New, Non-hormonal Target Identified for Advanced Prostate Cancer

[DrWrite]

Drug tested in lab studies halts cancer cells that are impervious to hormone therapy

DURHAM, N.C. – Hormone therapies for prostate cancer have greatly prolonged the lives of patients, but the drugs eventually become ineffective and the disease grows lethal.

Resistance occurs because a small percentage of prostate cancer cells are completely impervious to the therapies, and actually thrive when the drugs are used. Targeting this subset of virulent cancer cells is the focus of a study led by Duke Cancer Institute researchers.

The researchers, publishing online Dec. 4 in Science Translational Medicine, identified a cell surface receptor that is essential for the function and survival of resistant prostate cancer cells, and showed in laboratory studies that this receptor can be targeted to halt tumor growth. A clinical trial is underway using a drug originally intended for lung diseases.

“We noticed in prostate cancer there are two types of cells,” said senior author Jiaoti Huang, M.D., Ph.D., chair of Duke’s Department of Pathology. “The vast majority are luminal tumor cells, which are susceptible to hormone therapy. But a minor component of cells are neuroendocrine cells, and they are very important. They do not express the androgen receptor, so they will survive hormonal therapy.

“Our hypothesis was that this minor population, because they have the ability to survive, contribute to tumor recurrence,” Huang said. “And that’s exactly what we found.”

Huang and colleagues isolated the neuroendocrine cells from fresh human prostate cancer tissue and studied them in the lab. In early-stage prostate cancer, they constitute no more than 1% of all tumor cells, but their numbers are much larger in late-stage and metastatic disease, and they make up almost all of a particularly lethal form of prostate cancer called small cell neuroendocrine carcinoma.

Current prostate cancer treatments exclusively target the majority population of luminal tumor cells, and they do that job well. But not only do hormone therapies leave neuroendocrine tumor cells untouched, the researchers found, they actually enrich the neuroendocrine cell population.

This occurs because tumor growth is driven by a receptor on the surface of neuroendocrine cells called CXCR2, which creates the optimal environment for prostate tumor cells to proliferate and spread. CXCR2 is also expressed by immune cells and involved in inflammation, and a drug that inhibits its function is being developed for patients with chronic obstructive pulmonary disease (COPD).

Huang’s research team tested the drug, navarixin, in laboratory and animal studies, demonstrating that it killed hormone-resistant tumors in combination with enzalutamide, where enzalutamide failed on its own.

“Because CXCR2 is ubiquitously expressed by neuroendocrine cells in prostate cancer of all stages, targeting CXCR2 may particularly benefit patients whose tumors are advanced, recurrent, and resistant to currently available therapies,” Huang said.

“The real implications of our findings need to be tested in clinical settings to determine whether patients with advanced prostate cancer benefit from CXCR2 inhibition, alone or in combination with a hormone inhibitor,” he said.

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This study involved collaborations with other basic and translational researchers and physicians. In addition to Huang, study authors include Yanjing Li, Yiping He, William Butler, Lingfan Xu, Yan Chang, Kefeng Lei, Hong Zhang, Yinglu Zhou, Allen C Gao, Qingfu Zhang, Daniel G. Taylor, Donghui Cheng, Suzette Farber-Katz, Rachid Karam, Tyler Landrith, Bing Li, Sitao Wu, Vickie Hsuan, Qing Yang, Hailiang Hu, Xufeng Chen, Melissa Flowers, Shannon J. McCall, John K. Lee, Bryan A. Smith, Jung Wook Park, Andrew S. Goldstein, Owen N. Witte, Qianben Wang, Matthew B. Rettig, Andrew J. Armstrong and Qing Cheng.

The study received funding from the Prostate Cancer Foundation and the National Institutes of Health (1R01CA205001).

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[Alvin735]

Wow ... this is very exciting news .... let's all hope.

[pjoshea13]

Dr.W.

They write:

"Resistance occurs because a small percentage of prostate cancer cells are completely impervious to the therapies, and actually thrive when the drugs are used."

I believe that the following is closer to the truth:

"Nearly all prostate cancers start out as adenocarcinomas driven by the androgen receptor (AR). Neuroendocrine prostate cancer (NEPC) is a rare, AR-independent subtype with a poor prognosis and limited treatment options. Importantly, because of the widespread use of novel AR-targeting agents, the incidence of treatment-emergent (t)-NEPC is increasing in frequency." [1] (7/22/19)

At age 56, 15 years ago, I decided to put off Lupron for as long as possible because treatment-emergent adaptations (within 18-24 months) were very difficult to manage. The problem is worse today. The new drugs are very effective until resistance sets in, & then we discover that there isn't a Plan B to deal with the adaptations.

We need a supplemental drug that blocks the emergence of neuroendocrine cells, but the new study is good news.

Science Translational Medicine is an obscure journal IMO. It has an impact factor of 16.796 (the NEJM is 70.670).

From the Abstract [2]:

"Finding tumor cells and killing them too

"Treatments targeting the androgen receptor, a mainstay of prostate cancer therapy, do not usually cure the disease and eventually lose their effectiveness. A major cause of this therapeutic resistance is the presence of neuroendocrine tumor cells, which are not sensitive to androgen inhibition. Li et al. determined that neuroendocrine prostate cancer cells express a chemokine receptor called CXCR2 and showed that it can be used to help identify these cells in tumors and also plays a functional role in their resistance to treatment, making it a viable therapeutic target.

"Abstract

"Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR− neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/315...

[2] stm.sciencemag.org/content/...

[timotur]

This article describes how 2nd level ADT like Zytiga plays into the emergence of so called "treatment-emergent SCNC" (small-cell neuroendocrine cancer), clinically different from de-novo SCNC. About 20% of those treated with Zytiga develop this form of PCa.

"Just as multi-drug resistant bacteria didn’t exist before the invention of antibiotics, neither did CRPC exist before the advent of ADT. The same applies to abiraterone and/or enzalutamide resistant disease - this biological entity did not exist before the advent of these drugs. ...

One such treatment-emergent form of CRPC is small cell prostate cancer, frequently called small cell neuroendocrine tumor, or simply tSCNC. It is frequently lumped together with the rare, de novo ‘pure’ small cell prostate cancer, but is very different, and more common."

urotoday.com/center-of-exce...

[Bjry]

There are 2 clinical trials running on navarixin - NCT03473925

run by Merck and MK7123-034 : A Phase II Study of Navarixin (MK-7123) in Combination With Pembrolizumab (MK-3475) at the PeterMac clinic in Australia.

Looks really promising.

[henukit]

Thanks!

There it goes:

fiercebiotech.com/research/...

[6357axbz]

My MOs response to the article:

Many studies done on animals and in the laboratory may not pan out in the clinic (for a good reason).

But CXCR2-like targets in NE cells and CRPCa seem very reasonable because they are found in CSCs, (see link below), those very cells we know remain after remission on ADT, and which we don't know how to treat and very likely dictate the clinical course of disease.

Personally, when we manage to control the CSCs, we succeed in maintaining remissions and in enhancing the clinical efficacy of our standard and conventional treatments.

ncbi.nlm.nih.gov/pubmed/282...