Authors: Jerome H Check, Diane Check, Brooke Neumann.
Progesterone receptor (PR) modulators, e.g. mifepristone, have provided impressive palliative benefits and increase in overall survival in patients with a variety of end-stage cancers that are devoid of the classical nuclear nPR. The fact that the presence of the nPR is usually protective and affords a better prognosis for patients with cancers e.g., breast, ovarian, and endometrial, suggests that the mediocre response to PR modulator in cancers positive for the nPR may have been related to blocking the benefits of the nPR. The target for PR modulators is likely to be the immunosuppressive protein known as the progesterone induced blocking factor (PIBF) made by membrane (m)PRs. Another immunomodulatory protein requiring mPRs is known as the progesterone membrane receptor component-1 (PGRMC-1) protein. PGRMC-1 may stimulate PIBF by directing local P production by cancer cells. However, PGRMC-1 by itself, without its positive effect on increasing PIBF, may also increase cancer aggressiveness. The most common PR modulator used for treatment has been mifepristone. Interestingly, in high dosages mifepristone down regulates PGRMC-1 but in the 200-300mg dosage used in humans, which is a low dose, it actually may upregulate PGRMC-1. Thus, for the pharmaceutical industry, if they want to develop PR modulators more effective than mifepristone, they should try to develop PR modulators that will reduce both PIBF and PGRMC-1 in the dosages used. Alternatively, they could develop a monoclonal antibody against PGRMC-1 and use that concomitantly with mifepristone or develop a monoclonal antibody against PIBF, which then would not increase PGRMC-1 or use both types of monoclonal antibody drugs at the same time. Alternatively, they could find other chemicals that inhibit PGRMC-1, e.g., Ag-205 or also develops a pure PR antagonist that does not block the glucocorticoid receptor which may allow the use of higher dosages of the PR antagonist.
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