Prostate cancer growth is driven by male sex hormones called androgens. And so, lowering levels of these hormones can help slow the growth of cancer.

Hormone therapy has been successful in keeping metastatic, or advanced prostate cancer, under control. Patients with metastatic prostate cancer often receive treatment with anti-hormonal therapy, which inhibits the signal sent out by testosterone that stimulates tumor growth.

But eventually, the tumor cells could become resistant to it. An international team of researchers led by the Netherlands Cancer Institute has now unveiled an "unexpected potential" solution, not designed to fight cancer but to target proteins that regulate a cell’s circadian rhythm

The discovery has been published Monday in Cancer Discovery.

Proteins that dampen the effects of anti-hormonal therapy

While anti-hormonal therapy can keep prostate cancer under control, cancer manages to progress despite ongoing treatment, as the tumor cells have become resistant. This means that the greatest challenge in treating metastatic prostate cancer isn’t to find drugs that inhibit tumor growth itself but to find drugs that can prevent resistance to hormonal therapy.

Using tissue from patients with prostate cancer who had been treated with testosterone-inhibiting drugs, scientists from the Netherlands Cancer Institute and Oncode Institute made a surprising discovery.

They discovered that an unexpected class of proteins, namely proteins that normally regulate the circadian clock, dampens the effects of anti-hormonal therapy. "Prostate cancer cells no longer have a circadian rhythm," said Wilbert Zwart, one of the research leaders, in a statement. "But these 'circadian clock' proteins acquire an entirely new function in the tumor cells upon hormonal therapy: they keep these cancer cells alive, despite treatment. This has never been seen before."

The study was based on tissue from 56 patients with high-risk prostate cancer, who had received three months of anti-hormonal therapy before their surgery. After which their tissue was examined at the DNA level. "We noticed that the genes keeping the tumor cells alive despite the treatment, were suddenly controlled by a protein that normally regulates the circadian clock," said researcher Simon Linder, who will receive his Ph.D. for his research in this study.

Now that they've figured out the tumor's escape route, the researchers will next work together with Oncode towards the development of novel strategies to block this process, ultimately increasing the efficacy of anti-hormonal therapy against prostate cancer even further.

'Has our full attention'

"Our discovery has shown us that we will need to start thinking outside the box when it comes to new drugs to treat prostate cancer and test medicines that affect the circadian clock proteins to increase sensitivity to hormonal therapy in prostate cancer," said Zwart. "Fortunately, there are already several therapies that affect circadian proteins, and those can be combined with anti-hormonal therapies. This lead, which allows for a form of drug repurposing, could save a decade of research."

This surprising discovery also creates new opportunities, because inhibition of this circadian protein was found to further increase sensitivity to anti-hormonal therapy in prostate tumor cells in the lab as well as in mice.

The results of this study might raise questions if disturbances to the body’s circadian clock could increase the risk of therapy insensitivity in prostate cancer. "There is no evidence to support this," said medical oncologist André Bergman. "The circadian rhythm in prostate tumor cells is no longer functional, and the proteins have taken on an entirely new role. This new escape route of the tumor cell has our full attention now, and follow-up research will show whether inhibition of this process can improve prostate cancer treatment.," he adds.

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for circadian clock component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.