Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models

Squillace,Rachel  M.; Miller,David; Wardwell,Scott  D.; Wang,Frank; Clackson,Tim; Rivera,Victor  M.

doi:10.3892/ijo.2012.1487

Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models

Authors:
- Rachel M. Squillace
- David Miller
- Scott D. Wardwell
- Frank Wang
- Tim Clackson
- Victor M. Rivera
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Affiliations: Department of Biology, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA, Department of Pharmacology, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA
Published online on: May 18, 2012 https://doi.org/10.3892/ijo.2012.1487
Pages: 425-432
Copyright: © Squillace et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Although androgen ablation therapy is the foundation of current prostate cancer treatment, most patients ultimately develop castration-resistant disease. One proposed mechanism to account for androgen receptor (AR) activity in the castrate environment is via crosstalk with other signaling pathways. Specifically, reciprocal interactions between the AKT/mTOR and AR pathways have been implicated in prostate cancer progression. Here, we used the potent inhibitor ridaforolimus to target mTOR signaling alone and in combination with AR blockade by bicalutamide to examine the effect of abrogating these signaling pathways. Ridaforolimus treatment inhibited the proliferation of all six prostate cancer cell lines examined with the greatest sensitivity associated with loss of PTEN and elevated AKT/mTOR pathway activity. Dual inhibition of the AR and mTOR signaling pathways provided further benefit with the ridaforolimus-bicalutamide combination producing synergistic antiproliferative effects in prostate cancer cells in vitro when compared with each agent alone. Pharmacodynamic analysis confirmed that combination treatment resulted in full inhibition of each of the respective pathways. Importantly, the ridaforolimus-bicalutamide combination exhibited potent antitumor activity with parallel reductions in plasma PSA levels in vivo. Taken together, ridaforolimus exhibited potent antiproliferative and antitumor activity in prostate cancer models and the addition of bicalutamide represents a potentially effective combination strategy for patient therapy.

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1	Balk SP and Knudsen KE: AR, the cell cycle, and prostate cancer. Nucl Recept Signal. 6:E0012008.PubMed/NCBI
2	Lee JT, Lehmann BD, Terrian DM, et al: Targeting prostate cancer based on signal transduction and cell cycle pathways. Cell Cycle. 7:1745–1762. 2008. View Article : Google Scholar : PubMed/NCBI
3	Chen Y, Sawyers CL and Scher HI: Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol. 8:440–448. 2008. View Article : Google Scholar : PubMed/NCBI
4	Li J and Al-Azzawi F: Mechanism of androgen receptor action. Maturitas. 63:142–148. 2009. View Article : Google Scholar
5	Arnold JT and Isaacs JT: Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell’s fault. Endocr Relat Cancer. 9:61–73. 2002.
6	Montgomery RB, Mostaghel EA, Vessella R, et al: Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68:4447–4454. 2008. View Article : Google Scholar : PubMed/NCBI
7	NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer Journal V.3. 2010.
8	Tan WW: Novel agents and targets in managing patients with metastatic prostate cancer. Cancer Control. 13:194–198. 2006.PubMed/NCBI
9	Zhu ML and Kyprianou N: Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer. 15:841–849. 2008. View Article : Google Scholar : PubMed/NCBI
10	Cinar B, De Benedetti A and Freeman MR: Post-transcriptional regulation of the androgen receptor by Mammalian target of rapamycin. Cancer Res. 65:2547–2553. 2005. View Article : Google Scholar : PubMed/NCBI
11	Xu Y, Chen SY, Ross KN and Balk SP: Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res. 66:7783–7792. 2006. View Article : Google Scholar : PubMed/NCBI
12	Wang Y, Mikhailova M, Bose S, Pan CX, deVere White RW and Ghosh PM: Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene. 27:7106–7117. 2008. View Article : Google Scholar : PubMed/NCBI
13	Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 18:1926–1945. 2004. View Article : Google Scholar
14	Bjornsti MA and Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 4:335–348. 2004. View Article : Google Scholar : PubMed/NCBI
15	Guertin DA and Sabatini DM: An expanding role for mTOR in cancer. Trends Mol Med. 11:353–361. 2005. View Article : Google Scholar : PubMed/NCBI
16	Kremer CL, Klein RR, Mendelson J, et al: Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate. 66:1203–1212. 2006. View Article : Google Scholar : PubMed/NCBI
17	Suzuki H, Freije D, Nusskern DR, et al: Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res. 58:204–209. 1998.PubMed/NCBI
18	Wang SI, Parsons R and Ittmann M: Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin Cancer Res. 4:811–815. 1998.PubMed/NCBI
19	McCall P, Witton CJ, Grimsley S, Nielsen KV and Edwards J: Is PTEN loss associated with clinical outcome measures in human prostate cancer? Br J Cancer. 99:1296–1301. 2008. View Article : Google Scholar : PubMed/NCBI
20	Neshat MS, Mellinghoff IK, Tran C, et al: Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 98:10314–10319. 2001. View Article : Google Scholar : PubMed/NCBI
21	Mills GB, Lu Y and Kohn EC: Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc Natl Acad Sci USA. 98:10031–10033. 2001. View Article : Google Scholar
22	Podsypanina K, Lee RT, Politis C, et al: An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in PTEN^+/− mice. Proc Natl Acad Sci USA. 98:10320–10325. 2001. View Article : Google Scholar : PubMed/NCBI
23	Rivera VM, Squillace RM, Miller D, et al: Ridaforolimus (AP23573, MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther. 10:1059–1071. 2011. View Article : Google Scholar
24	Colombo N, McMeekin S, Schwartz P, et al: A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer. J Clin Oncol. 25(18S): 55162007.
25	Mutter GL: Pten, a protean tumor suppressor. Am J Pathol. 158:1895–1898. 2001. View Article : Google Scholar : PubMed/NCBI
26	Mutter GL, Lin MC, Fitzgerald JT, et al: Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 92:924–930. 2000. View Article : Google Scholar : PubMed/NCBI
27	Chow LM and Baker SJ: PTEN function in normal and neoplastic growth. Cancer Lett. 241:184–196. 2006. View Article : Google Scholar : PubMed/NCBI
28	Squillace RM, Miller D, Cookson M, et al: Antitumor activity of ridaforolimus and potential cell cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther. 10:1959–1968. 2011. View Article : Google Scholar : PubMed/NCBI
29	Majumder PK, Febbo PG, Bikoff R, et al: mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 10:594–601. 2004. View Article : Google Scholar : PubMed/NCBI
30	Mousses S, Wagner U, Chen Y, et al: Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene. 20:6718–6723. 2001. View Article : Google Scholar
31	Gao N, Zhang Z, Jiang BH and Shi X: Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun. 310:1124–1132. 2003. View Article : Google Scholar : PubMed/NCBI
32	Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
33	Zhang W, Zhu J, Efferson CL, et al: Inhibition of tumor growth progression by antiandrogens and mTOR inhibitor in a Pten-deficient mouse model of prostate cancer. Cancer Res. 69:7466–7472. 2009. View Article : Google Scholar : PubMed/NCBI
34	Gray IC, Phillips SM, Lee SJ, Neoptolemos JP, Weissenbach J and Spurr NK: Loss of the chromosomal region 10q23-25 in prostate cancer. Cancer Res. 55:4800–4803. 1995.PubMed/NCBI
35	Komiya A, Suzuki H, Ueda T, et al: Allelic losses at loci on chromosome 10 are associated with metastasis and progression of human prostate cancer. Genes Chromosomes Cancer. 17:245–253. 1996. View Article : Google Scholar : PubMed/NCBI
36	Gray IC, Stewart LM, Phillips SM, et al: Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br J Cancer. 78:1296–1300. 1998. View Article : Google Scholar : PubMed/NCBI
37	McMenamin ME, Soung P, Perera S, Kaplan I, Loda M and Sellers WR: Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 59:4291–4296. 1999.PubMed/NCBI
38	Burton JL, Oakley N and Anderson JB: Recent advances in the histopathology and molecular biology of prostate cancer. BJU Int. 85:87–94. 2000. View Article : Google Scholar : PubMed/NCBI
39	Wang S, Gao J, Lei Q, et al: Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 4:209–221. 2003. View Article : Google Scholar : PubMed/NCBI
40	Gao H, Ouyang X, Banach-Petrosky WA, Shen MM and Abate-Shen C: Emergence of androgen independence at early stages of prostate cancer progression in Nkx3.1; Pten mice. Cancer Res. 66:7929–7933. 2006. View Article : Google Scholar : PubMed/NCBI
41	Chen Z, Trotman LC, Shaffer D, et al: Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 436:725–730. 2005. View Article : Google Scholar : PubMed/NCBI
42	Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C and Pandolfi PP: Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet. 27:222–224. 2001.PubMed/NCBI
43	Hellerstedt BA and Pienta KJ: The current state of hormonal therapy for prostate cancer. CA Cancer J Clin. 52:154–179. 2002. View Article : Google Scholar : PubMed/NCBI
44	Schayowitz A, Sabnis G, Njar VC and Brodie AM: Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro. Mol Cancer Ther. 7:121–132. 2008. View Article : Google Scholar : PubMed/NCBI
45	Murillo H, Huang H, Schmidt LJ, Smith DI and Tindall DJ: Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology. 142:4795–4805. 2001. View Article : Google Scholar : PubMed/NCBI
46	Chan S: Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 91:1420–1424. 2004. View Article : Google Scholar : PubMed/NCBI
47	Thalmann GN, Anezinis PE, Chang SM, et al: Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 54:2577–2581. 1994.PubMed/NCBI
48	Thalmann GN, Sikes RA, Wu TT, et al: LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate. 44:91–103. 2000. View Article : Google Scholar : PubMed/NCBI
49	Dehm SM and Tindall DJ: Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. J Biol Chem. 281:27882–27893. 2006. View Article : Google Scholar : PubMed/NCBI
50	Nash AF and Melezinek I: The role of prostate specific antigen measurement in the detection and management of prostate cancer. Endocr Relat Cancer. 7:37–51. 2000. View Article : Google Scholar : PubMed/NCBI
51	Ryan CJ, Smith A, Lal P, et al: Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression. Urology. 68:834–839. 2006. View Article : Google Scholar