Source: www.cancer.gov/ncicancerbulletin
Author: Carmen Phillips

It began with chemotherapy-induced sleeplessness and some pie pans. At one point hot dogs were involved. It inspired residents of two small communities 1,300 miles apart, and eventually landed in the labs of two major academic medical centers. And, sadly, just 5 weeks ago, the man who began it all died of treatment complications after a nearly 7-year battle with B-cell leukemia.

The story of retired radio engineer and executive John Kanzius and the radiofrequency (RF) generator that he dreamed would one day be part of a highly effective cancer treatment captivated readers of Discover magazine and viewers of “60 Minutes.” Now his invention is maneuvering through the steps needed to demonstrate readiness for clinical testing in humans.

“Realistically, we still have hoops to jump through and things to prove,” said Dr. Steven A. Curley from the University of Texas M.D. Anderson Cancer Center, who, along with Dr. David Geller from the University of Pittsburgh Medical Center, has been part of this project since its earliest days. “But I’ll continue to work on this and move it forward because I think it has great promise.”

An image of pancreatic cancer cells treated with gold nanoparticles.
The cells on the left received 2 minutes of external radiofrequency (RF)
field treatment resulting in unstable nuclei and intracellular damage.
The cells on the right received no RF treatment and their nuclei and
organelles remain intact.  (Image courtesy of Dr. Stephen Curley)

A Trojan Horse…on Fire
RF, Mr. Kanzius realized one restless night, is an ideal way to attack cancer cells from outside the body. At low levels, it doesn’t harm healthy tissue, but in a matter of minutes it can heat up metal in the RF field to nearly 130 degrees Fahrenheit. So, figured Mr. Kanzius, why not use RF waves to heat up metal nanoparticles that have found their way into cancer cells?

At his summer home in Sanibel, FL, he used pie pans to create his first RF device. In the garage of his long-time home in Erie, PA, Mr. Kanzius tested the device on America’s favorite ballpark snack. He would eventually use his own money to build a more sophisticated RF generator that Dr. Geller, and later Dr. Curley, went on to use in cancer cell line and animal model studies.

In these studies, nanoparticles are introduced and exposed to low-level RF waves for just a few minutes. The intense heat generated in the infiltrated cells “denatures proteins, disrupts lipid bilayers, and results in irreparable damage to intracellular structures and organelles,” Dr. Curley and his colleagues at M.D. Anderson explained in their most recent paper.

While the preclinical work has proven successful, there is still much to be done, stressed Dr. Geller.

“It’s one thing to kill cancer cells in a test tube, or even an animal,” he said. “It’s another to kill a tumor in a human and make a cancer disappear.”

Reaching the Target
The work completed thus far demonstrates the rapid progression from a concept of blistering malignant cells with RF waves toward precisely focusing RF waves on cancer cells by using nanoparticles with targeting agents attached to them. The initial work by Dr. Curley’s team involved single-walled carbon nanotubes unadorned by a targeting molecule, given to Dr. Curley by a patient he was treating at the time—Dr. Richard Smalley, a Nobel Prize winner for nanotechnology research who died in 2005.

Both Dr. Curley’s and Dr. Geller’s groups are now using gold spherical nanoparticles. In their most recently published work, Dr. Curley’s group attached the EGFR-targeted monoclonal antibody cetuximab (Erbitux) to the gold nanoparticles.

Introducing these gold nanoparticles into cell lines of pancreatic and colorectal cancer, which both overexpress EGFR, and exposing them for just a minute to an RF field killed nearly 100 percent of the cancer cells, the M.D. Anderson team reported.

“We probably wouldn’t use cetuximab in humans,” Dr. Curley noted. “EGFR is highly expressed in many normal tissues, and we would get significant uptake in normal tissue in the RF field.”

Dr. Geller’s team has shown that they can use RF to heat up liver tumors in a rat model. They used “naked” gold nanoparticles in the experiments, however, that were injected directly into the tumors. Both Drs. Curley and Geller are still working to find molecules that are highly specific to cancer cells.

“For each cancer, we’re going to have to come up with unique strategies,” Dr. Geller explained. “What works for liver cancer may not work for breast or prostate cancer.”

The Path Forward
Tackling cancer in this way, said Dr. Piotr Grodzinski, program director for the NCI Alliance for Nanotechnology in Cancer, is “generally an attractive idea.” Other researchers, in fact, have developed similar approaches, he added, “with their own twists.”

Texas-based Nanospectra Biosciences, for example, has received FDA approval for a phase I study in patients with unresectable head and neck cancer using a device that emits near-infrared light to heat up gold nanoparticles in tumors. And the German company MagForce developed a device that employs an alternating magnetic field to heat up magnetized nanoparticles; the device is being tested in phase I and II trials in Europe for several cancers.

Other investigators, added Dr. Nicholas Panaro, a senior scientist in NCI’s Nanotechnology Characterization Laboratory, are studying different targeting molecules—DNA fragments called aptamers, and diabodies, which are antibody fragments—to see if they can more effectively deliver nanoparticles only to cancer cells.

Meanwhile, Therm Med, the company established by Mr. Kanzius to help commercialize his device, is in the process of scaling it up so that it can be used for large animal and eventually human studies. Drs. Geller and Curley believe that with continued progress and funding they can launch initial human trials in the next few years.

“John was a one of a kind,” said Dr. Geller. “We certainly hope to continue the research because that’s what he wanted us to do.”

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