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Tall Allen · 03-13-2011, 07:06 PM

PSA, the enzymatic protein released by diseased prostate cells, has been widely used as a marker to detect prostate disease, including prostate cancer. It has long been suspected that PSA, a protease, might play some role in PC initiation and progression. Now, for the first time, I believe, there is evidence that it does.

In a set of experiments at Johns Hopkins, researchers found that:

PC cells that were genetically altered to produce less PSA had dramatically decreased growth and proliferation. They stopped acting like PC cells.
A type of PC cell that does not produce PSA was genetically altered to produce active PSA. As a result, it grew and proliferated.

Here's the reference:
http://www.ncbi.nlm.nih.gov/pubmed/21394741

Whether the PSA or the PC came first is a chicken-or-the-egg kind of question. It seems that they are mutually reinforcing. PSA also has a known anti-angiogenic effect, limiting the blood supply to the tumor and moderating its growth.

This goes a long way to explain why hormone treatments that lower PSA expression can stop disease progression, and why 5-α-reductase inhibitors (like finasteride), which reduce PSA as well, seem to play a preventative role. Lowering PSA doesn't only indicate less PC, it also may help prevent PC.

Even more exciting for us is the possibility of novel PSA-Inhibitors (perhaps combined with an anti-angiogenic compound like statins). Scientists have developed peptide-boronic acid inhibitors that can do this, as well as the antibiotic puromycin. It would be wonderful if specific PSA-inhibitors could supplant the hormone blockers with their wide-ranging systemic effects. It also opens the possibility that early stage disease can be managed or at least slowed down with PSA-inhibitors.

While we're waiting for clinical trials of PSA-inhibitors, I think every man with high PSA should be on finasteride.

- Allen

Baptista · 03-20-2011, 09:23 AM

Allen

Your thread is an interesting post about biochemistry studies on PSA. I have been following studies on Abiraterone and how it works as an inhibitor in intertumoural environments. I believe this drug will replace traditional antiandrogens such as Casodex, and that many other drugs in the pipeline will successfully conduct to new ways of treating prostate cancer.

Recently I have posted in another forum a similar approach regarding biochemistry in the fight of prostate cancer. I believe that Genomics is the way to identify the “fundamental causes” of prostate cancer and in doing so, genomics can guide researchers in the development of a new treatment most probably eradicating cancer for good.

The biologist Marion Bussemakers in 1993 discovered the PCA3 (gene) in the urine which is associated to the prostate cancer. The urine test (PCA3) makes part of the group of tests used in the diagnosis of prostate cancer, and it is said to be more accurate than our “friendly” PSA which can give false alarms from enlarged benign hyperplasia.

Genetics also play a role in the risk factors for prostate cancer as it is associated to cases of Pca running in members of the same family or in ethnic groups like Western Europeans, Asians and African Americans. Studies based on genetic principles have identified several genetic variants which are contributors to the risk of developing prostate cancer.

I read that “…There are twentyfive genetic variants that are known to increase the risk of developing prostate cancer: seven on chromosome 8 (five of those in the 8q24 region), two on each of the following chromosomes: 2, 3, 7, 11, 17 and 19 and one on each of the following chromosomes: 4, 5, 6, 10, 22 and X.
This means that if those variants are identified in one’s DNA, most probably that person is prone to develop Pca.

Genetic testing for prostate cancer already exits but companies running the “business” are few and the test is very expensive ($500) when compared to the cost of a PSA, logically, very few patients are doing this test. BBC have announced about a “low cost DNA test” to determine a person’s chances of developing certain inherited diseases. I take this as a light of hope that we may see Genetics replacing PSA which would be the impulse to studies with sound principles, and therefore, manufacture of directional drugs, identify diets, supplements and behaviors beneficial to attack the cancer.

Benlysta is an inhibitor drug resulting from a study that identified genetic variants linked to the systemic lupus disease. The cause was the biological activity of B-lymphocyte stimulators that contribute to the production of autoantibodies (antibodies that attack the body’s own healthy tissues).
Drugs to “kill” prostate cancer can be produced on the same principle, as well as it could identify foods to combat risk variants, addressing the problem at earlier stages.

All this genomic identification are based in molecular biology regarding the formation, structure, and function of DNA, RNA and proteins, as well as their roles in the transmission of genetic information. From the “Human Genome” system we know that the genetic “information” encoded in a sequence of the DNA strand, passes to molecules of RNA through a process called transcription. RNA acts as a messenger (mRNA) to pass the information to proteins through a process called translation. The message transcribed from the gene is therefore translated into a protein product that is specialized for a particular function based on the instruction stored in the gene.
Knowing the function of each gene becomes essential to the development of molecular markers such as those used in the study you refer regarding PSA. Research funds should be spent in this line of approaches which in my view are in the good direction to find a noninvasive treatment for prostate cancer.

National Cancer Institute has representative videos showing how genetic information is passed and how cancer may develop;
(http://www.cancer.gov/newscenter/benchmarks-vol1-issue1/Video ).

Wishing you a continuous success in your case.
Baptista

Tall Allen · 03-20-2011, 11:19 AM

Baptista,

I agree with you that genomics and proteomics will someday provide cures for PC and so many other diseases. And because of high-throughput techniques there are new advances literally every day. The more I learn about the subject, however, the more complex it seems to be. Genes are not the simple protein templates we once thought they were: they interact, they overlap, they are multi-functional, they include internal and external control systems, some are redundant, they vary from individual to individual, and they are changed by their environment. And that is just DNA! We used to think RNA simply transcribed genes into proteins. Now, we have so far discovered dozens of different kinds of RNA that buzz around the DNA like worker bees, changing things all the time. And then there are the proteins with all their polymorphisms and varying roles in the processes and the location of those processes. It will take the power of supercomputers to optimize genomic treatments. It is indeed exciting to be on the verge of individually-based cures.

- Allen

IADT3since2000 · 03-20-2011, 04:21 PM

Hi Allen and Baptista for this interesting discussion. I've read through Allen's post #3 but am adding some comments to Baptista's post #2. I've heard speculation about PSA as a cause or growth agent before, but I too think this may be the first solid evidence.

[QUOTE=Baptista;4710951]Allen

Your thread is an interesting post about biochemistry studies on PSA. I have been following studies on Abiraterone and how it works as an inhibitor in intertumoural environments. I believe this drug will replace traditional antiandrogens such as Casodex, and that many other drugs in the pipeline will successfully conduct to new ways of treating prostate cancer.

Abiraterone, which completed its key clinical trial with flying colors and is considered a good bet for FDA approval this year, is one of the stars of the Department of Defense Congressionally Directed Medical Research Program's (CDMRP) Prostate Cancer Research Program (PCRP) arm that I highlighted in a new thread a few days ago. I too am curious about how big a profile it will have in the kind of hormonal therapy I have been on. Part of the answer may get down to cost. Casodex is now generic and far cheaper than it used to be as bicalutamide. Lupron is due to go generic in 2013.

Quote:

Recently I have posted in another forum a similar approach regarding biochemistry in the fight of prostate cancer. I believe that Genomics is the way to identify the “fundamental causes” of prostate cancer and in doing so, genomics can guide researchers in the development of a new treatment most probably eradicating cancer for good.

The influence of genes is great, but a few years ago I learned that cancer researchers are extremely interested in another influence, the immediate environment for the genes; it's known as the "epigenome". The idea is that it often governs whether genes will be turned on ("expressed") or not. The analogy I like is a light switch: if you have a gene, you have the light switch in your makeup; but, the environment for the switch often determines whether it will be turned on or not, and much of the environment is under our control.

Quote:

The biologist Marion Bussemakers in 1993 discovered the PCA3 (gene) in the urine which is associated to the prostate cancer. The urine test (PCA3) makes part of the group of tests used in the diagnosis of prostate cancer, and it is said to be more accurate than our “friendly” PSA which can give false alarms from enlarged benign hyperplasia.

One thing I like about the PCA3 test is that it is complementary to PSA, strong where PSA is weak, and vice versa. PSA is very sensitive, meaning it is likely to be elevated, in the vast majority of cases, if significant prostate cancer is present. PCA3 is not so sensitive; it may not reach a significant level even if prostate cancer is present. On the other hand, PSA is not very "specific," meaning an elevated level often indicates something other than cancer, such as benign growth or infection. In sharp contrast, the PCA3 test is highly specific: if substantially elevated, there is a strong likelihood of prostate cancer. PSA is like a hyper alert sentry, while PCA3 is like a very careful sentry. Both have their role.

Quote:

... I take this as a light of hope that we may see Genetics replacing PSA which would be the impulse to studies with sound principles, and therefore, manufacture of directional drugs, identify diets, supplements and behaviors beneficial to attack the cancer.

I too look forward to that time, and I think it will be affordable, reliable, and common within the next few years.

Quote:

...
All this genomic identification are based in molecular biology regarding the formation, structure, and function of DNA, RNA and proteins, as well as their roles in the transmission of genetic information. From the “Human Genome” system we know that the genetic “information” encoded in a sequence of the DNA strand, passes to molecules of RNA through a process called transcription. RNA acts as a messenger (mRNA) to pass the information to proteins through a process called translation. The message transcribed from the gene is therefore translated into a protein product that is specialized for a particular function based on the instruction stored in the gene.
Knowing the function of each gene becomes essential to the development of molecular markers such as those used in the study you refer regarding PSA. Research funds should be spent in this line of approaches which in my view are in the good direction to find a noninvasive treatment for prostate cancer.

Thanks for your clear comments on transcription and translation, two very important concepts. A great deal of such research is already underway. Some of it is done under the CDMRP and can be reviewed under its published posters presented at conferences such as the IMPaCT conference in that recent thread I started, but that program is more aimed at high-risk/high-reward work that is closer to clinical application. The American Association for Cancer Research (AACR) hosts a very large annual meeting and numerous sub-conferences throughout the year. While much of the work presented at these meetings is eventually published and available via www.pubmed.gov, work that has not yet been published is availabe in abstracts of posters presented at the meetings. The AACR for years has vigorously encouraged participation by cancer survivors in its meetings, especially the annual meeting, in its Scientist↔Survivor Program. I have enjoyed this all-expenses-paid program three times as one of about forty survivors from all over the world. This is where I have learned a lot about the basics of cancer science. Also, they treat us like royalty.

Quote:

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Take care,

Jim

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