An experimental drug PAC-1 has been cleared in the United States for clinical trial of patients diagnosed with anaplastic astrocytoma, a rare malignant brain tumor, and glioblastoma multiforme, an aggressive late-stage cancer of the brain.
Veterinary oncologist Dr. Timothy Fan and chemistry professor Paul Hergenrother, both based at the University of Illinois at Urbana-Champaign, aim to determine if PAC-1 can be used safely in combination with a standard brain-cancer chemotherapy drug, temozolomide.
Prof Hergenrother and Dr. Fan have already tested the drug successfully on human cell lines, rodents, and pet dogs with a variety of naturally occurring cancers. In dogs diagnosed with glioblastoma, daily oral doses of PAC-1 in combination with temozolomide and “curative-intent” radiation resulted in reduction in tumor size by more than 30 percent. One of the dogs even had a complete response with a 100 percent reduction in tumor mass. This was identified with the help of serial MRI scans.
The human clinical trials will be offered at the University of Illinois Cancer Center in Chicago; the Regions Hospital Cancer Care Center in St. Paul, Minnesota; and Johns Hopkins University School of Medicine in Baltimore.
The significance of the PAC-1 is that it is able to cross the blood-brain barrier which is a substantial obstacle to most anti-cancer drugs. Prof Hergenrother, who discovered PAC-1’s anti-cancer effects more than a decade ago, has said in a statement that PAC-1 targets procaspase-3, an enzyme that is found in excess in many cancer cells.
“Most cancers have elevated levels of procaspase-3,” he said. “When it is turned on, procaspase-3 kills cells.” However, cancer cells override this normal cell-recycling pathway. “PAC-1 restores the activation of procaspase-3 and targets cancer cells over non-cancerous cells,” the professor said.
A 2016 study had found the combination of PAC-1 with doxorubicin, a chemotherapeutic agent, useful in tumor reductions in all four dogs with lymphoma and in three of six dogs with osteosarcoma. The trials found PAC-1 to be safe, with few observable side effects apart from occasional gastrointestinal distress. The findings were published in the journal Oncotarget.
The scientists conducted trials on dogs because some cancers in dogs are genetically similar to those in humans and respond to the same medications. Dogs also are similar in size to humans, and so can be better models to evaluate how well drug agents perform on larger tumor masses.
However, Dr. Fan has cautioned that not all discoveries in pet dogs will necessarily translate in a similar manner to humans.
So far, the trial in human patients have showed that the drug is well-tolerated at doses up to 450 milligrams per day with no significant side effects. The next phase involves using a PAC-1 dose of 375 mg per day and increasing it incrementally to test safety in combination with temozolomide.
Anaplastic astrocytoma is treated by surgery, followed by chemotherapy with temozolomide. Treatment for glioblastoma multiforme, on the other hand, involves surgery to remove the tumor followed by radiation and oral treatment with temozolomide. Since it is next to impossible to remove all cancer cells during surgery and because the tumor can spread silently along the blood vessels inside the brain, most patients report a relapse of the disease even after surgery and radiation. In addition, the median survival time for humans with glioblastoma even with the currently available standard treatment is only about 15 months.
The survival time can enhance significantly depending on the outcome of the PAC-1 human trials. However, scientists concur that determining the true safety and efficacy profile of PAC-1 will take several rounds of clinical trials with human patients.