**2. Animal studies with mifepristone in cancers that are, and are not, known to Be associated with the classic P nuclear receptor**

In humans, the progesterone receptor (PR) is expressed in prostate stroma. Reduced PR expression in cancer-associated stroma can be conducive to a tumor microenvironment favorable for cancer cell invasion and tumor metastases [36]. Thus, if the presence of the PR somehow inhibits tumor invasion and metastases, treating with a PR antagonist may worsen the condition.

However, it may be that the loss of the PR receptor merely suggests a higher percentage of more aggressive cells, and thus, mifepristone, by suppressing PIBF, may inhibit prostate cancer proliferation. Indeed, gavaging mice with spontaneous prostate cancer with mifepristone (which on a weight basis was equivalent to 200 mg daily in humans) improved longevity of survival and body condition scores compared to placebo gavaged C57BL/6 mice [37].

Controlled studies were also performed in mice where there was no knowledge of the presence of the classic nuclear PR. Beneficial effect on longevity and quality of life (body conditioning score) were observed in 129 Pd/J mice with a strong predisposition for testicular cancer, in aldo-keto reductase/J mice with spontaneous lymphocytic leukemia and A/J mice with spontaneous lung cancer [37–39]. As an example, in A/J mice with spontaneous lung cancer, 67.4% treated with mifepristone survived 1 year vs. 27% of the controls [39]. Even more important, there were 66.7% of mice gavaged with the equivalent of 200 mg/day in humans with mifepristone who had no sick days (body conditioning score less than 4) vs. zero % for controls [39]. These murine carcinoma studies supported the concept that the benefit of mifepristone is not merely for cancers positive for the classic nuclear PR. If the mechanism of improvement did operate through the PIBF mechanism, the presence of the classic nuclear PR is not needed for production of PIBF expression by the tumor cells.

### **3. Case reports**

Based on cell line studies and controlled animal studies, we wanted to determine if the mifepristone could provide increased longevity and/or improved quality of life in human patients with advanced cancer. Unfortunately, though physicians generally have the right to use drugs off-label, there was a restriction for mifepristone. This was not related to risk of the drug, but related to appeasing antiabortion groups who feared that the drug could find easy use to cause abortions. Thus, to use mifepristone as an anticancer drug, one needs to obtain from the Food and Drug Administration a compassionate use investigational new drug (IND) approval to use mifepristone to treat cancer.

#### **3.1 Case 1**

The first patient we treated with oral daily mifepristone 200 mg/day was a 46-year-old woman diagnosed with a rare thymic epithelial cell cancer. Over a one-year period following initial surgery and radiotherapy more cancerous lesions developed in the lung. There was no standard chemotherapy, but she was approved for experimental octreotide. However, the cancer still progressed. After starting mifepristone 200 mg/daily, though, her lung and mediastinum lesions did not regress, they remained stable. Clinically, she was feeling much better in that she had much less shortness of breath, much less cough and, marked improvement in fatigue. This clinical improvement persisted for over 2 years. Her oncologist decided that since the lesions were stable, this could be the opportunity to attempt a "cure" by a second course of radiotherapy to the mediastinum. She developed pulmonary fibrosis from this second course of radiotherapy. According to the thymic Cancer Carcinoma Society, she had survived the second longest time of any patient with this type of cancer [40]. Now, with more clinical experience, she would have

#### *Progesterone and Glucocorticoid Receptor Modulator Mifepristone (RU-486) as Treatment… DOI: http://dx.doi.org/10.5772/intechopen.93545*

been advised against more radiotherapy and just continue the mifepristone. Most metastatic cancers will not be "cured." The end point of treatment with mifepristone should be quality of life and increased longevity. This first case of our series of anecdotal cases treated with mifepristone first started treatment in 2004. It is important to note that thyroid epithelial cell cancer is not known to be associated with the classic nuclear P receptor.
