Because of its tissue selectivity, EMP is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells.EMP was originally developed as a dual ester prodrug of an estrogen and normustine as a nitrogen mustard alkylating antineoplastic agent which, due to the affinity of the estrogen moiety for estrogen receptors, would be selectively accumulated in estrogen target tissues and hence estrogen receptor-positive tumor cells. Consequentially, it was thought that EMP would preferentially deliver the alkylating normustine moiety to these tissues, allowing for reduced cytostatic effects in healthy tissues and hence improved efficacy and tolerability. However, subsequent research found that there is very limited and slow cleavage of the normustine ester and that EMP is devoid of alkylating activity. In addition, it appears that estramustine and estromustine may be preferentially accumulated in estrogen target tissues not due to affinity for the estrogen receptors, but instead due to affinity for the distinct EMBP.Extremely high, pregnancy-like levels of estradiol may be responsible for the leukocytosis (increased white blood cell count) that is observed in individuals treated with EMP. This side effect is in contrast to most other cytotoxic agents, which instead cause myelosuppression (bone marrow suppression), leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count). Antigonadotropic effects
EMP at a dosage 280 mg/day has been found to suppress testosterone levels in men into the castrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days.
Epidemiology
ASPS is an extremely rare cancer. While sarcomas comprise about 1% of all newly diagnosed cancers, and 15% of all childhood cancers, ASPS comprises less than 1% of sarcomas. According to the American Cancer Society, about 9530 new cases of soft tissue sarcoma will be diagnosed in the USA in 2006. This predicts under 100 new cases of ASPS. Such low numbers of occurrence seriously impede the search for a cure by making it hard to gather any meaningful statistics about the disease. As a result, finding the best treatment option often involves making a lot of educated guesses. Research
The first xenograft model of ASPS (for type one) was established in mice by David Vistica at the National Cancer Institute in Frederick, MD in 2009. The same authors subsequently generated the first publicly available ASPS cell line (designated ASPS-1).An important advance involved demonstrating that the ASPL–TFE3 fusion protein (a transcription factor) enhanced expression of the receptor tyrosine kinase c-MET, making ASPS sensitive to small-molecule kinase inhibitor such as sunitinib.Current clinical trials are exploring the utility of kinase inhibitors (targeting growth factor pathways and angiogenesis); checkpoint inhibitors and cellular immunotherapies in the treatment of ASPS.Researchers at the Huntsman Cancer Institute (HCI) in Utah demonstrated that ASPS might be driven in part by lactate both being used as a fuel and driving angiogenesis.In terms of origin, it was recently demonstrated that although ASPS generally arises in muscle tissue, the cells do not express muscle markers at the mRNA level and more closely resemble mesenchymal stromal cells.