Cancer drug shows incredible promise in human clinical trials

Photo by U.I. researchers. Illinois professor of veterinary clinical medicine Dr. Timothy Fan (left) and professor of chemistry Paul Hergenrother. The U. of I. team found that the compound PAC-1 has therapeutic potential in pet dogs with spontaneously occurring cancer. Animal studies paved the way for human clinical trials. (CREDIT: Fred Zwicky)

Phase I clinical trials of PAC-1, a drug that causes programmed cancer cell death, have found only minor side effects in patients with end-stage cancer. The drug stopped tumor growth in five people in the neuroendocrine cancer study and reduced tumor size in two of those patients. It has also shown some therapeutic activity against sarcomas, scientists and clinicians report in the British Journal of Cancer.

The drug was first identified and developed as an anti-cancer agent by scientists at the University of Illinois at Urbana-Champaign.

The clinical trial results are noteworthy because the drug has been tested in a small number of patients with advanced disease, said clinical trial leader Dr. Arkadiusz Dudek, an oncologist at the HealthPartners Cancer Center at the Regional Hospital in St. Paul, Minnesota, and the Mayo Clinic in Rochester, Minnesota. Phase I clinical trials are designed to test whether a new drug compound has worrisome side effects or toxicity in human patients, Dudek said. But scientists may also be looking for early evidence of therapeutic benefits. The study included cancer patients with advanced disease who had run out of other treatment options.

“We’ve had patients with colon cancer, breast cancer, pancreatic cancer, adenocarcinoma, melanoma and others,” he said.

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The clinical trial – and another PAC-1 trial against brain cancer – involves patients and doctors from three institutions: the regional hospital, the University of Chicago of Illinois, and Johns Hopkins University.

Phase I clinical trials track side effects in patients who are initially given very low doses of a test compound. If the drug is well tolerated and does not cause noticeable toxicity within a month, the dose is gradually increased. This process could take several months before a potentially therapeutic dose is delivered, says Dr. Oana Danchiu, a medical oncologist and associate director of clinical research at the University of Illinois Cancer Center at Chicago, who led the clinical trials.

Researchers at the University of Italy first identified PAC-1 as a potential anti-cancer compound in the early 2000s when they discovered that it could turn on a pathway that is downregulated in cancer cells. The first step of this pathway involves the conversion of procaspase-3, a protein present in most cells, to caspase-3, an enzyme that, when activated, initiates programmed cell death.

Pharmacokinetics of PAC-1. (CREDIT: Nature Communications)

Led by chemistry professor Paul Hergenrother, the University of Italy team also recognized that pro-caspase-3 is found in higher numbers in many cancer cells compared to healthy tissues. This characteristic, along with its tendency not to be activated in cancer cells, has made it a good target for anti-cancer therapy.

In animal trials involving domestic dogs with spontaneously occurring lymphomas, meningiomas, and osteosarcomas, Hergenrother and Dr. Timothy Fan, professor of veterinary clinical medicine at Indiana University, found that an early form of PAC-1 has anti-cancer effects.

Their work in cells and animals paved the way for human clinical trials, which were launched several years ago with funding from an anonymous business angel. Hergenrother founded the biotech company Vanquish Oncology to spearhead this effort.

Expression of procaspase-3 (PC-3) in tumors of varying histology is classified as moderate to strong immunostaining intensity.

Clinicians are currently looking for additional funding to move the drug into a Phase 2 clinical trial that will involve many more, much healthier patients with very similar cancer profiles to each other.

“Our strategy is to figure out which type of tumor will be the most sensitive and push for that,” Dudek said. “We are therefore very pleased with the results for neuroendocrine tumors because there are not many drugs available for this disease.”

More results from a phase I PAC-1 clinical trial in patients with glioblastoma multiforme, an aggressive form of brain cancer for which only one drug is available, are expected soon. In a new clinical trial, the team combined PAC-1 with this drug, temozolomide.

In previous studies, researchers have found that PAC-1 crosses the blood-brain barrier, which is essential for any brain cancer treatment. They also saw promising results with PAC-1 combined with the drug temozolomide and radiation therapy in pet dogs with brain cancer.

If clinical trials show that PAC-1 is a therapeutic agent against one or more types of cancer, and the drug is approved for use in these populations, testing it against other types of cancer will become less costly, the researchers say.

An approved drug may also be prescribed for “off-label use” by physicians who believe their patients may benefit from including it in their cancer treatment protocols.

It could be many years before the results of new clinical trials are available, and even longer before a new drug like PAC-1 is approved for cancer, the researchers said.

Hergenroter and Fan are affiliates of the Institute for Genomic Biology. Carl R. Woese at the University of Illinois and members of the Illinois Cancer Center.

This study was supported by Vanquish Oncology, the University of Illinois Cancer Center, the National Institutes of Health, and the Engdahl Family Foundation.

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Note. Materials provided above by the University of Illinois at Urbana-Champaign. Content can be edited for style and length.

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