Taking the Lethal out of Prostate Cancer; plus Entirely New Class of Drug Shows Promise Against Advanced Disease (video)
Prostate Cancer Foundation Young Investigator, Dr. Alumkal outlines efforts underway to end mortality from prostate cancer and presents research that c-MYC is an it gene to target in treatment-resistant prostate cancer.
Prostate Cancer Foundation Young Investigator Joshi Alumkal, MD talks about PCF-funded research that he believes will change what is now known as treatment-resistant prostate cancer (also known as castration-resistant prostate cancer) from a lethal disease into one that can be managed well as a chronic condition.
Entirely New Class of Drug Shows Promise Against Advanced Prostate Cancer
May 13, 2013 -- Dr. Alumkal recently presented data from his research into prostate cancer at the American Association for Cancer Research (AACR) meeting in Washington, D.C. this spring—research that may contribute to the transformation of lethal cases prostate cancer into a chronic condition that can be managed with therapy.
His poster title: “Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation,” might sound like Greek speak, but here’s the translation:
- Researchers know that prostate cancer is fueled by male hormones (such as testosterone) known as androgens.
- Those androgens bind to a protein known as androgen receptor (AR).
- When it is activated by binding to androgens, the AR protein becomes a sort of androgen superhighway into the cell’s nucleus where it can act as a regulator of genes, turning them on or off.
- For over 70 years, Androgen Deprivation Therapy (ADT) has been a mainstay of treating advanced prostate cancer. By lowering levels of androgens in the body, and limiting their ability to bind to the androgen receptor, prostate cancer is denied its fuel and cancer progression usually slows.
- However, eventually all patients treated with ADT fail to respond to the treatment and tumor growth returns and progresses.
- When this occurs, in most cases, AR levels are quite high, despite being starved of male androgens that activate them. Thus it seems that when resistance to ADT occurs, the AR protein receptor has found a way to worm its way into the cell’s nucleus and boss other genes around, turning them on or off--without the usually necessary step of having testosterone or another form of male androgen bind to AR.
- Think of it this way: In certain treatment-resistant prostate cancers, the AR protein somehow learns to drive itself into the cell’s nucleus, along the AR superhighway without any fuel. Testosterone is the fuel and AR is the car engine. But in this form of advanced, treatment-resistant prostate cancer, the engine has somehow learned to run without any gas.
- That means researchers must find another way to shut down the AR protein car engine so it can’t get into the cell’s nuclease and regulate other genes. Or, they need to find which genes the fuel-less treatment-resistant AR car engine turns on once it gets into the cell’s nucleus.
- It is not well understood what genes are regulated by the AR protein that has learned to drive without gas, or in science-speak, once AR is ligand independent. (It’s generally thought that AR that still relies on androgens for fuel regulates gene expression differently than AR that has become androgen-independent, or ligand-independent.)
- Dr. Alumkal’s poster shows that one gene (c-MYC)--which is a key player in progression of prostate cancer that has become ligand-independent--is a target gene of ligand-independent AR. That is: when AR learns to drive into the nucleus without testosterone gas, it drives up to c-MYC and turns that gene on, producing very high levels of the c-MYC protein.
- Alumkal and colleagues show that suppressing both AR and c-MYC gene expression reduces growth of prostate cancer cells that are resistant to ADT. Additionally, they show that upregulation of c-MYC leads to prostate cancer cell survival even when androgen levels are diminished.
- So in a sort of vicious cycle: AR learns to drive without gas, whereby it acts on cMYC gene, increasing the c-MYC protein. And that in turn may make androgen-lowering drugs, such as Lupron, less effective.
- The good news: Alumkal’s team found that a drug compound (JQ1) previously shown to suppress c-MYC, did in fact, diminish androgen-independent prostate cancer cell survival.
- JQI belongs to an entirely new class of drugs known as bromodomain inhibitors that were developed by Jay Bradner at the Dana Farber Cancer Institute. These drugs are being tested in other cancers and are set to enter Phase I clinical trials shortly. Dr. Alumkal is doing the preliminary research needed before clinical trials can be done in prostate cancer patients. His research findings presented at AACR this spring have been accepted for publication.
Bottom Line: It is possible that drug therapy may be needed to suppress c-MYC protein production in addition to therapeutics currently used to suppress AR in order to effectively manage treatment-resistant prostate cancer. Targeting c-MYC is a promising approach that may provide added benefit to patients beyond simply lowering levels of androgen in the body.
“It’s well known that both AR and c-MYC are important for prostate cancer progression,” says Alumkal, “what wasn’t known until now: how these two proteins are connected; that c-MYC is regulated by AR; and AR can turn on c-MYC even without male androgens.”
Alumkal points out that targeting c-MYC with drug therapy has been notoriously difficult. “That's why it’s very exciting to see a new class of compounds known as bromodomain inhibitors decrease prostate cancer cell survival, even when male hormones are not around, or when the gas tank is empty,” says Alumkal.
Dr. Alumkal preforms his research at Oregon Health & Science University Knight Cancer Institute where he also practices Oncology.
You can read more about Alumkal here.
And read his AACR abstract here.