Wednesday, October 1, 2014

Prostate Cancer Updates



We continue to see a back and forth on measuring the aggressiveness of PCa. The range is from determining a specific gene aberration to panels of multiple genes. We briefly examine two recent presentations which highlight the continuing issue of cause and prognostic tests. The discussion herein is an extension of what we have discussed previously[1].

In a recent paper the authors at Oncogene describe why the TMPRSS2:ERG translocation results in AR PCa[2].

The biological outcome of TMPRSS2:ERG chromosomal translocations in prostate cancer (PC) remains poorly understood. To address this, we compared the transcriptional effects of TMPRSS2:ERG expression in a transgenic mouse model with those of ERG knockdown in a TMPRSS2:ERG-positive PC cell line. This reveals that ERG represses the expression of a previously unreported set of androgen receptor (AR)—independent neuronal genes that are indicative of neuroendocrine (NE) cell differentiation—in addition to previously reported AR-regulated luminal genes. Cell sorting and proliferation assays performed after sustained ERG knockdown indicate that ERG drives proliferation and blocks the differentiation of prostate cells to both NE and luminal cell types.

Inhibition of ERG expression in TMPRSS2:ERG-positive PC cells through blockade of AR signaling is tracked with increased NE gene expression. We also provide evidence that these NE cells are resistant to pharmacological AR inhibition and can revert to the phenotype of parental cells upon restoration of AR/ERG signaling. Our findings highlight an ERG-regulated mechanism capable of repopulating the parent tumor through the transient generation of an anti-androgen therapy-resistant cell population, suggesting that ERG may have a direct role in preventing resistance to anti-androgen therapy.

Now as we have already stated[3]:

ERG produces a protein which is a transcriptional regulator in the nucleus. ERG is also known for its movement from its base location 21q.22.3 and binds to TMPRSS2 at 21q22.3  . This is effect a gene fusion and is frequently found in Androgen Resistant PCa. We demonstrate this change below, by showing the exons of TPMRSS2 and ERG and how they get fused producing a new gene with deleted exons but producing an oncogene product. In essence TMPRSS2 is androgen activated and the ERG gene becomes a promoter more fully activated via the TMPRSS2 association. In a sense it is not a true translocation, namely the genes have not been moved from the original chromosome like that in CML but a section is removed and they are joined.

But it is the recognition that ERG represses AR that is a significant factor. This paper opens another door in explaining why the ERG fusion can be so serious a factor in PCa. Specifically as we show below the AR loss of control results in aggressive PCa.

 Now we have also previously shown the relationship of ERG to other pathway elements as shown below.

Finally the ERG fusion can be viewed as below.
 

Now in contrast to the attention to a specific gene and a specific function we have the other extreme of mapping multiple genes onto a metric for assessing aggressive PCa. In a recent ESMO conference we have the report as seen on Businesswire[4]:
… multiple studies across different cancer types demonstrating how its genomic test Oncotype DX has led to a greater understanding of cancer at the molecular level, enabling more personalised treatment decisions.

    “The results of this study confirm that the information provided by the Oncotype DX prostate cancer test can help physicians and patients choose the most appropriate treatment approach, based on an individualized risk assessment.”

Data from the additional prostate cancer clinical validation study confirm that the Genomic Prostate Score (GPS) provided by the Oncotype DX prostate cancer test is a significant predictor of disease aggressiveness at the time of diagnosis based on assessment of biopsies from the tumour and provides information beyond currently available risk factors. In particular, this new study confirms Oncotype DX as a predictor of adverse pathology from the biopsy, as previously demonstrated in a published validation study, and demonstrates the test’s ability to predict the risk of recurrence after surgery….

The Oncotype DX prostate cancer test measures the level of expression of 17 genes across four biological pathways to predict prostate cancer aggressiveness. The test results are reported as a Genomic Prostate Score (GPS) that ranges from 0 to 100 and is combined with other clinical factors to further clarify a man’s risk prior to treatment intervention. This first-of-its-kind, multi-gene test has been validated to guide treatment decisions using the prostate needle biopsy sample taken before the prostate is removed − thereby providing the opportunity for low-risk patients to avoid invasive treatments such as radical prostatectomy or radiation.

What is unfortunate are the following:

1. Methylation effects as well as miRNA effects have not been incorporated in many of these studies. A gene may not be expressed due to the methylation of the promoter or some similar controlling region. Also we may have histone methylation again turning on or off any transcription. Translation may also be blocked by miRNAs and there are now dozens of possible candidates.

2. Which cell or cells should we test? Selecting prostate cells for testing may become a significant demand on the analysis of the grade of PCa. At one extreme we may want to find a stem cell and at the other extreme we may need to profile the tumor across all cells. Generally no one cancer cell is genomically expressive as all others. There is variability. We have examined techniques that would allow for such analysis but they are still in the R&D state. Yet having this ability to genomically profile the entire tumor mass will become mandatory. There will then be a profile of the mass. This profile must also include any transcriptional and translational influences from methylation and miRNAs.
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