New developments in prostate cancer from UCLA

Today we’re bringing you a research update from a CIRM-funded team at UCLA that’s dedicated to finding a cure for prostate cancer. The team is led by Dr. Owen Witte, the director of the UCLA Broad Stem Cell Research Center and a Howard Hughes Investigator. Dr. Witte is well known for his work in leukemia and epithelial cancer stem cells. His interests have also expanded into prostate cancer and identifying new therapeutic targets for the most aggressive types of prostate tumors.

His team’s latest efforts, which were published in Cancer Cell last week, have unearthed a possible target for late-stage neuroendocrine prostate cancer treatment. This is a particularly nasty form of prostate cancer that is resistant to standard cancer treatments and is the cause of approximately a quarter of prostate cancer related deaths.

Myc-ing prostate cells cancerous

To study how neuroendocrine prostate cancer (NEPC) develops into uncontrollable tumors, Witte and his team developed a novel human stem cell model. They knew that patients with NEPC had abnormally high levels of a protein called N-Myc in their tumors. Witte had a hunch that maybe N-Myc was the “bad guy” that was transforming normal human prostate cells into deadly, aggressive cancer cells. So the team went on an adventure to find some answers.

Normal prostate cells (left) and neuroendocrine prostate cancer cells (right). (UCLA news release)

Normal prostate cells (left) and neuroendocrine prostate cancer cells (right). (UCLA news release)

They took normal human prostate cells from healthy donors and added the MYCN gene which then produced large amounts of N-Myc protein. After receiving an N-Myc boost, the normal basal cells developed into aggressive tumor cells. When these transformed cells were transplanted into mice, they generated NEPC tumors.

Naturally, Witte didn’t stop there. He was interested in understanding what was going on at the cellular level to transform normal prostate cells into cancer. Witte explained in a UCLA press release:

“Identifying the cellular changes that happen in cancer cells is key to the development of drugs that inhibit those changes and thereby stop the progression of the disease.”

 

Finding drugs that target prostate cancer

Further experiments revealed that N-Myc was required for maintaining the deadly nature of the NEPC tumors. If N-Myc expression was disrupted, then the tumors in the mice actually shrank. After establishing N-Myc as a therapeutic target, they went on a hunt for drugs that could block its tumor amplifying activity.

They tested a drug that originally was designed to treat childhood brain cancers that also had an N-Myc related cause. The drug, CD532, acts on a protein called Aurora A kinase. The kinase physically interacts with N-Myc and is required to keep N-Myc stable and able to do its job. When mice with NEPC tumors were treated with CD532, the effects were dramatic – their tumors shrank by as much as 80%.

Witte believes that some of the cellular mechanisms behind the growth of different cancers are conserved. He explained,

Owen Witte and first author John Lee (UCLA).

Owen Witte and first author John Lee (UCLA).

“Kinase activity is known to be implicated in many types of cancers, including chronic myelogenous leukemia, which is no longer fatal for many people due to the success of Gleevec. I believe we can accomplish this same result for people with neuroendocrine prostate cancer.”

According to Witte, the next chapter in this story will be to find other drugs that can treat NEPC possibly by targeting N-Myc. Testing CD532 in clinical trials is also an option. Thus far, the drug has only been tested in preclinical experiments and hasn’t progressed into clinical trials for safety and efficacy testing in humans.


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