in-human studies. But it also came with a substantial load of paperwork and was a long process since the NCI must identify a subcontract laboratory to handle the testing. (NCI has since discontinued the RAID program and replaced it with a new program called NExT, for NCI Experimental Therapeutics Program.)

Once Chen was ready to publish his team’s findings on the new compounds, he sent an invention disclosure, along with the manuscripts, to Jane New, associate director of Ohio State’s Office of Technology, Licensing, and Commercialization. Her office filed patent applications to protect the intellectual property rights for the agents, then worked to secure an appropriate industrial partner to license the technology for further development. By the end of 2007, a deal was signed with Parsippany, New Jersey-based Arno Therapeutics, a biopharmaceutical company with expertise in cancer therapies.

“The RAID-sponsored studies put a stamp of approval on our work because it is a very vigorous review process, and it generated a substantial amount of data for the IND application,” Chen says. “That saves a partnering company a lot of time and money when filing the IND,” Chen says.

In 2009, AR-12 began being tested in a phase-I clinical trial in patients with advanced or recurrent breast, colon, lung or prostate cancers or lymphoma who had failed previous chemotherapy treatments. AR-42 began phase-I testing in the fall of 2010 in hematological cancer patients, specifically multiple myeloma, chronic lymphocytic leukemia (CLL), and lymphoma patients whose cancer has progressed after standard therapies.

Craig Hofmeister, M.D., assistant professor of medicine and a myeloma specialist, is overseeing the trial of AR-42 which will determine the proper dosing regimen of the drug including monitoring safety, side effects, and feasibility. Hofmeister notes that HDAC inhibitors as a class have a history of causing heartbeat irregularities, fatigue, and stomach upset, but so far he isn’t seeing those issues in the patients taking AR-42.

Because the protocol for this trial was designed by Ohio State investigators (and funded by an NCI grant to Grever and Byrd), Hofmeister explains that it will go a step beyond safety and also monitor patient responses or resistance to the drug,

“This trial is especially unusual because it is investigator-initiated, meaning the protocol was developed at Ohio State and has correlative studies attached to it that involve collecting patients samples and investigating the drug’s mechanism of action,” Hofmeister says.

That means that six months later, researchers will have the blood or bone marrow biopsy samples from all patients given AR-42 to perhaps determine why some patients responded to the drug and others did not. Both the myeloma patients and the CLL patients, Hofmeister explains, exhibit easily trackable biomarkers that show whether their cancers are progressing, stable, or regressing at a given point in time. This data can be used to decide early on which types of patients might benefit the most from the drug.

“People often think that drug discovery takes a tremendous amount of resources that are only available in industry,” Chen says. “But our success in developing these two drugs from design to clinical trials shows that drug discovery is doable in the academic setting.”

A Speedier Pipeline

Grever and Chen both envision a drug-development process in the future that takes even greater advantage of local resources and collaboration with Ohio State’s colleges and Battelle.

Battelle is the world’s largest, independent research and development organization and manages seven national laboratories. It has facilities that cover all parts of the drug discovery and development pipeline, including pre-IND toxicology, pharmacology, and safety research. In addition, Grever points out that the dean of Ohio State’s Fisher College of Business, Christine Poon, is a former executive who most recently managed the pharmaceutical businesses of Johnson & Johnson. “Between Battelle and the resources on campus, we are in a unique position to move things through the pipeline more rapidly, which would be a tremendous value to our patients,” says Grever. Several planning meetings including scientists from both Ohio State and Battelle are exploring the feasibility of this exciting scientific collaboration.

Grever expects that such a facilitated pipeline on campus, with less bureaucratic red tape and more local interactions, would potentially shave one to two years off the preclinical development process. “That is important to investors, who don’t want to lose those years of patent life,” he notes. “Furthermore, it is most important to our cancer patients who want to try an investigational therapy in an attempt to help their condition.”

Such a pipeline program would first focus on Ohio State’s strengths in the development of anti-cancer agents. Grever expects that the OSUCCC – James would work closely with Dean Poon to develop a business model to help secure the financial resources needed to fund drug discovery and development. These efforts would also capitalize on the decades of experience the OSUCCC – James has in running phase-I and II trials.

“With our large phase-I program in place, we have many patients who need access to new, experimental drugs,” says Grever.

Compounds likely to move forward through such a pipeline would be completely novel chemical structures or biological molecules. When a research team has worked out the mechanism of action of a novel compound and knows it is hitting a targeted pathway in cancer or overcoming a known mechanism of drug resistance, then it should move ahead to be tested in both healthy and tumor-bearing animals. If the drug’s delivery and absorption in animals seems straightforward, then that would bode well for a compound moving into the much more expensive and detailed studies required for the IND application—studies that can cost $800,000 to $1 million.

At that point, the Office of Technology, Licensing, and Commercialization would step in to facilitate the partnership with a company that would invest that money to complete the IND. New says a stronger commitment to drug development on campus would attract more industry partners.

“When it comes to pharmaceuticals, the more development [a university] can do, the more things to move it along the pathway, the easier it makes it on a company to better pick up something and move it to a commercial, FDA launch,” says New. “The more hurdles we can overcome, means reducing the risk for the company and increasing the return to the university. Especially, if we can manage to do it quicker.”

Dean Robert Brueggemeier of the College of Pharmacy has been a major supporter of Chen’s research from the start. He notes that Chen’s collaborative, cross-campus approach is a hallmark of both the College and the OSUCCC – James. “A number of critical faculty in each of the colleges working together on a problem come up with novel solutions that they wouldn’t have come up with individually. The College of Pharmacy supports and facilitates that team-science approach.”

Ohio State has the advantage of having chemists in the College of Pharmacy who specialize in early drug discovery and development, clinician-scientists at the OSUCCC – James who specialize in oncology treatment and running clinical trials, and resources such as the Pharmaceutical Analysis Shared Resource (PHASR), which can measure the concentration of drugs in a patient’s blood or urine sample in real-time. In addition, the key things OSU lacks — such as toxicology experts and a GMP facility to produce drugs suitable for use in humans — can be found nextdoor at Battelle.

“We have a very unique opportunity here in central Ohio,” says Brueggemeier. “Strengthening the partnership between OSU and Battelle will be really critical for putting together a drug development pipeline here.”

Grever concurs, noting that the confluence of local expertise is key not only for moving potential new therapies along in development, but also for the initial conversations — such as the one between Byrd and Chen —that generate the seeds of drug discovery in the first place: “Through the Experimental Therapeutics Program, we have the ability for chemists, biologists, and physicians to get together and have these collaborative discussions. We’re lucky that we’re all on one campus and not split up.”

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