Friday, July 20, 2012

PSMA as a therapeutic target for most cancers: one step closer to the clinic

As I mentioned previously, there's several papers that I want to blog about right now but I have been too busy writing grants and papers.  But as another paper goes off today, I am going to write about this really awesome work that was published a couple of weeks ago by Sam Denmeade and John Isaacs, and their collaborators.  Sam and John are at Hopkins, and have been working on targeting PSMA for a very long time - Let me digress for a minute and give some of the background - PSMA is an abbreviation for Prostate-Specific Membrane Antigen, but the term is somewhat a misnomer as it is expressed in a variety of tissues. The protein and the gene encoding it were identified in the lab of Skip Heston in 1993 --  who was at that time leading a lab at Memorial Sloan-Kettering Cancer Center.  Skip was actually looking to use a bacterial glutamate carboxypeptidase to activate methotrexate triglutamate, a prodrug (meaning once the additional glutamates are removed, the drug will be active).  I like to think of this story as a classic example as to how including the correct controls in an experiment, and being open to the unexpected, might lead to a serendipitous finding - in this case (as the story was told to me), the control cells (no bacterial glutamate carboxypeptidase added), unexpectedly died after addition of the prodrug.  The cells were LNCaP, a prostate cancer cell line that, like most prostate cancer, expresses large amounts of PSMA. Together with John Pinto and apparently over a couple of beers, Skip figured out that PSMA was a glutamate carboxypeptidase itself, and in fact it is the previously sought-after folate hydrolase that removes glutamates from dietary folates so that they can be absorbed by the small intestine.  Dean Bacich - at the time a postdoc in Skip's lab at Sloan made several types of PSMA transgenic mice - mice don't normally express PSMA in the prostate so Dean engineered the mice so that they expressed moderate levels (equivalent to humans) in the prostate epithelial cells.  These mice got what is considered the precursor to prostate cancer, PIN, suggesting that PSMA expression can cause or promote cancer, and later he showed that if the mice lived as long as humans, it would have been cancer.  David Silver and Sam Chang, both fellows at Sloan were the lead authors on papers showing the expression of PSMA on tumor-associated vasculature.  This was really exciting because almost all tumors that we looked at expressed PSMA in the endothelial cells of the vasculature, and the one non malignant tumor we looked at, which from memory was a hemangioma, did not express it -- and so the idea of targeting PSMA in tumor-associated vasculature was born.  Although he officially retired on July 1, Skip is now at the Cleveland Clinic and still working on targeting PSMA (the word retirement is not exactly in his vocabulary...but anyone who knows him won't be surprised about that).  As Bob Silverman pointed out at Skip's "transition" party, there are currently 26 clinical trials registered that target PSMA either as a therapeutic or for imaging for prostate and kidney cancer.  So back to the current work -- the major leaders of this study, Sam and John, are two of the guys whom I most respect as scientists.  It seems to me that a lot of people are in this field for all the wrong reasons -- but these guys are genuinely driven to help people -- and are truly excited by science [I'm sorry but its almost impossible to stop John from talking about his and anybody else's research - not that that's a bad thing :) - we could use a lot more people like him around here!] -- their paper, published in Science Translational Medicine, is entitled "Engineering a Prostate-Specific Membrane Antigen Activated Tumor Endothelial Cell Prodrug for Cancer Therapy".  To summarize, they took a peptide that specifically binds to PSMA, and coupled it to the toxin thapsigargin (and called it G202). There are two major differences between this and other chemotherapeutic drugs; first, it targets the tumor vasculature, meaning the cells that supply the tumor with the nutrients it needs to grow.  Secondly, the cells don't need to be dividing to be effected - most chemotherapies target some aspect of dividing cells, which is also why any other rapidly dividing cells, for example gut cells, are also targeted, leading to side-effects for the patient.  They tested the drug in mice against a number of human cancers, and it caused regression while causing very little toxicity to the animals.  The drug is now entering a phase I clinical trial.  I highly recommend reading this paper - it may seem like a logical series of successful experiments, but it is really the culmination of nearly 20 years of work done by many dedicated scientists, whom I feel honored to be acquainted with.

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