Combination therapy for neoplasia treatment

#The present invention relates to the pharmaceutical treatment of neoplasia, including benign and malignant tumors.

#Prostate cancer is the most common malignancy diagnosed in males and a leading cause of mortality in western countries (American Cancer Society, 2010 (http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-026238.pdf)). Androgens and stimulation of their receptor, androgen receptor (AR), are essential for the development and function of the normal prostate gland, and the development and progression of prostate cancer (reviewed in Basu S et al., Horm Cancer. 2010 October; 1(5):223-8.; Yadav N et al., Minerva Urol Nefrol. 2012 March; 64(1):35-49). For metastatic prostate cancer, androgen deprivation therapy remains the standard treatment. Despite the fact that initially more than 90% of patients respond to androgen deprivation therapy, the clinical benefits are temporary with tumors becoming refractory and progressing to androgen-independent/castration-resistant prostate cancer (CRPC) (Rini B I et al., Curr Treat Options Oncol. 2002 October; 3(5):437-46.; Carles J et al., Clin Transl Oncol. 2012 March; 14(3):169-76). CRPC is associated with continued androgen receptor (AR) activation despite hormonal castration and/or treatment with currently available anti-androgens. The molecular mechanism of androgen stimulation of prostate cancer growth and the switch to androgen independence is not fully clear. The progression to androgen independence may be explained by changes with the androgen receptor, such as amplification, mutations, or altered activity of splice variants. Other possible mechanisms include tumor cell autonomous production of androgens, ligand-independent activation of AR by kinases like ERK or AKT (reviewed in Dutt S S et al., Future Oncol. 2009 November; 5(9):1403-13. and Attar R M et al., Clin Cancer Res. 2009 May 15; 15(10):3251-5) or that androgens may regulate prostate cancer proliferation by up-regulating autocrine loops involving peptide growth factors and their cognate receptors (De Bellis A et al., J Clin Endocrinol Metab 1996; 81:4148-54.). All these mechanisms could result in independence to endocrine androgens.

#Benign prostatic hyperplasia (BPH) can be detected in the vast majority of men as they age (Parsons J K., Curr Bladder Dysfunct Rep. 2010 December; 5(4):212-218). BPH can be defined as a non-cancerous enlargement of the prostate resulting from a proliferation of both benign stromal, and to a lesser extent, epithelial cells (Foster C S. Prostate 2000; 9:4-14.). In both of these cell types, dihydrotestosterone (DHT), a metabolite of testosterone that is 10 times more potent because it dissociates from the androgen receptor more slowly than testosterone, binds to nuclear androgen receptors resulting in the transcription of growth factors that are mitogenic to the epithelial and stromal cells. In the prostate, testosterone is converted to DHT by the enzyme 5α-reductase, type 2. In the condition of BPH, local testosterone levels can be elevated more than 100-fold above serum levels leading to an increased availability of DHT (Gat Y et al., Andrologia 2008 October; 40(5):273-81). Therapy with 5α-reductase inhibitors, such as finasteride, markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and, in many cases, BPH symptoms. Androgens are thought to be essential for BPH to occur, but do not seem to be the only cause for the condition.

#FIG. 1A-F. Inhibitory effect of IGF and AR signaling blockade on VCaP, MDA PCa 2b and DUCaP cell proliferation

#VCaP, MDA PCa 2b and DUCaP cells were treated with MDV-3100 and IGF ligand-neutralizing antibodies as single agents and in combination. FIGS. 1A-F show the inhibitory effect of the IGF mAb_1 (FIGS. 1A+1C+1E) and IGF mAb_2 (FIGS. 1B+1D+1F) antibodies and MDV-3100, alone and in combination, on the 2D proliferation of prostate cancer-derived VCaP cells (FIGS. 1A+1B), MDA PCa 2b cells (FIGS. 1C+1D) and DUCaP cells (FIGS. 1E+1F) in 10% FCS-containing growth medium. In all three cell lines, single agent treatment with both IGF antibodies and MDV-3100 resulted in inhibition of cell proliferation which could be enhanced by the combination of both agents leading to a complete inhibition of proliferation.

#FIG. 2A-G. Inhibitory effect of IGF signaling and androgen synthesis blockade on VCaP, MDA PCa 2b and DUCaP cell proliferation

#In one aspect, the present invention pertains to an insulin-like growth factor (IGF) receptor antagonist for use in the treatment of prostate neoplasia, including benign prostatic hyperplasia (BPH), prostate cancer, and particularly CRPC in combination with an androgen receptor antagonist.

#In another embodiment, the invention relates to a method of treatment of prostate neoplasia, including benign prostatic hyperplasia (BPH), prostate cancer, and particularly CRPC comprising administering a therapeutically effective amount of an IGF receptor antagonist to a patient in need thereof, and additionally administering a therapeutically effective amount of an androgen receptor antagonist to the same patient on the same day, or one, two, three, four, five, six or seven days before or after administration of the IGF receptor antagonist.

#The present invention relates to the treatment of prostate neoplasia.