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For about 70 years, prostate cancer researchers have known that the male sex hormone testosterone, an androgen, along with androgen receptor signaling on prostate cancer cells, are linked to survival rates in prostate cancer. As a result, androgen-deprivation therapy, or ADT, which suppresses the production of these sex hormones, has been a cornerstone of prostate cancer treatment for decades.
“We’ve been really effective at blocking that hormone, that target, in prostate cancer,” said Dr. John Lee, a Fred Hutchinson Cancer Center oncologist and researcher. “But it’s not a cure, not in metastatic disease. It will make the disease regress and be controlled for a couple of years, but eventually the prostate cancer will figure out a way to keep going, independent of androgens and sometimes independent of androgen receptors.”
Are new options needed? “Absolutely,” Lee said.
“Once it reaches a phase called castration-resistant, it’s considered to be the end-stage of the disease. And while there have been a couple of treatment options that have emerged over the last decade, they only extend survival for a couple of months. We definitely need more.”
A three-year, $750,000 grant from the San Antonio, Texas-based Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation will allow Lee and Fred Hutch collaborators Drs. Pete Nelson and Roland Strong to explore that more — specifically through the use of immunotherapy.
“The human immune system is a much more potent cancer fighter than any sort of treatment we could apply,” Lee said. “If we could coax the immune system into better recognizing the cancer and eliminating the cancer cells, that would provide a lot of hope.”
Allowing cells to 'let their freak flags fly'
According to Lee, immunotherapies like checkpoint inhibitors have achieved response rates of around 20% to 30% in many different solid tumor types, but they have not worked as well in prostate cancers.
One reason, he believes, is because prostate cancers don’t have a lot of DNA mutations, or as he puts it, they have a “low mutational burden.”
“The importance of that is that the immune system has to figure out what is ‘self' and what is ‘non-self' or foreign,” he said. “Cancer develops in our body, so it’s part of us. If there are mutations, the proteins that are presented or flagged on the surface appear abnormal to the immune system.”
But with a low mutational burden, there aren’t many abnormal flags flying.
“That makes it difficult for the immune system to even act,” Lee said. “And on top of that, prostate cancers have an environment that is very inhospitable to the activity of immune cells.”
Lee and his team have come up with a potential workaround, though. Since the immune system usually recognizes cancer cells by their abnormal flags — or antigens — and prostate cancer has few mutations (making for few flags), the researchers devised a plan to force cancer’s hand.
They plan to target a protein called ERAP1, which plays a critical role in the presentation of protein fragments to the immune system. Lee and his team will use an ERAP1 inhibitor on mice with human-derived tumors to see if the prostate cancer will display abnormal fragments from proteins that are then recognized by the immune system.
“The hope is that, by inhibiting ERAP1, you’re raising the flag of these antigens that the immune system can recognize to slow down or decrease the growth of these tumors,” he said.
Lee said the first aim of the study is to use ERAP1 inhibition paired with existing immunotherapies to see if it even works. The second aim, he said, is to figure out what those abnormal flags are.
“By allowing the cells to let their freak flags fly, the immunotherapy should recognize them as abnormal and try to eliminate the cancer,” Lee said. “But we really need to figure out what flags are raised when you treat with an ERAP1 inhibitor, so we can define what the immune system is recognizing on these cancers. Our second aim is about isolating those neopeptides that are generated from the prostate cancer-associated proteins and figuring that out.”
Creating novel cellular therapies
The third aim of the study is to use the information gleaned from ERAP1 inhibition to eventually create new cellular immunotherapies for patients with treatment-resistant metastatic prostate cancer.
“If we can figure out what freak flags the cancer is showing and then figure out the other side — what T cells and receptors are identifying cancer in this way — we can generate an army of these T cells that we can infuse into patients to treat them,” Lee said, explaining that the team will use single-cell sequencing to identify the T-cell receptors.
Marty Chakoian, chair of the Patient Advocacy Committee for the Pacific Northwest Prostate Cancer SPORE to which Lee presented his proposal, said the new research could be a game changer for men with this disease.
'Immunotherapy is really important. It could be a way to treat the cancer without all the side effects of androgen deprivation therapy, ADT, which can be really serious.'
— Fred Hutch prostate cancer patient advocate Marty Chakoian
“Immunotherapy is really important,” he said. “It could be a way to treat the cancer without all the side effects of androgen deprivation therapy, ADT, which can be really serious.”
Chakoian said ADT can cause loss of bone mass, muscle tone and cognitive function, along with menopause-type symptoms like hot flashes and night sweats.
“You get presented with a long menu of horrible things,” Chakoian said. “And some of them have negative emotional impact for men, like the fact that when you’re on ADT, it makes it difficult or impossible to achieve an erection. It completely eliminates testosterone.”
Equally troubling, ADT is usually only effective for a limited number of years before it becomes castration-resistant prostate cancer. New treatments, particularly immunotherapies that don’t have the same kind of sexual side effects, are desperately needed, Chakoian said.
“It’s been challenge developing immunotherapies for solid tumor cancers,” he said. “What Dr. John Lee and his collaborators are doing is really important.”
In addition to working with patient advocates, Lee, Strong and Nelson have partnered with a UK-based biotech company, Grey Wolf Therapeutics, which has developed the ERAP1 inhibitor.
“We’ve enjoyed a nice collaboration with them over the course of a year,” Lee said. “We’ve done some pilot work and shared some data with them, and they are very interested in applying their small molecule to prostate cancer. If our studies in prostate cancer look good, it’s certainly a reality that we could think about establishing a clinical trial.”
Could it work in other cancers?
Even better, there’s a possibility that this innovative approach may lead to immunotherapies for other solid tumors.
“Over 30,000 men pass away every year in the U.S. from metastatic prostate cancer,” Lee said. “We’re hoping that these two strategies can be leveraged to develop new treatment combinations for that disease and expand the powerful reach of immunotherapies for advanced prostate cancer. And we’re also hoping that if successful, this concept can be broadly applied in the future to other cancer types.”
Chakoian said the potential to expand into additional cancers is what’s most exciting for him.
“If he can break through that conundrum and develop new therapies for prostate cancer, some of the principles that he’s come up with may be applicable to other solid tumor cancers,” Chakoian said. “That’s the part of this project that I’m excited about, finding new ways for the T cells to find the cancer cells and kill them. That’s brilliant.”
Lee, who has been at Fred Hutch for nearly five years, admits his project is “ambitious,” and he said much credit goes to the Kleberg Foundation for their financial support.
“The Foundation tends to fund high-risk, high-reward projects,” he said. “Conventional funding mechanisms tend to shy away from those type of projects unless it’s under some specific mechanism. It is so incredibly important to have funders who are willing to support research that could be risky but could also achieve significant advances in the field. Currently, the funding line for the National Institutes of Health is about 11%. I am so very grateful for this funding opportunity.”
The Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation has previously funded research by Drs. Filippo Milano and Andrew Hsieh.