Endometrial cancer is one of the most common invasive gynecologic cancers. Currently no therapy of recurrent or metastatic endometrial carcinoma is available to patients.
Growth of the uterine endometrium is controlled by estrogen and progesterone. Endometrial carcinogenesis is related to estrogen overexposure that is not modulated by the differentiating effects of progesterone. The role of progesterone in the glandular epithelium of the endometrium is primarily to induce cellular differentiation and to antagonize estrogen-mediated cell proliferation. The biological functions of progesterone are mediated through progesterone receptors, which function as ligand-responsive transcription factors in the nucleus.
Expression of progesterone receptor (PR) has been positively correlated with response to progestin treatment and a good prognosis (Creasman et al., Obstet Gynecol 1980; 55:363-370). The overall response rate has been reported to be 72% in patients with progesterone receptor-rich tumors but only 12% in patients with progesterone receptor-poor lesions (Ehrlich et al., Am J Obstet Gynecol 1988; 158:796-807). Unfortunately, progestin treatment leads to depletion of PRs within the target tissue (Satyaswaroop et al., Cancer Lett 1992; 62:107-114). Thus, persistent expression of functional PR is likely to be required for successful progestin treatment.
The duration of efficacy for treatment with progestins is relatively short with progression-free intervals ranging from 2.5 to 8.5 months (Jacobsen et al., J Biol Chem. 2002; 277(31): 27793-27800). PR− cancers, especially primary PR− cancers, have previously been considered not treatable by hormone therapy. Some clinical guidelines recommend treatment of endometrial cancer (EC) with progestins, but only if it is PR+. See, e.g., M. M. Baekelandt 1 & M. Castiglione, Endometrial carcinoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up, Annals of Oncology 20 (Supplement 4): iv29-iv31, iv30 (2009) (“Progestational agents . . . are active in steroid receptor-positive tumors).
One of the main treatment modalities for non-operable breast cancer is hormonal therapy using antiestrogens. However, while such therapy is effective in 40-50% of breast cancer patients with tumors that are estrogen receptor-positive (ER+), it is effective only in 7-8% of patients with estrogen receptor-negative (ER−) disease (Parl et al., Cancer 1984; 54:2237-2242; Crowe et al., Surg Gynecol Obstet. 1991; 173:273-278; Aaltomaa et al., Ann Med. 1991; 23:643-648; Fisher et al., Lancet 2004; 364:858-868).
USPTO Backgrounds
USPTO Backgrounds