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.

Continue reading “A Possible Cause of Resistance to Antiandrogen Treatment for Advanced Prostate Cancer Identified”

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.

Continue reading “Nuclear Gatekeeper Could Block Undruggable Prostate Cancer Targets”

Genomic Landscape of Metastatic Prostate Cancer Unveiled in New Study

Analysis of Prostate Tumors Reveals Clues to Cancer’s Aggressiveness
Sequencing finds genetic errors common in metastatic tumors

PSA Rising August 4 2018. A comprehensive genetic analysis of metastatic prostate cancer has, for the first time, revealed a number of major ways in which abnormal alterations of the genome propel this aggressive form of the disease.

Using genetic sequencing, scientists revealed the complete DNA makeup of more than 100 aggressive prostate tumors, pinpointing important genetic errors these deadly tumors have in common. The multicenter study lays the foundation for finding new ways to treat prostate cancer, particularly for the most aggressive forms of the disease.

Genomic hallmarks of metastatic prostate cancer
Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. Graphical Abstract, source: Cell

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An ‘Achilles Heel’ for Aggressive Prostate Cancer Found, UCSF says

Resistant Cancers Self-Destruct When Exposed to Experimental Drug

May 3, 2018. PSA Rising / UCSF / San Francisco researchers have discovered a promising new line of attack against lethal, treatment-resistant prostate cancer. Analysis of hundreds of human prostate tumors revealed that the most aggressive cancers depend on a built-in cellular stress response to put a brake on their own hot-wired physiology. Experiments in mice and with human cells showed that blocking this stress response with an experimental drug — previously shown to enhance cognition and restore memory after brain damage in rodents — causes treatment-resistant cancer cells to self-destruct while leaving normal cells unaffected.

Metastatic prostate cancer cells treated with experimental drug ISRIB.
Metastatic human prostate cancer cells transplanted into a mouse self-destruct (red) when treated with ISRIB, an experimental drug that exposes cancer cells to their full, unhealthy appetite for protein synthesis. Credit: Ruggero Lab / UCSF

The new study was published online May 2, 2018 in Science Translational Medicine. Continue reading “An ‘Achilles Heel’ for Aggressive Prostate Cancer Found, UCSF says”