The Prostate Cancer Foundation has been an early accelerator of research that is now coming to fruition, including the early research into PSMA and the discovery that two FDA-approved PARP inhibitors, olaparib (Lynparza) and rucaparib (Rubraca) could work against mutant genes in prostate cancer.
Florin of Medical Detection Dogs/Photo Courtesy of Medical Detection Dogs, UK
Early detection is critical to the treatment of serious disease, and after a 2020 campaign with a record seven Food and Drug Administration (FDA) approvals, the Prostate Cancer Foundation is leveraging newly discovered biomarkers, precision medicines, and even researching a robotic dog’s nose to make this cancer history.
“We may end up preventing most prostate cancer so it doesn’t really become a metastatic problem,” said Dr. Jonathan Simons, the President, Chief Executive Officer, and self-professed cheerleader for the foundation. Then he proceeded to describe the path PCF is charting in this direction, beginning with a couple of new biomarkers.
“Circulating free DNA (cfDNA) is emerging as an important biomarker, new technology, in medical oncology, for precision medicines,” said Simons.
He explained that cfDNA is instrumental in enabling the cutting-edge poly-ADP ribose polymerase (PARP) inhibitors, which work by inhibiting the PARP protein responsible for the repair of damaged DNA in tumor cells, thereby killing the cells.
“[These drugs] require the diagnosis in the metastatic tumor of mutations in genes that make the drugs effective. So you can’t prescribe, scientifically, these new precision medicines without doing DNA sequencing.”
This is where circulating-free DNA comes into play, because some prostate cancer cells effectively show their hand.
“It’s possible, rather than have a fine needle aspirate…just to use the blood itself because there are enough circulating prostate cancer cells in the blood that are kind of broken apart that leak their tumor DNA in a way in which the DNA can be detected,” said Simons.
Another very recent advance in prostate cancer is the Food and Drug Administration (FDA) approval of Gallium PSMA-11, the first drug for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA), allowing for better staging of disease.
“The FDA approval of PSMA PET makes it the first actionable FDA-approved surface biomarker for getting a better assessment of sites of metastatic disease and sites of recurrence, so that’s huge. It’s really the first in medical oncology. It’s the first biomarker for imaging that actually changes the clinical decision making in up to 70% of patients using that biomarker,” said Simons.
The Prostate Cancer Foundation has been an early accelerator of research that is now coming to fruition, including the early research into PSMA and the discovery that two FDA-approved PARP inhibitors, olaparib (Lynparza) and rucaparib (Rubraca) could work against mutant genes in prostate cancer.
“We do first-in-field funding in university laboratories. We’re the first money in very often,” said Simons. “Let’s say it takes $100 million or $500 million dollars to develop a new drug, we try to be the first $10-$20 million in the university laboratory. Then, if things are successful, the government funding moves in, biotech and pharma. So you end up getting an enormous amount of leverage from that. We are very interested in finding partners. The ‘P’ in PCF literally could stand for ‘Partners Curing Foundation.’”
Simons added that the foundation often takes a chance on high-risk ventures.
“We believe very strongly in partnerships with biotech and pharma and government. We fund riskier things that have less data but are potentially quite disruptive. And we don’t get everything right, but we’ve had quite a track record of success,” he said.
One of these disruptive projects is using an artificial dog’s nose to research whether or not a biomarker called Volatile Organic Compounds (VOCs) – also known as an odor – exists in the urine of men with the most aggressive forms of prostate cancer.
“We’re very interested in the development of an artificial dog’s nose that could find the volatile organic compounds from prostate cancers years earlier than the PSA test, the current test,” said Simons.
According to the results of a multi-national, cross-disciplinary study run by PCF, Medical Detection Dogs (MDD), Massachusetts Institute of Technology (MIT), and Johns Hopkins University published today in PLOS ONE, this research – and the foundation’s investment – is paying off.
The controlled study combined canine olfaction detection, artificial intelligence (AI)-assisted chemical analysis of the VOCs in urine samples and microbial analysis of the same urine samples of men who had undergone biopsy for suspected prostate cancer.
The olfaction systems of Florin, a Labrador retriever, and Midas, a Vizsla, were shown to be 71% sensitive and 70-76% specific in accurately ignoring negative samples including those containing other diseases, in the process of detecting Gleason 9 prostate cancer from blinded samples. The pair also correctly recognized 73% of blinded samples not containing the disease.
Dr. Andreas Mershin, a Physicist at MIT’s Center for Bits and Atoms and one of the study’s lead scientists, said that the end goal is to develop a smartphone sensitive enough to detect the most aggressive and lethal forms of prostate cancer.
“We weren’t trying to achieve the best possible diagnosis in itself…the 75% and 73% that we got is because our goal was different. We wanted to see how close we could get the machines to behave like the dogs. The dogs have demonstrated now to be able to detect the most lethal form of prostate cancer, and it’s not a huge stretch of the imagination to think that quite soon, we’ll be able to train dogs that can tell the difference between lethal and indolent prostate cancer. This means that even with just the dogs, we’ll be able to avoid many of the unnecessarily invasive and perhaps sometimes completely unnecessary biopsies for prostate cancer.”
Mershin added that the Prostate Cancer Foundation’s approach to funding was instrumental in the execution of the study.
“If you compare it to NIH, or even to DARPA who are famously very fast…what they do at the Prostate Cancer Foundation, is they send actual human beings with actual eyeballs. They send those people to your lab and they watch you do it, and then they make a decision right there on the spot. Then they also work hard to make sure you have what you need in the way of collaborators,” he said.
Another innovative research avenue the foundation is especially keen on solving is the increased risk of prostate cancer in black men through genetic studies.
“We really believe that black lives matter. In human genetics for cancer, the number one cancer where we think we can make progress is actually going to be in black men in prostate cancer. We’re pretty invested in that,” said Simons. “Prostate cancer is basically twice as common in black men and two times as deadly, and we’re funding research on developing a test in blood or saliva that would identify black men who have a 2-10 times higher chance of getting prostate cancer than men of European descent.”
Simons explained that the increased risk is “like in a deck of cards, based on more than one gene, but the weight of getting a bad hand of genes gives you a much higher chance of getting the disease. We’ve identified several of these genes that are not the same genes that are a part of the new genetic testing. That’s called the Polygenic Risk Score. It works in men of European descent, but those genes are much less common We think that will be very disruptive..”
As for the future, what if prostate cancer could one day be managed in much the same way as cholesterol-driven illnesses?
This could be realized with the identification of genes revealing a biochemistry that could allow for the alteration of lifestyle or development of novel therapeutics.
“What we believe is driving this process in the prostate is DNA mutations from a unique form of inflammation,” said Simons. “With this bad hand of cards, it’s like your prostate is smoking cigarettes all the time. It’s not smoking cigarettes, but it’s generating carcinogens, so you want an anti-prostate carcinogenic diet, or you want to develop drugs that are safe, that really stop or block that biochemistry. We think both those things are possible, but just like in cholesterol, we need to know every step in the chemistry.”
The COVID-19 vaccine race has injected a lot of optimism into the field of oncology, and Simons feels that there is a place for prophylaxis in this space as well.
“Messenger RNA vaccines and the protein fusion vaccines like Novavax – the platforms for COVID are very attractive for making antigen-specific, or prostate-specific vaccines if we can better understand what is going on in a man’s prostate that sort of shields the immune system from seeing the cancer in the first place,” he said. “All of that depends on our really understanding the deck of cards, and we’ve narrowed it down to 269 genes. So we’ve gone from 22 000 thousand in the human genome to 269. It’s still complicated, but it’s possible.”
