Role in Prostate Cancer
It was found that there were multiple potential start sites for PSMA as well as multiple alternative splice forms that vary in the type of membrane protein formed or having a cytosolic location and each form probably varies regarding caboxypeptidase activity given the restriction for enzymatic activity for PSMA. PSMA is strongly expressed in the human prostate, being a hundredfold greater than the expression in most other tissues. In cancer, it is upregulated in expression and has been called the second-most-upregulated gene in prostate cancer, with increase of 8- to 12-fold over the noncancerous prostate. Because of this high expression, it is being developed as a target for therapy and imaging. In human prostate cancer, the higher expressing tumors are associated with quicker time to progression and a greater percentage of patients suffering relapse. PSMA is the target of an approved imaging agent for prostate cancer, capromabpentide, PROSTASCINT. Second-generation antibodies and low-molecular-weight ligands for imaging and therapy are being developed.
In addition to the expression in the human prostate and prostate cancer, PSMA is also found to be highly expressed in tumor neovasculature but not normal vasculature of all types of solid tumors as kidney, breast, colon, etc. In terms of imaging, no non-tumor site such as normal kidney, small intestine, or CNS has been imaged using second-generation antibody imaging agents, while sites even in bone are being detected with better sensitivity than with technetium scans, and the tumors expressing PSMA in their neovasculature are also being imaged. Low-molecular-weight ligands exhibit different binding with imaging seen in the kidney of the mouse, however mouse has much higher levels of PSMA in kidney and brain than the human. In the mouse, it was only the normal kidney and prostate tumors that were imaged, and not other tissues, not even CNS suggesting the imprortance of the blood–brain barrier. In kidney, it is a subset of tubules that contain PSMA. Thus, imaging studies will have to be performed in humans with the low-molecular-weight ligands to define their potential for imaging and targeting. Still, in terms of potential toxicities, knockout animals were normal on most tests, which reduces somewhat concerns about toxicity in targeting PSMA. In the CNS, PSMA is present only in a sub-set of glial cells, again suggesting that toxin trageting would likely have minimal toxicity to the host even if the blood–brain barrier were not intact.
Read more about this topic: Glutamate Carboxypeptidase II
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