Clinical benefits of progesterone receptor antagonists in cancers devoid of nuclear progesterone receptors: 25 years of experience

Background: There is evidence that malignant tumors proliferate and metastasize at least in part by secreting immunomodulatory proteins similar to the fetus. One of them is called the progesterone-induced blocking factor (PIBF). The secretion of PIBF requires activation of membrane progesterone receptors (mPRs) not nuclear receptors. Observation: Treating mice and humans with the PR modulator mifepristone may suppress the production of PIBF which is the best hypothesis to explain why patients with a variety of different very advanced cancers frequently have a considerable extension of life- (sometimes over 5 years) despite their terminal state. Interestingly, the large majority of these patients gain marked palliative benefits, e.g., pain relief and renewed energy, within a short period of time even before there is evidence of tumor regression. Generally, CT scans show partial remission or stable disease but rarely show complete remission. However, even if a given primary or metastatic lesion begins to increase in size, continued palliative benefits and life extension will usually continue. Stopping the drug for even 2 weeks will usually lead to death in a short period of time related to rapid proliferation of the cancer. One caveat, if used at an earlier stage of cancer, it seems to be best for cancers devoid of the nPR since the nPR in the minority of cancer types where it is present produces factors that inhibit cancer progression. The oral dosage of mifepristone for these studies have been mostly 200mg per day and a few patients were treated with 300mg per day. Conclusion/Relevance: The efficacy of mifepristone needs to be confirmed in larger clinical trials. Related to the lack of need for production of mPRs or nPRs in normal non-pregnant life, suppression of the PR has little or no side effects. PR antagonists, e.g., mifepristone, or perhaps even improved PR antagonist versions, have the potential to provide a major anti-cancer therapy either alone or combined with other anti-cancer therapies.