The first tests of the anticancer drug PAC-1 in human clinical trials show promise

PAC-1, a drug that stimulates programmed cell death in cancer cells, was found in phase I clinical trials with only mild side effects
in patients with end-stage cancer.
In the five neuroendocrine cancer patients who participated in the trial, the drug stopped tumor growth and shrunk the tumor size
in 2 of them.
Scientists and clinicians report in the British Journal of Cancer that it also shows some anti-sarcoma therapeutic activity
.

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

Dr.
Arkadiusz Dudek, clinical director of the study, an oncologist at HealthPartners Cancer Center at St.
Paul's Regional Hospital in Minnesota and the Mayo Clinic in Rochester, Minnesota, said the findings from the clinical trial are notable because the drug was tested on a small number of patients with advanced disease
.
Dudek said the phase I clinical trial is designed to test whether a new drug compound has worrisome side effects or toxicity
in human patients.
But scientists can also look for early evidence
of the effects of treatments.
The trial recruited patients
with advanced cancer who had exhausted other treatment options.

"We have patients with
colon, breast, pancreatic, adenocarcinoma, melanoma and other cancers," he said.

The clinical trial — and another trial testing PAC-1 against brain cancer — involved patients and clinicians at three institutions: the regional hospital, the University of Illinois at Chicago and Johns Hopkins University
.

Phase I clinical trials tracked side effects
in patients who were given very low doses of the compound tested for the first time.
If the drug is well tolerated and there is no significant toxicity within a month, the dose
is gradually increased.
Dr.
Oana Danciu, a medical oncologist and associate director of clinical research at the University of Illinois Cancer Center in Chicago, said the process could take months before a therapeutic dose
was given.

Researchers at the University of Illinois first identified PAC-1 as a potential cancer-fighting compound in the early 21st century when they discovered that it could open up a pathway
that is inhibited in cancer cells.
The first step in this pathway involves the conversion of procaspase-3, a protein found in most cells, to caspase-3, an enzyme that, when activated, initiates programmed cell death.

Led by chemistry professor Paul Hergenrother, the University of Illinois team also found that procaspase-3 is higher in many cancer cells compared to healthy tissue
.
This property, along with its tendency not to be activated in cancer cells, makes it a good target for anti-cancer treatments
.

Horgan Rosser and Dr.
Timothy Fan, a clinical professor of veterinary medicine at the University of Illinois, found that an early formulation of PAC-1 had anticancer effects
in animal tests on pet dogs with spontaneous lymphoma, meningioma, and osteosarcoma.
Their studies on cells and animals have laid the foundation
for human clinical trials.
A few years ago, with funding from an anonymous angel investor, human clinical trials began
.
Hergenrother founded the biotechnology company Vanquish Oncology to lead the effort
.

Clinicians are currently seeking further funding to move the drug into Phase II clinical trials, where more patients with much healthier cancer characteristics will participate
.

"Our strategy is to find out the most sensitive tumor types and continue to study
," Dudeck said.
"So we're very excited about the results of the study on neuroendocrine tumors because there aren't many
drugs to treat this disease.
"

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

In previous studies, researchers found that PAC-1 can cross the blood-brain barrier, which is crucial
for any brain cancer treatment.
They also saw promising results
of PAC-1 in combination with temozolomide drugs and radiation therapy in pet dogs with brain cancer.

If clinical trials show that PAC-1 has a therapeutic effect on one or more cancers, and the drug is approved for use in these populations, the cost of testing for other cancers will be reduced
, the researchers said.
An approved drug can also be prescribed "off-label" by doctors who believe adding the drug to a cancer treatment regimen may be beneficial
to patients.

The researchers say it could take many years for new clinical trial results to come in, while it will take longer for new drugs like PAC-1 to be approved for cancer treatment
.

Hergenrother and Fan are members of the Carl R.
Woese Institute for Genomic Biology at the University of Illinois and a member of
the Illinois Cancer Center.