Significant Palliative Benefits Following Therapy With Mifepristone for Advanced Treatment Resistant Small Cell Lung Cancer.

BACKGROUND/AIM: Progesterone receptor antagonists have been found to provide significant extension of life and considerable palliative benefits in a large variety of very advanced cancers. Most of these treated cancers lack the classical nuclear progesterone receptor (nPR). The hypothesized targets are membrane (m) PRs to inhibit progesterone induced blocking factor (PIBF). To date, there have been no case reports documenting the efficacy of PR antagonists for small cell lung cancer (SCLC) confirmed by pathological analysis. The case reported here demonstrates the efficacy of the single oral agent mifepristone in treating resistant SCLC. CASE REPORT: A 58-year-old man, presenting with a persistent cough, dyspnea on exertion, and marked weakness, was diagnosed with stage IV non-SCLC (NSCLC) that tested positive for the EGFR mutation. He was treated with the single agent osimertinib. When symptoms returned eight months later, along with radiographic evidence of marked cancer progression, a lung biopsy showed SCLC. He failed to respond to pembrolizumab and subsequently to atezolizumab. He was then treated with the single agent mifepristone 200 mg per day orally. He showed marked clinical improvement associated with marked radiographic improvement. Though clinically doing very well, after one year, his dominant lesion increased in size. His oncologist elected to stop mifepristone and treat with camrelizumab with anlototinib. His clinical condition deteriorated on these drugs, and he died five months later. CONCLUSION: SCLC can be added to the long list of very advanced cancers that are treatment resistant to standard therapy, but respond well to PR antagonists.

Lung Cancer - Standard Therapy and the Use of a Novel, Highly Effective, Well Tolerated, Treatment With Progesterone Receptor Modulators.

The most recent successful advances in lung cancer therapy have directly and increasingly focused on personalized tumor genetic/epigenetic/immunologic profiling, and the identification and development of novel pharmacologic agents aimed at those mutations [e.g., epidermal growth factor receptor (EGFR), Kristen rat sarcoma viral oncogene homolog (KRAS), anaplastic lymphoma kinase (ALK) and immunotherapy against programmed cell death protein 1 (PD-1) and its ligands] which have extended life and provided palliation for lung cancer-patients positive for these mutations. The objective of this study is to provide a review of the large number of drugs and their efficacy as of 2022, for lung cancer, but also introduce a novel treatment that has the potential, based on one controlled murine lung cancer study and 5 anecdotal human cases, that showed marked palliative and longevity benefits in very advanced lung cancer with no other treatment options, i.e., progesterone receptor (PR) antagonists targeting the immunosuppressive protein, the progesterone induced blocking factor (PIBF). Credibility, however, will only be provided when the efficacy can be demonstrated in a large series of lung cancer cases ideally with certain controls. Thus, the ultimate objective of the review is to interest oncologists with a large population of lung cancer patients to perform a well powered study to corroborate or refute the limited experience to date with PR antagonist therapy.

The role of progesterone and the progesterone receptor in cancer: progress in the last 5 years.

INTRODUCTION: Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR). AREAS COVERED: Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells. EXPERT OPINION: The marked clinical improvement following 200-300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.

New Insights as to Why Progesterone Receptor Modulators, such as Mifepristone, Seem to Be More Effective in Treating Cancers that Are Devoid of the Classical Nuclear Progesterone Receptor.

Mifepristone treatment for advanced cancer has demonstrated considerable improvement in both length and quality of life in patients who no longer have any other treatment options. The target is the progesterone induced blocking factor (PIBF), which helps the tumor to invade the normal tissue and proliferate and suppress cellular immunity. Most of the benefit has been observed in cancers not associated with the classical nuclear progesterone receptor (nPR). There are data showing that the presence of a nPR may be associated with a better prognosis. Membrane PRs seem to be responsible for PIBF secretion. Mifepristone, possibly fails to block another P associated protein that enables the tumor to proliferate, e.g., the progesterone receptor membrane component-1 (PGRMC-1) protein. One hypothesis is that the nPR helps to inhibit tumor production of PGRMC-1 protein. Thus, mifepristone may inhibit tumor spread by suppressing PIBF, but this may be negated by blocking the nPR, allowing PGRMC-1 levels to increase.

A Hypothetical Model Suggesting Some Possible Ways That the Progesterone Receptor May Be Involved in Cancer Proliferation.

Cancer and the fetal-placental semi-allograft share certain characteristics, e.g., rapid proliferation, the capacity to invade normal tissue, and, related to the presence of antigens foreign to the host, the need to evade immune surveillance. Many present-day methods to treat cancer use drugs that can block a key molecule that is important for one or more of these characteristics and thus reduce side effects. The ideal molecule would be one that is essential for both the survival of the fetus and malignant tumor, but not needed for normal cells. There is a potential suitable candidate, the progesterone induced blocking factor (PIBF). The parent 90 kilodalton (kDa) form seems to be required for cell-cycle regulation, required by both the fetal-placental unit and malignant tumors. The parent form may be converted to splice variants that help both the fetus and tumors escape immune surveillance, especially in the fetal and tumor microenvironment. Evidence suggests that membrane progesterone receptors are involved in PIBF production, and indeed there has been anecdotal evidence that progesterone receptor antagonists, e.g., mifepristone, can significantly improve longevity and quality of life, with few side effects.

Palliative Benefits of Oral Mifepristone for the Treatment of Metastatic Fibroblastic Osteosarcoma.

BACKGROUND/AIM: It has been hypothesized that many, or even most cancers, utilize a unique immunomodulatory protein, called the progesterone induced blocking factor (PIBF) to allow spread of the cancer. Support for this concept has been provided by cancer cell line studies showing that PIBF is produced by these cancer cells and mifepristone suppresses this protein and inhibits proliferation of these cells. Furthermore, controlled murine studies with several spontaneous different types of cancer showed a clear beneficial effect of mifepristone over placebo control. Finally, there have been a variety of anecdotal reports showing efficacy of mifepristone in providing increased length and quality of life in patients with different types of advanced cancers. CASE REPORT: Single agent mifepristone was found to provide significant palliative benefit for a 51-year-old male whose metastatic advanced fibroblastic osteosarcoma progressed despite surgery, radiotherapy, multiagent chemotherapy, and targeted therapy. CONCLUSION: Thus, osteosarcoma can be added to the list of cancers, not necessarily associated with the classic nuclear progesterone receptor, that seem to respond to progesterone receptor antagonist therapy.

Treatment With Mifepristone Allows a Patient With End-stage Pancreatic Cancer in Hospice on a Morphine Drip to Restore a Decent Quality of Life.

BACKGROUND: There is evidence that a unique immunomodulatory protein, known as the progesterone induced blocking factor (PIBF), is utilized by a large variety of cancers to escape immune surveillance. Mifepristone, a progesterone receptor antagonist/modulator, anecdotally, has been found to increase both length and quality of life in many different types of advanced cancers. CASE REPORT: Though there was one previous case of pancreatic cancer that showed a significant reduction in pain for the one month she took mifepristone before changing to an experimental drug, the case presented here provided much greater evidence that this drug can markedly improve both length and quality of life, in at least some patients, with very advanced pancreatic cancer. CONCLUSION: It is hoped that this case report will influence others to prescribe mifepristone off-label and hopefully substantiate this finding of marked palliative benefit in the majority of a larger series of patients.

Therapy Aimed to Suppress the Production of the Immunosuppressive Protein Progesterone Induced Blocking Factor (PIBF) May Provide Palliation and/or Increased Longevity for Patients With a Variety of Different Advanced Cancers - A Review.

Progesterone induced blocking factor (PIBF) is a unique protein that is not present in normal cells, but is found predominantly in rapidly growing cells of the fetal placental unit or cancer cells. There is a larger "parent" form that is a nuclear protein involved in cell to cell regulation, allowing tumor cells to proliferate and invade tissues. The parent compound is cleaved into smaller intracytoplasmic isoforms that can suppress cellular immune response, especially, but not limited to natural killer cells. The progesterone receptor antagonist mifepristone can suppress messenger RNA for PIBF, but can also suppress the intracytoplasmic protein. Treating cancer cell lines, intact animals with a variety of spontaneous cancers, and people with various cancers with mifepristone, has been found to inhibit cancer growth, and provide both palliation of symptoms and longevity possibly by suppressing this unique immunomodulatory protein.

Mifepristone Extends Both Length and Quality of Life in a Patient With Advanced Non-small Cell Lung Cancer that Has Progressed Despite Chemotherapy and a Check-point Inhibitor.

CASE REPORT: Case 1 of an investigator-initiated study using oral single agent mifepristone to halt stage IV non-small cell lung cancer whose tumor was devoid of any targeted markers has remained ECOG zero and in good health for over 3 years. Case 2, reported here, is a 68-year-old woman with stage IV non-small cell lung cancer whose tumor was positive for the programmed death ligand-1 (PD-L1) marker. Her cancer progressed despite treatment with a check-point inhibitor (nivolumab), besides 3 rounds of multi-agent chemotherapy. After 1 ½ years of treatment with single agent mifepristone, her cancer remains stable (even some tumor regression) and her quality of life is only impaired by her pre-existing chronic obstructive lung disease, not her cancer. CONCLUSION: Mifepristone therapy may provide a method to halt metastatic lung cancer positive for the PD-L1 marker when check-point inhibitors are no longer effective.

Long-term High-quality Survival with Single-agent Mifepristone Treatment Despite Advanced Cancer.

CASE REPORT: We show long-term high-quality survival following single-agent treatment with a progesterone receptor antagonist in two cases of advanced metastatic cancer. Because no biopsy was performed (patient refused) the exact type of lung cancer was not determined but the majority of oncologists who evaluated the patient thought that the rapid onset and syndrome of inappropriate anti-diuretic hormone was more consistent with small-cell lung cancer. The US Food and Drug Association granted a compassionate-use investigational new drug approval for use of single-agent 200 mg mifepristone orally/day to a moribund woman with never-treated metastatic lung cancer and a male with bilateral renal cell carcinoma who had undergone only a unilateral hemi-nephrectomy. Both had long-term high-quality survival (5 years for the patient with lung cancer with complete remission of all lung lesions, and 12 years for the male patient with kidney cancer). Neither patient had any side-effects from mifepristone therapy. CONCLUSION: These cases helped influence the US Food and Drug Association in granting an investigator-initiated investigational new drug study on advanced non-small cell lung cancer.

Mifepristone causing complete remission of rapidly advancing leukemia with measurement of progesterone-induced blocking factor.

BACKGROUND: Mifepristone has been demonstrated to cause palliation from murine and human cancer, even in cancers not known to be positive for expression of progesterone receptors. The aim of the present study was to determine if rapidly advancing chronic lymphocytic leukemia responds to mifepristone therapy, and if so, is this effect related to increased expression of the progesterone-induced blocking factor? CASE REPORT: An 81-year-old woman with chronic lymphocytic leukemia whose condition progressed to the acute rapidly progressing stage agreed to be exclusively treated orally with 200 mg mifepristone daily. RESULTS: The patient showed a dramatic improvement after a short exposure time to mifepristone. Complete remission has persisted so far for 12 months on exclusive mifepristone therapy. Her PIBF levels were normal before mifepristone therapy and did not change after treatment. CONCLUSION: Mifepristone can provide marked improvement of human leukemia even in the absence of increased serum PIBF levels.

Live delivery and implantation rates of donor oocyte recipients in their late forties are similar to younger recipients.

OBJECTIVE: To determine if there is a certain age when the uterus is somewhat less receptive to successful pregnancy despite the transfer of embryos from donated oocytes. STUDY DESIGN: We conducted a retrospective evaluation of donor oocyte recipient cycles according to specific ages. The recipients used an oral/vaginal graduated estradiol regimen followed by intramuscular and vaginal progesterone. Only recipients sharing oocytes with either the donor or another recipient were included. RESULTS: Evaluating the pregnancy rate by each year of age from 40-49 following transfer of embryos derived from donor oocytes showed no trend for lower pregnancy rates up to age 49. In fact the highest live delivery pregnancy rates (though not significant) were found at ages 47 (64.3%) and 49 (63.6%). The live delivered pregnancy rates for recipients < or = 39 was 52.5% vs. 55.6% for women > or = age 46. The live delivered pregnancy rate was 34.6% for women > or = age 50. The pregnancy and implantation rates were similar whether the source was infertile women sharing half their oocytes or compensated donors. CONCLUSION: The uterus does not seem to have a diminished capacity for implantation up to the age of 49, but it may be slightly less receptive after age 50.

Progesterone receptor antagonist therapy has therapeutic potential even in cancer restricted to males as evidenced from murine testicular and prostate cancer studies.

BACKGROUND: Treatment with the progesterone receptor antagonist mifepristone has been shown to improve the length and quality of life in mice with spontaneous leukemia, breast cancer, and lung cancer. The present study evaluated the efficacy of mifepristone therapy in murine tumors restricted to males, i.e. testicular and prostate cancer. MATERIALS AND METHODS: Eight-week-old mice with a strong predisposition to testicular or prostate cancer were gavaged with mifepristone. Olive oil was used in place of mifepristone in order to provide a control. Survival rates and body conditioning scores were compared after one year of treatment. RESULTS: Non-significant trends in survival rates were found in both types of murine cancers. Mifepristone significantly reduced the number of sick days in mice with testicular cancer. There was a significant reduction of adverse events (i.e. a tumor >1 cm or bleeding from the penis) in those with prostate cancer treated with mifepristone. CONCLUSION: These data support the hypothesis that various cancers may utilize a mechanism that is present in normal pregnancy that involves secretion of a progesterone-induced protein that blocks natural killer cell activity. The hypothesis that the cancer cells have the capacity to direct local progesterone production is supported by demonstrating the benefit of a progesterone receptor antagonist in tumors restricted to males.

Efficacy of the progesterone receptor antagonist mifepristone for palliative therapy of patients with a variety of advanced cancer types.

BACKGROUND: Mifepristone has been demonstrated to improve longevity and quality of life in mice with spontaneous murine cancer without progesterone receptors and in human colon cancer. The present study evaluated the palliative effect of mifepristone in a variety of different types of human cancer. PATIENTS AND METHODS: Mifepristone was given at 200 mg daily orally with permission from the Food and Drug Administration to people with widely metastatic human cancer no longer responsive to other chemotherapy regimens. RESULTS: Improvement in pain and energy and/or length of life was found in thymic epithelial cell carcinoma, transitional cell carcinoma of the renal pelvis, leiomyosarcoma, pancreatic carcinoma, malignant fibrous histiocytoma and another case of adenocarcinoma of the colon. CONCLUSION: Our data demonstrate a palliative role for the use of mifepristone in cancer therapy. Progesterone receptor antagonists should be given a therapeutic trial in larger controlled studies of various malignancies in humans.

Mifepristone may halt progression of extensively metastatic human adenocarcinoma of the colon - case report.

BACKGROUND: Mifepristone, a progesterone receptor antagonist has been found to improve the length and quality of life in various spontaneous murine cancer models including tumors without progesterone receptors theoretically by inhibiting an immunomodulatory protein that suppresses natural killer cell function in the tumor microenvironment. MATERIALS AND METHODS: Mifepristone 200 mg per day by mouth was given to two patients with stage 4 colon cancer with extensive metastases. RESULTS: Both patients not only survived far longer than expected but had marked improvement in their quality of life similar to mice. Though the metastatic lesions did not disappear, no new ones appeared for a long time and the ones present did not grow. The drug was extremely well tolerated. CONCLUSION: The use of progesterone receptor antagonists may present a novel immunotherapy to help fight cancer. A larger controlled study is needed.