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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Screening for Prostate Cancer in African American Men – Judd Moul

Judd Moul reviews the history of the U.S. Preventative Services Task Force screening guidelines and highlights the US trends and patterns of disparities in cancer mortality among U.S. counties from 1980 to 2014. Full Video online at UroToday July 12 2018. Our transcript, August 7 2018, is from the section Moul calls “the bottom line.”

Judd Moul MD
Judd Moul MD

“There have been no randomized trials of prostate cancer screening for black men. The only 2 randomized screening trials (one in Europe, one in the USA) included very few African American men.  And one of the things that really bothers me … Why hasn’t there been … a true randomized trial focusing on African American men, to answer the question … “Is it beneficial to screen for prostate cancer in this high risk group? What is the proper age to initiate screening for African American men? Is it 40, 45, 50, or is it 55? We don’t know that, it’s only speculation. Continue reading “Screening for Prostate Cancer in African American Men – Judd Moul”

Excess Zinc in Muscles Contributes to Wasting Syndrome in Cancer

Discovery could lead to treatments for this condition, cachexia

PSA Rising August 5, 2018 (NEW YORK, NY, June 6, 2018)—About one-third of all cancer deaths are caused not by the cancer itself but by cachexia—a debilitating muscle-wasting syndrome that affects an estimated 80 percent of advanced cancer patients. Cachexia is linked to reduced tolerance for cancer therapy, poor quality of life, and accelerated death, but there are no effective treatments and its cause is still largely unknown.

A new multicenter, internal study led by researchers at Columbia University Irving Medical Center suggests that an overload of zinc in patients’ muscles may be the culprit. The findings, published online June 6 in Nature Medicine, could pave the way for the development of drugs to treat or prevent muscle wasting in advanced cancer patients. Continue reading “Excess Zinc in Muscles Contributes to Wasting Syndrome in Cancer”

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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