UCLA scientists find new targets for late-stage prostate cancer

Prostate cancer, which currently affects 3 million men in the United States, is no longer a death sentence if caught early. The five-year survival rate is very high (~98%) because of effective treatments like hormone therapy, chemotherapy, surgery, and radiation—and for many men with slow progressing tumors, the wait-and-watch approach offers an alternative to treatment.

However, for those patients who have more aggressive forms of prostate cancer, where the tumors spread to other organs and tissues, the five-year survival rate is much lower (~28%) and standard therapies only work temporarily until the tumors become resistant to them. Thus there is a need for finding new therapeutic targets that would lead to more effective and longer-lasting treatments.

Kinases are ABL to cause cancer

We recently wrote a blog about prostate cancer featuring the work of a pioneer in cancer research, Dr. Owen Witte from the UCLA Broad Stem Cell Research Center. Dr. Witte is well known for his work on understanding the biology of blood cancers (leukemias) and the role of cancer stem cells. One of his key discoveries was that the cancer-causing BCR-ABL gene produces an overactive protein kinase that causes chronic myelogenous leukemia (CML).

Protein kinases are enzymes that turn on important cell processes like growth, signaling, and metabolism, but they also can be involved in causing several different forms of cancer. This has made some kinases a prime target for developing cancer drugs that block their cancer-causing activity.

New targets for late-stage prostate cancer

Recently, Dr. Witte’s interests have turned to understanding and finding new treatments for aggressive prostate cancers. He has been on the hunt for new targets, and this week, Witte and his group published a CIRM-funded study in the journal PNAS showing that a specific set of kinases are involved in causing advanced stage prostate cancer that spreads to bones.

They selected a group of 125 kinases that are known to be active in aggressive forms of human cancers. From this pool, they found that 20 of these kinases caused metastasis, or the spreading of cancer cells from the starting tumor to different areas of the body, when activated in mouse prostate cancer cells that were injected into the tail veins of mice.

To narrow down the pool further, they activated each of the 20 kinases in human prostate cancer cells and injected these cells into the tails of mice. They found that five of the kinases caused the cancer cells to leave the tail and metastasize into the bones. When they compared the activity of these five kinases in the late-stage and early-stage prostate cancer cells as well as normal prostate cells, they only saw activity of these kinases in the late-stage cancer cells.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

New treatment option?

Witte and his colleagues concluded that these five kinases can cause prostate tumor cells to spread and metastasize into bones, and that targeting kinase activity could be a new therapeutic strategy for late-stage prostate cancer patients that have exhausted normal treatment options.

In a UCLA press release, Claire Faltermeier, the study’s first author and a medical and doctoral student in Witte’s lab commented:

Our findings show that non-mutated protein kinases can drive prostate cancer bone metastasis. Now we can investigate if therapeutic targeting of these kinases can block or inhibit the growth of prostate cancer bone metastasis.

 

Dr. Witte followed up by mentioning the promise of targeting kinase activity for late-stage prostate cancer:

Cancer-causing kinase activity has been successfully targeted and inhibited before. As a result, chronic myelogenous leukemia is no longer fatal for many people. I believe we can accomplish this same result with advanced stages of prostate cancer with a fundamental understanding of the cellular nature of the disease.

UCLA scientists Owen Witte and

UCLA scientists Owen Witte and Claire Faltermeier


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Smoking out Leukemia Cells to Prevent Cancer Relapse

Ninety-five percent of all patients with chronic myeloid leukemia (CML), carry a Frankenstein-like gene, called BCR-ABL, created from an abnormal fusion of two genes normally found on two separate chromosomes. Like a water faucet without a shutoff valve, the resulting mutant protein is stuck in an “on” position and leads to uncontrolled cell division and eventually to CML as well as other blood cancers.

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An oversized bone marrow cell, typical of chronic myeloid leukemia. Credit:  Difu Wu

Gleevec, a revolutionary, targeted cancer drug that specifically blocks the BCR-ABL protein was approved by the FDA in 2001 and doubled 5-year survival rates for CML patients (31 to 59%) over that decade. Still, some patients who are responsive to the Gleevec class of drugs, become resistant to the treatment and suffer a relapse. Up until now, research studies pointed to an accumulation of additional DNA mutations as the driving force behind a rebound of the cancer cells.

But on Monday, a CIRM-funded UC San Diego team reported in PNAS that a reduction in just one protein, called MBNL3, in CML cancer cells activates a cascade of genes normally responsible for the unlimited self-renewing capacity of embryonic stem cells. Much like a researcher can reprogram a skin cell back into an embryonic like state via the induced pluripotent stem cell (iPSC) technique, this finding suggests that CML enhances its ability to spread by exploiting the same cellular reprogramming machinery.

CML is a slowly progressing cancer that initially begins with a chronic phase. At this stage, the cancerous cells, called blast cells, make up less than five percent of cells in the bone marrow. The phase usually lasts several years and is well controlled by drug treatment. A blast crisis phase follows when the blast cells make up 20 to 30% of the blood or bone marrow. At this stage, the patient’s condition deteriorates as symptoms like anemia and frequent infections worsen.

The UCSD team, led by Catriona Jamieson, director of Stem Cell Research at Moores Cancer Center, did a comparative analysis of CML patient samples and found that a reduction of MBNL3, a RNA binding protein, corresponded with CML progression from the chronic to blast phase. If you took intro biology in high school or college, you may recall that RNA acts as a messenger molecule critical to the translation of DNA’s genetic code into proteins. Some splicing and trimming of the RNA molecule occurs to prep it for this translation process. It turns out the decrease in MBNL3 in blast phase cells frees up stretches of RNA that leads to alternate splicing and, in turn, alternate forms of a given protein.

The study showed that in response to the decrease of MBNL3, an alternate form of the protein CD44, aptly named CD44 variant 3 (CD44v3), is increased in CML blast phase cells compared with chronic phase cells. Artificially over producing CD44v3 increased the activity of SOX2 and OCT4, two genes that are critical for maintaining the properties of embryonic stem cells. Genes involved with homing blood cells to the bone marrow were also upregulated.

Put together, these data suggest that this alternate RNA splicing not only helps CML blast phase cells preserve stem cell-like qualities, but it also helps sequester them in the bone marrow. Other studies have shown that the BCR-ABL protein inhibitor drugs are not effective in eradicating blast phase cells in the bone marrow, perhaps the reason behind relapse in some CML patients.

To try to smoke out these hiding blast phase cells in mouse CML studies, the team tested a combination treatment of a CD44 inhibitor along with the BCR-ABL inhibitor. While either treatment alone effectively removed the CML blast phase cells from the spleen and blood, only the combination significantly reduced survival of the cells in the bone marrow.

This tantalizing result has motivated the Jamieson team to pursue the clinical development of a CD44 blocking antibody with combination with the existing BCR-ABL inhibitors. As reported by Bradley Fikes in a San Diego Union Tribune story, the CD44 blocking antibody was not stable so more work is still needed to generate a new antibody.

But the goal remains the same as Jamieson mentions in a UCSD press release:

“If we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase [for example, BCR-ABL] inhibitors, we may be able to circumvent cancer relapse – a leading cause of cancer-related mortality.”