Abstract 485: Evidence that mifepristone, a progesterone receptor antagonist, can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV.

Abstract

The prognosis of patients with malignant glioma remains extremely poor despite surgery and improvement in radio and chemo therapies. Unfortunately few drugs cross the blood-brain barrier. Therapeutic treatment with chemotherapy agents, e.g., temozolomide, 1,3 bis (2-chloroethinyl)-1 nitrosurea carmustine wafers or tipifarnib have not significantly improved patient survival. Mifepristone has been found to provide significant palliative benefit to both mice with various types of malignancies and also humans with a wide variety of advanced cancers no longer or unresponsive to chemotherapy. The hypothesized mechanism of action is that tumor cells either directly secrete or cause gamma delta T cells in the tumor microenvironment to secrete a similar immunomodulatory protein as in normal pregnancies which inhibits natural killer (NK) cell cytotoxicity and causes a shift from thymic helper (TH)1 cytokines which stimulate cellular immune responses to TH2cytokines which evoke a humoral response. This protein is called the progesterone induced blocking factor (PIBF). The hypothesis suggests that also similar to pregnancy, progesterone or a P-like substance secreted by the tumor up-regulates PIBF response. Mifepristone has been found to down-regulate PIBF expression from human leukemia cell lines. Whether this is the precise mechanism of action or not, the progesterone receptor antagonist seems to inhibit tumor growth and provide extended and better quality of life. The objective of the present study was to determine if mifepristone may cross the blood brain barrier and provide a palliative benefit to patients with stage IV glioblastoma multiforme. A 43 year old male with a large glioblastoma multiforme grade IV malignant brain tumor arising originally from the temporal lobe with metastases to the spinal cord was told that he was no longer a candidate for anymore chemo or radiation therapy. He was advised that death should occur within 2 months. Indeed 2 months later death was considered imminent. He slept most of the day and was unable to converse. He was completely paralyzed from the neck down and his hands were in a clenched position. After 2 weeks of taking 200mg/day of mifepristone he became alert and was able to carry out intelligent conversations. He was now able to open his hand. He remained alert for 3 months, but paralysis had spread making swallowing difficult. He could not longer ingest the mifepristone. He died 2 weeks later. This case proves that mifepristone can cross the blood brain barrier and provide palliative benefits for grade IV glioblastoma multiforme. It is well tolerated with minimal or no side effects at this dosage. In view of the paucity of effective therapy for this type of cancer, mifepristone should be given consideration for treatment earlier than this extremely advanced stage. Citation Format: Jerome H. Check, Carrie Wilson, Diane Check. Evidence that mifepristone, a progesterone receptor antagonist, can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 485. doi:10.1158/1538-7445.AM2013-485

The role of progesterone and the progesterone receptor in human reproduction and cancer

“…The authors subsequently published some anecdotal reports showing significant palliative effects in patients with very advanced and highly metastatic cancers, all of which were resistant to standard therapies including colon cancer, thymic cell epithelial cell cancer, transitional cell carcinoma of the renal pelvis, leiomyosarcoma, pancreatic cancer, malignant fibrous histiocytoma and acute leukemia [125][126][127]. Recently, mifepristone was shown to cross the blood-brain barrier by demonstrating an objective clinical improvement in a male with end-stage glioblastoma multiforme [128]. In some of these aforementioned studies, there was demonstration of significant improvement on predicted length of life and marked clinical improvement [125][126][127].…”

Two controls of cell proliferation underlie cancer relapse

“…Metformin is a diabetes drug. It selectively targets CSC, and acts together with chemotherapy to block tumor growth and prolong remission in vivo (Check, et al, ). Double treatment with Metformin and doxorubicin kills both CSC and non‐stem cancer cells (Hirsch, et al, ).…”

“…Numerous developments and technologies (Gamarra-Luques, Hapon, Goyeneche, & Telleria, 2014;Takebe, et al, 2015) have been applied to determine the molecules involved in the downstream and acts together with chemotherapy to block tumor growth and prolong remission in vivo (Check, et al, 2014). Double treatment with Metformin and doxorubicin kills both CSC and non-stem cancer cells (Hirsch, et al, 2009).…”

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

“…The progesterone receptor modulator, mifepristone, has been found to improve quality of life, and extend the length of life when used as a single agent treatment in patients with a variety of advanced metastatic cancers that have progressed despite standard therapy, or were not candidates for chemo or immunotherapy, even when the tumors were devoid of the classic nuclear progesterone receptor (1)(2)(3)(4).…”

“…Based on anecdotal evidence showing considerable palliation and increased longevity when used in treating a variety of cancers, and on controlled studies in spontaneous murine cancers, the United States Food and Drug Administration (FDA) approved an investigator-initiated investigative new drug approval (IND), to treat up to 40 patients with stage IIIB or IV non-small cell lung cancer, that had progressed despite a minimum of two chemotherapy or immunotherapy regimens ("A phase II study of treatment with oral mifepristone as salvage therapy in patients with advanced or metastatic non-small cell lung cancer who have failed two or more previous chemotherapy regimens") (www.clinicaltrials.gov) (1)(2)(3)(4)(12)(13)(14). The study was approved by the Chesapeake Institutional Review Board (approval number Pr000011306).…”