BY KEN THOMPSON
Medical history has had its moments of accidental discovery that led to life-saving drugs and procedures.
A stack of uncleaned petri dishes eventually allowed Alexander Fleming to produce penicillin. Experiments with cathode ray tubes, gas and electricity would lead to the X-ray.
A slip of a catheter during a routine imaging test sent dye into a patient’s nearby coronary artery, producing the first coronary angiogram.
For Purdue University researcher Dr. Philip Low, the invention of an imaging drug that will help surgeons identify cancer cells began innocently 35 years ago from simple plant cells.
The drug, Cytalux, was approved in November 2021 by the Food and Drug Administration (FDA). Marketed by West Lafayette-based On Target Laboratories, Inc., the drug uses fluorescent technology to identify cancerous lesions and cells.
“Plant cells took up the vitamin biotin and would gobble up anything biotin was attached to, so we could attach biotin on any number of different molecules and fool the cells into gobbling them up,” says Low, the Ralph C. Corley Distinguished Professor of Chemistry in the Purdue University College of Science.
“So after we accidentally discovered this as a mechanism to deliver anything we wanted into plant cells, I asked the question whether something similar might be possible in human cells.”
Performing a similar study with folic acid, a vitamin you can find listed on the side of a Wheaties cereal box, Low learned that only cancer cells took up folic acid and folate-linked molecules.
“We immediately saw the obvious benefits of that; we could deliver drugs selectively to cancer cells simply by attaching them to folic acid,” Low says.
“That selectivity would avoid the collateral toxicity that always occurs when good drugs go into healthy cells. … The healthy cells ignore the folate-targeted drugs.”
Low admits to many high and low moments over the 35-year process. The highs included the moment he discovered that folate linked to a bright fluorescent dye would ignore healthy human cells in a dish while causing all cancer cells in the dish to glow.
A low point came during a study of live animals that had cancer. The drug was found to be absorbed not solely by cancer cells but kidney cells also.
“Then we found the kidney cells actually weren’t damaged by the drugs,” Low says. “They didn’t retain the folate-linked drugs very long. After the kidney cells captured them from the urine, they transferred them back into the blood stream.”
A number of drugs were then tested on humans, and the results were encouraging.
“We find that within an hour after injecting the Cytalux … the tumor-targeted fluorescent molecule helps the surgeon find a lot of hidden malignant lesions, nodules, and tumor masses that would have otherwise gone undetected because they glow very brightly. The surgeon opens the patient up, turns on the fluorescent lamp, finds the brightly glowing cancer tissue and cuts it out.”
Cytalux was demonstrated on ovarian cancers first. A recent demonstration on lung cancer patients was eye-opening. In 57 percent of the lung cancer patients, extra disease was found that would have been missed otherwise.
“That’s extraordinary,” Low says. “That tells you first of all that the surgery without this new tool is not highly accurate. It also tells you that with this new ability to see malignant nodules the chances of removing all the cancer and creating a cure are greatly increased.”
The next step is to test Cytalux in other cancers and obtain broad FDA approval to use it in all cancers.
Those of us who have sat through lengthy prime-time commercials for prescription drugs for such ailments as asthma, type 2 diabetes and overactive bladder have wondered about the expense, not only of the time on network TV but for developing the drug itself.
Low says the average cost of bringing a new drug through clinical trials from discovery to the hospital is about $2 billion. Not to mention the years-long process to gain FDA approval.
In comparison, Cytalux was done “on the cheap,” Low says. Venture capitalists put up more than $100 million to run Low’s studies, beginning with the elaborate studies on animals, through the human clinical trials.
“These are FDA-overseen clinical trials,” Low says. “They are very carefully monitored. You have to record every ‘hiccup’ of a patient, so you follow them like a ‘helicopter mom.’ ”
In all, approximately 232,000 documents were turned into the FDA to obtain regulatory approval for Cytalux. Listed in those documents were everything that happened in manufacturing, the stability of Cytalux, toxicity in the animals, all the therapeutic data in humans, the benefit to the patient, the percentage of the patients in which surgeons found extra cancer and detailed description of how the drug would be shipped.
“You can’t just go down to the post office and send a package to each hospital,” Low says.
The work really began once Cytalux was approved by the FDA: Hiring a company to do the manufacturing, followed by hiring a sales staff to visit surgeons across the United States, Europe and the Far East.
A few months later, Low received approval from the FDA for a drug that targets prostate cancer. One form of that drug also can be used for fluorescence-guided surgery of prostate cancer.
“But more importantly, we also made a radioactive version that is targeted specifically to prostate cancer cells,” Low says. “This was given ‘breakthrough status’ by the FDA on March 23 … because it successfully treats drug-resistant prostate cancer.”
Almost one-third of patients who have the metastatic, castration-resistant prostate cancer respond to Low’s drug, whereas only 2 percent of the same patient population respond to other available therapies.
Switzerland-based Novartis saw such promise in the prostate cancer treatment that it bought the company Low founded, Endocyte, for $2.1 billion just to obtain the drug.
“They expect it to be a blockbuster drug,” he says. “It significantly exceeds the capability or performance of any other prostate drug.”
It’s been quite a career for the son of a Purdue faculty member. Low caught the science bug while taking chemistry courses from Jim Guy at West Lafayette High School. It wasn’t all work and no play for Low, who played basketball for Hall of Fame coach Bill Berberian.
Seeking to be a chemistry major, Low ventured west to Brigham Young University for his bachelor’s degree. He earned a Ph.D. in biochemistry at the University of California-San Diego.
Originally not planning to be medically focused, Low’s life changed when he happened upon “this crazy discovery that plant cells would eat up biotin along with anything attached to it, that I got the idea to look for something similar in animals. It just turned out fortuitously that folate went specifically into cancer cells.”
Even though he is 10 years past many people’s retirement age, the 75-year-old says it’s been too difficult to retire.
“I’m just grateful to be part of the process,” Low says. “It’s very rewarding. I enjoy what I’m doing.”★