Prostate Cancer Foundation-funded researchers published two studies this fall that help explain why androgen deprivation therapy improves survival when given with radiation therapy; ability to repair broken DNA implicated. Findings may predict which men are most likely to benefit from combination therapy, and could lead to novel treatments for advanced prostate cancer.

“This research identifies the DNAPK enzyme as a very viable therapeutic target against prostate cancer.”
– Karen Knudsen, PhD

March 28, 2014 — A 2011 study in the New England Journal of Medicine provided definitive evidence that adding a short course of androgen deprivation therapy (ADT) to radiation therapy in men being treated for prostate cancer increased their chances of survival. “The addition of hormone therapy can cure you vs. not cure you,” says William Polkinghorn, MD, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York, and a Prostate Cancer Foundation-funded researcher. “So we knew this combination worked, but no one knew why it worked,” he adds. Now, thanks to two side-by-side studies recently published in Cancer Discovery, one by Polkinghorn and colleagues, the other led by Karen Knudsen, PhD, of Thomas Jefferson University in Philadelphia, who is also a Prostate Cancer Foundation-funded researcher, the fix is in: ADT retards the ability of cancer cells to repair DNA damage caused by the radiation therapy.

Radiation injures cells by causing severe DNA damage. Cancer cells then try to survive this insult by firing up DNA-repair mechanisms. It works like this: radiation-injured cells sense damaged DNA and turn on DNA repair pathways, involving many specialized enzymes that perform functions such as pasting broken DNA strands back together. If DNA can be repaired, the cells will go on to survive and divide. But if not, cells have embedded suicide programs that force them to die in order to avoid passing on mutations to future generations of cells. Such cell-suicide programs function to block cancer growth.

One pathway to cancer growth is when this programed cell death in response to DNA or genome damage fails to occur. Just as “survival of the fittest” is used to describe Darwin’s theory of natural selection in the evolution of species, the ability of cancer cells to cheat death when their DNA is damaged allows them to acquire even more mutations, leading to the evolution and rapid outgrowth of the most competitive cells. Understanding how cancer cells can survive DNA-damaging insults such as radiation therapy will lead to more effective treatments for cancer patients and the prevention of aggressive cancers that are highly resistant to radiotherapy and other treatments.

Prostate cancer cells are highly reliant on the androgen receptor (AR) protein for growth and survival. Blocking AR activity via androgen deprivation therapy (ADT) is a primary treatment against prostate cancer. Over time however, the cancer cells that remain even after ADT acquire new mutations, and patients will all too commonly suffer from recurrences with aggressive tumors that can grow even under androgen-depleted conditions. It is vitally important to more fully understand how prostate cancers grow despite AR depletion, in order to cure prostate cancer once and for all.

The primary roles of AR in prostate cancer are to turn on genes that promote growth and survival of cancer cells, and to produce proteins that are normally secreted by prostate cells, such as prostate specific antigen (PSA). Is has long been known that simultaneously blocking AR with ADT, while damaging DNA with radiation therapy, leads to a synergistic killing of prostate cancer cells that is powerful enough to even cure a fraction of patients. The effectiveness of this bilateral punch hinted that AR had yet-unknown functions in managing responses to DNA damage. With the goal of improving therapy for prostate cancer patients, both Polkinghorn and Knudsen set out to unravel this mystery.

Solving the mystery of why radiation therapy plus hormone therapy cures more men

Dr. Polkinghorn began his investigation by identifying the genes that are turned on or turned off in prostate cancer cell lines when AR is shut down with ADT. Surprisingly, he found that when AR was turned off, so was the expression of a large number of genes involved in repairing damaged DNA. Next, Polkinghorn studied the genes expressed in primary tumors from prostate cancer patients, and identified a set of 32 DNA-repair genes that appear to be directly regulated by AR. (He found 144 DNA-repair genes in total that have related but less direct connections to AR activity.)

Above: During a visit to the Prostate Cancer Foundation this winter, Dr. William Polkinghorn shares the details of his latest research with staff. Left: Dr. Polkinghorn (Left) with Dr. Soule, chief science officer, PCF.

His study then confirmed that AR is a necessary DNA-repair governor in prostate cancer cells—suppression of AR by ADT led to an accumulation of broken DNA, and when ADT was combined with radiation treatment, DNA damage was super-enhanced and many more cells died. Or in other words: the androgen receptor gooses the activity of genes that repair DNA. Lowering AR levels with hormone therapy, will fudge up the ability of cancer cells to fix their damaged DNA, leading to greater cancer cell death.

 

“These results indicate that a subset of prostate cancer patients may preferentially benefit from the addition of ADT to radiation therapy.”
– Dr. William Polkinghorn, MD

Based on these findings, Polkinghorn concluded that, “AR acts like a sunscreen, to protect prostate cancer cells from radiation. These results indicate that a subset of prostate cancer patients — those with more sunscreen, i.e., higher levels of AR activity and consequentially higher levels of DNA repair gene expression—may preferentially benefit from the addition of ADT to radiation therapy.”

The DNAPK enzyme and the androgen receptor protein function as partners in crime

At the 2014 AACR – PCF Advances in Prostate Cancer Research Conference, held in January in San Diego, CA, Dr. Knudsen presented findings from several studies including research from her Cancer Discovery study published alongside Polkinghorn’s, in which she followed a different route to uncover AR’s “sunscreen” function, as well as exactly how AR acts as a DNA-repair governor to protect tumor cells from radiation therapy-induced DNA damage and cell death.

Knudsen’s team found that DNA damage to prostate cancer cells caused by radiation actually activates AR, which then causes AR to turn on expression of a major DNA-repair enzyme, DNAPK. This enzyme in turn, enhances the activity of AR—a positive feedback circuit. Similar to what Polkinghorn observed, when Knudsen co-treated prostate cancer cells or mice with the disease, with radiation therapy plus ADT, the combination led to better killing of tumor cells than either treatment alone.

Importantly, Knudsen demonstrated that activation of the DNAPK enzyme by AR was a critical factor in the synergy between these two therapies. Radiation therapy causes DNAPK and AR to essentially amplify one another, to fix broken DNA, enabling prostate cancer cells to survive radiation therapy. Radiation plus ADT puts the breaks on this collusion, and is the reason why this combination is so much more effective in killing tumor cells than radiation alone. These studies also indicate that DNAPK itself may be an important therapeutic target.

Men whose tumors become resistant to ADT will eventually succumb to their disease. Knudsen made a very clinically important observation when she treated mice with ADT-resistant tumors: the combination of radiation and ADT led to super-enhanced tumor cell killing, while as expected, ADT had no effect on its own. Knudsen says that while ADT-resistant tumors no longer need AR for growth and survival, some still rely on AR to turn on DNA-repair programs in order to survive radiation therapy. Combining ADT with radiation therapy may be an effective treatment strategy for patients with late-stage ADT-resistant disease, whom in the past might have been considered poor candidates for such a regimen.

Intriguingly, in a study published in Cancer Discovery in 2012, Knudsen had discovered a similar dual-amplification paradigm between AR and another DNA-repair gene that has an infamous oncogenic role in breast and other cancers, PARP1. Polkinghorn’s study identified PARP1 as a gene that is directly turned on by AR, while Knudsen’s research found that PARP1 not only functions in DNA-repair, but promotes the activity of AR. According to Knudsen, “these dual functions of PARP1 [DNA-repair and promoting AR activity] can be leveraged to improve outcome for advanced prostate cancer.” Based on these studies, Knudsen and others have initiated a series of clinical trials with PARP-inhibitors in various combinations with AR-targeting therapies. (PARP-inhibitors on their own show positive results in early results of Phase I clinical trials underway.)

At the AACR-PCF Conference, Knudsen presented additional support for the theory that aberrant DNA-repair programs contribute heavily to the development of late-stage prostate cancer. Knudsen discovered that DNAPK levels in prostate tumors predicted the subsequent development of cancer spread, or metastasis—the higher the levels of this enzyme in tumors, the more likely men were to have their cancer recur. She also observed that as prostate cancers transition into ADT-resistant states, mutations are acquired in many genes that mediate DNA repair. These mutations enhanced expression or function of DNA repair enzymes. For example, p53, a DNA-repair gene that typically acts as a tumor suppressor and is deleted in many cancers, develops unique mutations that instead appear to spur development of ADT-resistant disease. This indicates that when AR is scrubbed from prostate cancer cells by ADT, cancer cells still can survive by evolving bypass mechanisms to maintain the integrity of their genome. And an intact genome means better cell survival.

Understanding this molecular crosstalk leads to new clinical trial designs

Scientists are constantly uncovering new functions for genes that have been studied for decades. This of course is exciting for biologists, but these discoveries are of tremendously greater importance when centered on genes critical in diseases such as cancer: new understandings invariably pave the way toward novel treatments for patients. “We need to start thinking of AR as having three functions,” says Knudsen. “One, a prostate secretory function (i.e. secretion of PSA); two, a tumor cell proliferation and survival function; and now, three, as a regulator of DNA repair and resistance to DNA damage.” Together, Polkinghorn and Knudsen’s findings indicate that this third, “sunscreen” function of AR as a DNA-repair governor, is critical to the development of drug-resistant, lethal prostate cancer.

“AR-DNA-repair crosstalk is a targetable, critical effector of disease progression,” says Knudsen. Targeting DNA-repair genes, such as PARP1, DNAPK, mutant p53 molecules, or any other of Polkinghorn’s 144 AR-associated genes, in combination with AR-inhibiting therapies and/or radiation therapy may achieve significantly greater therapeutic impact. Knudsen revealed that in addition to ongoing prostate cancer clinical trials with PARP1 inhibitors, trials with candidate agents that target DNAPK are being planned. Results from these trials are eagerly awaited.

Key Points

  • Two Prostate Cancer Foundation-funded researchers have uncovered the mystery of why adding a short course of androgen deprivation therapy (ADT) to radiation therapy improves outcomes.
  • Also, a new gene signature was discovered that may help identify which men most likely to benefit from combination radiation therapy and ADT.
  • In addition, an enzyme involved in repairing DNA damage (DNAPK) identified as a highly promising target for novel drug development. (Another DNA-repair enzyme PARP1, is currently in clinical trials against prostate cancer.)
  • The androgen receptor (AR) drives prostate cancer growth. Researchers discover “cross-talk” between AR and DNAPK enables cancer cells to better survive radiation therapy. Blocking AR with ADT interferes with this “crosstalk” during treatment with radiation therapy, resulting in increased cancer cell death.
  • Blocking the DNAPK enzyme may also boost cancer cell death, and researchers plan to investigate immediately. Blocking both AR and DNAPK may cure even more men undergoing radiation therapy.

 

Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ, Arora VK, Yen WF, Cai L, Zheng D, Carver BS, Chen Y, Watson PA, Shah NP, Fujisawa S, Goglia AG, Gopalan A, Hieronymus H, Wongvipat J, Scardino PT, Zelefsky MJ, Jasin M, Chaudhuri J, Powell SN, Sawyers CL. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013 Nov;3(11):1245-53. doi: 10.1158/2159-8290.CD-13-0172. Epub 2013 Sep 11.

Goodwin JF, Schiewer MJ, Dean JL, Schrecengost RS, de Leeuw R, Han S, Ma T, Den RB, Dicker AP, Feng FY, Knudsen KE. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 2013 Nov;3(11):1254-71. doi: 10.1158/2159-8290.CD-13-0108. Epub 2013 Sep 11.

Schiewer MJ1, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, Liu F, Planck JL, Ravindranathan P, Chinnaiyan AM, McCue P, Gomella LG, Raj GV, Dicker AP, Brody JR, Pascal JM, Centenera MM, Butler LM, Tilley WD, Feng FY, Knudsen KE. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012 Dec;2(12):1134-49. doi: 10.1158/2159-8290.CD-12-0120. Epub 2012 Sep 19.

Dr. Andrea Miyahira has a PhD in cancer immunology, and is Manager of Scientific Programs at the Prostate Cancer Foundation.