Combination therapy could help stave off new “escape variant” of disease that arises in response to powerful treatments.

The character of recurrent prostate cancer is changing in response to more targeted treatments, according to work published in the journal Cancer Cell by scientists at Fred Hutchinson Cancer Research Center and the University of Washington. The team found that as treatments more effectively target the androgen receptor—the molecular engine that drives prostate cancer growth—prostate tumors developed a new way to resist treatment: by ditching the androgen receptor and turning on an entirely different pathway to fuel growth.

The findings support a growing movement toward combination therapy in prostate cancer treatment as a way to head off new drug-resistant forms of the disease.

The recurrent prostate cancer cells have found “a bypass mechanism that allows these cells to survive” and begin to resist treatment, said Dr. Pete Nelson, the paper’s senior author. Nelson, a prostate cancer researcher at Fred Hutch who also treats prostate cancer patients at Seattle Cancer Care Alliance, holds the Endowed Chair for Prostate Cancer Research at Fred Hutch.

The vast majority of men diagnosed with prostate cancer can expect to live long, full lives. Right now, the 10-year survival rate is 91%. But in some men, the disease rears its head again or presents in an advanced stage. Once it recurs, oncologists keep prostate cancer in check with treatments that prevent sex hormones like testosterone from feeding tumor growth.

New, more potent versions of these treatments aren't raising the rate of prostate cancer recurrence—in fact, men being treated with today's androgen receptor–targeting therapies are living longer than ever. But when tumors do resist treatment with these drugs, the rate at which they're developing the new bypass is rising, said Nelson.

In general, the androgen receptor is the engine of prostate tumors. It guzzles sex hormones known as androgens, of which testosterone is best known, to fuel prostate tumors. Today’s most effective treatments for advanced prostate cancer work by either blocking the androgen receptor from binding testosterone or depriving it of androgens.

But while each therapy can work for a while, eventually prostate cancer cells find a way to duck them, resurging as what’s known as hormone-refractory or castration-resistant prostate cancer. At that point, the vast majority of tumor cells have either reactivated the androgen receptor pathway or transformed into a different cancer type. In about 10% of men whose disease recurs after androgen-targeting therapy, it manifests as a neuroendocrine, or small-cell, tumor. For nearly all the rest, the androgen receptor runs the show.

But Nelson and first author Dr. Eric Bluemn wondered how cancer cells would respond as therapies that target the androgen receptor became ever more potent. They suspected that prostate cancer cells would find another way to survive.

“I was pretty convinced that you’re either going to cure prostate cancer if you truly, completely, block the androgen receptor—but that’s a pretty tall order— or you would see some way that the cell would figure out to get around it,” said Nelson. “We didn’t know what was likely to emerge as the bypass. We just thought there would be something.”

Nelson and Bluemn teamed up with a host of collaborators at Fred Hutch and UW, including co–first author Ilsa Coleman, a research scientist in Nelson’s lab, and co–senior author Dr. Colm Morrissey, to survey drug resistance in recurrent prostate tumors. The team looked back over 20 years at recurrent, castration-resistant prostate tumors from 85 patients who had been treated with sequential doses of different androgen receptor–targeting drugs. They discovered a previously unrecognized type of tumor, which had neither reactivated the androgen receptor pathway nor changed into a small-cell tumor. They dubbed these “double-negative” prostate cancers, or DNPCs.

From 1997–2011, prior to the advent of potent androgen receptor–targeting drugs, the team found that only about five percent of 176 tumors from 56 patients with recurrent disease were DNPCs. In the 124 tumors taken from 30 men during 2012–2016, they saw the rate of DNPCs jump to over 20%. Meanwhile, the rate of recurrent tumors that had become small-cell tumors held steady at roughly 10%. But the new escape variant was no surprise to Nelson and Bluemn. They had predicted just this type of tumor 10 years ago.

While a graduate student in Nelson’s lab, Bluemn developed laboratory models to try to predict what a non-androgen receptor, non-neuroendocrine escape route might look like. He was able to create prostate cancer cells that no longer had any need for the androgen receptor, but hadn’t turned into a neuroendocrine cell—just like the DNPCs they eventually saw in patients.

When Bluemn developed his models, he also zeroed in on what kept them ticking. It turned out that they had turned on the fibroblast growth factor (FGF) pathway, named after a growth-promoting molecule important in skin cells. In every androgen receptor–independent model Bluemn developed, suppressing the FGF pathway blocked tumor cell growth.

In Nelson and Bluemn’s study, the DNPCs from patients rely on exactly this same bypass. The good news is that there are drugs already in development for other cancers that target this pathway. This could accelerate the process of testing them against prostate cancer.

The FGF pathway is now a tantalizing target for Nelson and his collaborators. With Morrissey and Dr. Eva Corey at UW, Nelson is creating preclinical models using samples from patients’ tumors that can be used to understand how this pathway gets turned on in prostate tumors—and possibly how to block it most effectively.

It’s too soon to know whether drugs that block the FGF pathway will work in prostate cancer patients, said Nelson, but he and his team are working with potential partners in industry to try the strategy. If those drugs do prove effective, they could form the basis of a combination therapy to prevent prostate cancer cells from taking that bypass, he said.

If the drugs work, “maybe upfront or early in the disease you should co-target the androgen receptor and the FGF pathway and see if that would either kill more tumor cells or further delay recurrence,” he said.

Unlike other cancers, prostate cancer treatment generally relies on a sequential strategy—using a single drug, then switching to a new one when the first stops working, and so on. And patients with advanced prostate cancer can expect to be treated indefinitely.

But studies are beginning to show that a combination approach can help patients by extending survival. Nelson thinks this could signal a shift in how to treat advanced prostate cancer patients.

“To me, the take-home is figuring out the right upfront combinations of therapies that you could give for a short period of time, but maybe more intensely,” Nelson said.

The article is titled, "Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling."