A Possible Cause of Resistance to Antiandrogen Treatment for Advanced Prostate Cancer Identified

Analysis of androgen receptor patterns also uncovers a new therapeutic target for advanced disease

A team of researchers in the USA and China led by Dr. Dean Tang at New York State’s Roswell Park Comprehensive Cancer Center has examined androgen receptor (AR) expression patterns in 89 patients with castration-resistant prostate cancer.  Dr. Tang’s team has linked the development of castration-resistant prostate cancer and treatment resistance to a lack of androgen receptor (AR) expression in prostate cancer cells.

The team has also identified a new therapeutic target for advanced prostate cancer. Results of their study appeared September 6 in the journal Nature Communications.

Further research confirmed that cells lacking AR did not respond to treatment with enzalutamide (brand name Xtandi). The researchers report new evidence that combination treatment with enzalutamide  and ABT-199 (brand name Venetoclax), a newly FDA-approved BCL-2 inhibitor, markedly inhibits experimental castrate-resistant prostate cancer. Roswell Park’s Dr. Dean Tang has initiated a phase Ib/II clinical trial based on these findings.

The new findings identify 3 distinct patterns of androgen receptor (AR) expression. AR, a key driver of prostate cancer, is a protein that binds to male hormones. As a way to overcome treatment resistance, the team investigated targeting the protein BCL-2.

Dr. Dean Tang
Dean Tang, MD PhD, Roswell Park researcher.

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Androgen-deprivation therapy before radical surgery for prostate cancer may harm a subset of patients, help others, study suggests

A study from Japan suggests that men should probably avoid androgen blockade before prostate surgery if they are above 65 or have low testosterone levels.

This round of treatment, known as neoadjuvant ADT, may be prescribed with a view to improving odds for patients who have some adverse markers.

Led by  Prof. Masatoshi Eto, the Japanese team analyzed results for 711 patients with clinically localized prostate cancer who were treated with radical prostatectomy (RP) between 2000 and 2013. Some patients underwent androgen deprivation therapy before the surgery, some did not. Continue reading “Androgen-deprivation therapy before radical surgery for prostate cancer may harm a subset of patients, help others, study suggests”

Viewing Cancer Treatment as a Game to Find Strategies That Improve Patient Outcomes

Game theory-wise treatment plans to advance the standard of care include  men with advanced prostate cancer

August 9. 2018. Game theory can be used to identify potential flaws in current cancer treatment approaches and to select new strategies to improve outcomes in patients with metastatic cancer, according to a review study published online today, August 9, in JAMA Oncology.

Authored by a mathematician, an evolutionary biologist, and clinical physicians from the Moffitt Cancer Center and Maastricht University in the Netherlands, the study challenges decades-old methods. The usual method of treating metastatic cancer involves repeatedly administering the same drug(s) until disease progression. The drugs are given according to Maximum Tolerated Dose (MTD), i.e. the highest dose of a drug or treatment that does not cause intolerable side effects. The maximum tolerated dose is decided via clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.

“Current treatments for metastatic cancers, by giving the same drug repeatedly at the maximum tolerated dose, can inadvertently increase the speed with which cancer cells can evolve effective counter measures and then regrow,” said Robert A. Gatenby, M.D., co-director of Moffitt’s Center of Excellence in Evolutionary Therapy, one of the leaders of this new line of research. Continue reading “Viewing Cancer Treatment as a Game to Find Strategies That Improve Patient Outcomes”

Nuclear Gatekeeper Could Block Undruggable Prostate Cancer Targets

Nuclear Pores
The DNA in cell nuclei is stained blue, with the nuclear pores surrounding the nuclei in yellow. Proteins that influence which genes are turned on or off must first pass through these yellow gatekeepers to access the DNA. Blocking these pores could offer a way to target undruggable molecules in cancer. Credit: Labs of Veronica Rodriguez-Bravo, and Josep Domingo-Domenech at Jefferson (Philadelphia University + Thomas Jefferson University)
The DNA in cell nuclei is stained blue, with the nuclear pores surrounding the nuclei in yellow. Proteins that influence which genes are turned on or off must first pass through these yellow gatekeepers to access the DNA. Blocking these pores could offer a way to target undruggable molecules in cancer. Credit: Labs of Veronica Rodriguez-Bravo, and Josep Domingo-Domenech at Jefferson (Philadelphia University + Thomas Jefferson University)

August 9, 2018. Certain molecular drivers of cancer growth are “undruggable” – it’s been nearly impossible to develop chemicals that would block their action and prevent cancer growth. Many of these molecules function by passing cancer-promoting information through a gate in the nucleus, where the instructions are carried out.

Now researchers at the Sidney Kimmel Cancer Center – Jefferson Health have found a way to block the nuclear gates used by these molecules, and have shown that this inhibition can halt aggressive prostate cancer in mice implanted with human tumors.

Co-led by Veronica Rodriguez-Bravo, PhD, and Josep Domingo-Domenech, MD, PhD, this research is published in Cell August 9, 2018.

Verónica Rodríguez and Josep Domingo-Domenech
Verónica Rodríguez and Josep Domingo-Domenech

“We found that a particular gatekeeper, the nuclear pore protein called POM121, traffics molecules that boost tumor aggressiveness,” Dr. Rodriguez-Bravo said. “Blocking this gatekeeper prevents several molecules from reaching their targets in the nucleus, thus decreasing tumor growth.” The researchers also showed that blocking POM121 transport helps restore chemotherapy efficacy in pre-clinical models of the disease.

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AR-V7 blood test can predict optimal treatment for advanced prostate cancer, study finds

An international collaborative study is one of the first to demonstrate that a blood test can predict how patients with advanced prostate cancer will respond to specific treatments, leading to improved survival.

Dr. Alison Allan, scientist at Lawson Health Research Institute.
Dr. Alison Allan PhD, scientist at Lawson Health Research Institute, Canada.

The study used a liquid biopsy test developed by molecular diagnostics company Epic Sciences that examines circulating tumor cells (CTCs) in blood samples from patients with advanced prostate cancer who are deciding whether to switch from hormone-targeting therapy to chemotherapy. CTCs are cancer cells that leave a tumor, enter the blood stream and invade other parts of the body, causing the spread of cancer.

The test identifies whether or not a patient’s CTCs contain a protein called AR-V7 in the cell’s nucleus. The researchers set out to determine whether the presence of this protein predicted which treatment would best prolong a patient’s life.

They found that patients who tested positive for AR-V7 responded best to taxane-based chemotherapy while those who tested negative for the protein responded best to hormone-targeting therapy with drugs called androgen-receptor signaling (ARS) inhibitors. These are the two most widely used drug classes to treat advanced prostate cancer.

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