Nijhout, H. F. Development and evolution of adaptive polyphenisms. Evol. Dev. 5, 9–18 (2003).
Huggins, C. & Hodges, C. V. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J. Clin. 22, 232–240 (1972).
Knudsen, K. E. & Scher, H. I. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin. Cancer Res. 15, 4792–4798 (2009).
Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).
Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33–39 (2004).
Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).
de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).
Tran, C. et al. Development of a second- generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).
Qin, J. et al. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 10, 556–569 (2012).
Epstein, J. I. et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol. 38, 756–767 (2014).
Beltran, H. et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1, 487–495 (2011).
Yao, J. L. et al. Small cell carcinoma of the prostate: an immunohistochemical study. Am. J. Surg. Pathol. 30, 705–712 (2006).
Komiya, A. et al. Neuroendocrine differentiation in the progression of prostate cancer. Int. J. Urol. 16, 37–44 (2009).
Pienta, K. J. & Bradley, D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin. Cancer Res. 12, 1665–1671 (2006).
Visakorpi, T. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat. Genet. 9, 401–406 (1995).
Beltran, H. et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur. Urol. 63, 920–926 (2013).
Korpal, M. et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 3, 1030–1043 (2013).
Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).
Guo, Z. et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 69, 2305–2313 (2009).
Arora, V. K. et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013).
Isikbay, M. et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Hormones Cancer 5, 72–89 (2014).
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).
Richard, G. et al. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Mol. Med. 8, 1143–1161 (2016).
Small, E. J. et al. Clinical and genomic characterization of metastatic small cell/neuroendocrine prostate cancer (SCNC) and intermediate atypical prostate cancer (IAC): results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT) [abstract]. J. Clin. Oncol. 34, (Suppl.), 5019 (2016).
Beltran, H. et al. Challenges in recognizing treatment-related neuroendocrine prostate cancer. J. Clin. Oncol. 30, e386–e389 (2012).
Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).
Zou, M. et al. Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-16-1174 (2017).
Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Nieto, M. A. Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342, 1234850 (2013).
Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
Shook, D. & Keller, R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech. Dev. 120, 1351–1383 (2003).
Hay, E. D. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev. Dynam. 233, 706–720 (2005).
Acloque, H., Adams, M. S., Fishwick, K., Bronner-Fraser, M. & Nieto, M. A. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J. Clin. Invest. 119, 1438–1449 (2009).
Nieto, M. A. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu. Rev. Cell Dev. Biol. 27, 347–376 (2011).
Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).
Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).
Graham, T. R. et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 68, 2479–2488 (2008).
Zhang, Q. et al. Nuclear factor-kappaB-mediated transforming growth factor-beta-induced expression of vimentin is an independent predictor of biochemical recurrence after radical prostatectomy. Clin. Cancer Res. 15, 3557–3567 (2009).
Umbas, R. et al. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res. 52, 5104–5109 (1992).
Cheng, L., Nagabhushan, M., Pretlow, T. P., Amini, S. B. & Pretlow, T. G. Expression of E-cadherin in primary and metastatic prostate cancer. Am. J. Pathol. 148, 1375–1380 (1996).
Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).
Tanaka, H. et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat. Med. 16, 1414–1420 (2010).
Kong, D. et al. Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate 75, 161–174 (2015).
Cottard, F. et al. Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells. PloS ONE 8, e63466 (2013).
Sun, F. et al. Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J. Biol. Chem. 289, 1529–1539 (2014).
Njar, V. C. & Brodie, A. M. Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J. Med. Chem. 58, 2077–2087 (2015).
Kwegyir-Afful, A. K., Ramalingam, S., Purushottamachar, P., Ramamurthy, V. P. & Njar, V. C. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. Oncotarget 6, 27440–27460 (2015).
Kwegyir-Afful, A. K., Bruno, R. D., Purushottamachar, P., Murigi, F. N. & Njar, V. C. Galeterone and VNPT55 disrupt Mnk-eIF4E to inhibit prostate cancer cell migration and invasion. FEBS J. 283, 3898–3918 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02438007 (2017).
Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
Morel, A. P. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PloS ONE 3, e2888 (2008).
Nieto, M. A., Huang, R. Y., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).
Celia-Terrassa, T. et al. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J. Clin. Invest. 122, 1849–1868 (2012).
Bae, K. M. et al. Expression of pluripotent stem cell reprogramming factors by prostate tumor initiating cells. J. Urol. 183, 2045–2053 (2010).
Kong, D. et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PloS ONE 5, e12445 (2010).
Sun, Y. et al. Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res. 72, 527–536 (2012).
Klarmann, G. J. et al. Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clin. Exp. Metastasis 26, 433–446 (2009).
Mulholland, D. J. et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 72, 1878–1889 (2012).
Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).
Li, R. et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51–63 (2010).
Redmer, T. et al. E-Cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming. EMBO Rep. 12, 720–726 (2011).
Battula, V. L. et al. Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells 28, 1435–1445 (2010).
Miyamoto, D. T. et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 349, 1351–1356 (2015).
Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012).
Vega, S. et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131–1143 (2004).
Nouri, M. et al. Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance. Oncotarget 8, 18949–18967 (2017).
Lee, S. O. et al. New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor versus non-stem/progenitor cells. J. Mol. Cell Biol. 5, 14–26 (2013).
Germann, M. et al. Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. Stem Cells 30, 1076–1086 (2012).
Seiler, D. et al. Enrichment of putative prostate cancer stem cells after androgen deprivation: upregulation of pluripotency transactivators concurs with resistance to androgen deprivation in LNCaP cell lines. Prostate 73, 1378–1390 (2013).
Yuan, T. C. et al. Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocr. Relat. Cancer 13, 151–167 (2006).
Lipianskaya, J. et al. Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation. Asian J. Androl. 16, 541–544 (2014).
Hirano, D., Okada, Y., Minei, S., Takimoto, Y. & Nemoto, N. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur. Urol. 45, 586–592 (2004).
Zhang, D. et al. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat. Commun. 7, 10798 (2016).
Smith, B. A. et al. A basal stem cell signature identifies aggressive prostate cancer phenotypes. Proc. Natl Acad. Sci. USA 112, E6544–E6552 (2015).
McKeithen, D., Graham, T., Chung, L. W. & Odero-Marah, V. Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells. Prostate 70, 982–992 (2010).
Akamatsu, S. et al. The placental gene PEG10 promotes progression of neuroendocrine prostate cancer. Cell Rep. 12, 922–936 (2015).
Dardenne, E. et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 30, 563–577 (2016).
Hargrave, M. et al. Expression of the Sox11 gene in mouse embryos suggests roles in neuronal maturation and epithelio-mesenchymal induction. Dev. Dynam. 210, 79–86 (1997).
Plisov, S. Y. et al. Mesenchymal-epithelial transition in the developing metanephric kidney: gene expression study by differential display. Genesis 27, 22–31 (2000).
Bishop, J. L., Thaper, D. & Zoubeidi, A. The multifaceted roles of STAT3 signaling in the progression of prostate cancer. Cancers 6, 829–859 (2014).
Schroeder, A. et al. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res. 74, 1227–1237 (2014).
Rojas, A. et al. IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR. Oncogene 30, 2345–2355 (2011).
Uysal-Onganer, P. et al. Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells. Mol. Cancer 9, 55 (2010).
Chang, P. C. et al. Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. PloS ONE 9, e88556 (2014).
Shiota, M. et al. Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res. 73, 3109–3119 (2013).
Nakashima, J. et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin. Cancer Res. 6, 2702–2706 (2000).
Rajan, P. et al. Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy. Eur. Urol. 66, 32–39 (2014).
Li, X. et al. Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis. Oncogene 27, 7118–7130 (2008).
Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 18, 1359–1368 (2012).
Bisson, I. & Prowse, D. M. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 19, 683–697 (2009).
Yu, X., Wang, Y., DeGraff, D. J., Wills, M. L. & Matusik, R. J. Wnt/beta-catenin activation promotes prostate tumor progression in a mouse model. Oncogene 30, 1868–1879 (2011).
Lee, E. et al. Inhibition of androgen receptor and beta-catenin activity in prostate cancer. Proc. Natl Acad. Sci. USA 110, 15710–15715 (2013).
Hao, J., Li, T. G., Qi, X., Zhao, D. F. & Zhao, G. Q. WNT/beta-catenin pathway up-regulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells. Dev. Biol. 290, 81–91 (2006).
Carstens, J. L. et al. FGFR1-WNT-TGF-beta signaling in prostate cancer mouse models recapitulates human reactive stroma. Cancer Res. 74, 609–620 (2014).
Gujral, T. S. et al. A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell 159, 844–856 (2014).
Aruffo, A., Stamenkovic, I., Melnick, M., Underhill, C. B. & Seed, B. CD44 is the principal cell surface receptor for hyaluronate. Cell 61, 1303–1313 (1990).
Shang, Z. et al. A switch from CD44(+) cell to EMT cell drives the metastasis of prostate cancer. Oncotarget 6, 1202–1216 (2015).
Marin-Aguilera, M. et al. Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol. Cancer Ther. 13, 1270–1284 (2014).
Deep, G. et al. SNAI1 is critical for the aggressiveness of prostate cancer cells with low E-cadherin. Mol. Cancer 13, 37 (2014).
Palapattu, G. S. et al. Selective expression of CD44, a putative prostate cancer stem cell marker, in neuroendocrine tumor cells of human prostate cancer. Prostate 69, 787–798 (2009).
Salvatori, L. et al. Cell-to-cell signaling influences the fate of prostate cancer stem cells and their potential to generate more aggressive tumors. PloS ONE 7, e31467 (2012).
Sotomayor, P., Godoy, A., Smith, G. J. & Huss, W. J. Oct4A is expressed by a subpopulation of prostate neuroendocrine cells. Prostate 69, 401–410 (2009).
Beltran, H. et al. The initial detection and partial characterization of circulating tumor cells in neuroendocrine prostate cancer. Clin. Cancer Res. 22, 1510–1519 (2016).
Tan, H. L. et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin. Cancer Res. 20, 890–903 (2014).
Varlakhanova, N. V. et al. myc maintains embryonic stem cell pluripotency and self-renewal. Differentiation 80, 9–19 (2010).
Wey, A. & Knoepfler, P. S. c-Myc and N-myc promote active stem cell metabolism and cycling as architects of the developing brain. Oncotarget 1, 120–130 (2010).
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 26, 101–106 (2008).
Lee, J. K. et al. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. Cancer Cell 29, 536–547 (2016).
Zhou, Z. et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 66, 7889–7898 (2006).
Greenberg, N. M. et al. Prostate cancer in a transgenic mouse. Proc. Natl Acad. Sci. USA 92, 3439–3443 (1995).
Masumori, N. et al. A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential. Cancer Res. 61, 2239–2249 (2001).
Kawamura, T. et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140–1144 (2009).
Sarkar, A. & Hochedlinger, K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell 12, 15–30 (2013).
Ferone, G. et al. SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell 30, 519–532 (2016).
Murai, F. et al. EZH2 promotes progression of small cell lung cancer by suppressing the TGF-beta-Smad-ASCL1 pathway. Cell Discov. 1, 15026 (2015).
Lin, D. et al. High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res. 74, 1272–1283 (2014).
Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).
Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).
Clermont, P. L. et al. Polycomb-mediated silencing in neuroendocrine prostate cancer. Clin. Epigenet. 7, 40 (2015).
Lapuk, A. V. et al. From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. J. Pathol. 227, 286–297 (2012).
Svensson, C. et al. REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer. Nucleic Acids Res. 42, 999–1015 (2014).
Schoenherr, C. J. & Anderson, D. J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360–1363 (1995).
Ballas, N., Grunseich, C., Lu, D. D., Speh, J. C. & Mandel, G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005).
Li, Y. et al. SRRM4 drives neuroendocrine transdifferentiation of prostate adenocarcinoma under androgen receptor pathway inhibition. Eur. Urol. 71, 68–78 (2017).
Raj, B. et al. A global regulatory mechanism for activating an exon network required for neurogenesis. Mol. Cell 56, 90–103 (2014).
Zhang, X. et al. SRRM4 expression and the loss of REST activity may promote the emergence of the neuroendocrine phenotype in castration-resistant prostate cancer. Clin. Cancer Res. 21, 4698–4708 (2015).
Bishop, J. L. et al. The master neural transcription factor BRN2 is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer. Cancer Discov. 7, 54–71 (2017).
Ishii, J. et al. POU domain transcription factor BRN2 is crucial for expression of ASCL1, ND1 and neuroendocrine marker molecules and cell growth in small cell lung cancer. Pathol. Int. 63, 158–168 (2013).
Sakaeda, M. et al. Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer. Lab. Invest. 93, 408–421 (2013).
Tian, C. et al. Selective generation of dopaminergic precursors from mouse fibroblasts by direct lineage conversion. Sci. Rep. 5, 12622 (2015).
Domanskyi, A., Alter, H., Vogt, M. A., Gass, P. & Vinnikov, I. A. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance. Front. Cell. Neurosci. 8, 275 (2014).
Chiaverotti, T. et al. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am. J. Pathol. 172, 236–246 (2008).
Mirosevich, J. et al. Expression and role of Foxa proteins in prostate cancer. Prostate 66, 1013–1028 (2006).
Qi, J. et al. Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell 18, 23–38 (2010).
Chen, W. J. et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat. Commun. 5, 3472 (2014).
Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).
Lu, T. et al. Targeting androgen receptor to suppress macrophage-induced EMT and benign prostatic hyperplasia (BPH) development. Mol. Endocrinol. 26, 1707–1715 (2012).
Lau, E. Y. et al. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling. Cell Rep. 15, 1175–1189 (2016).
Ma, Y. et al. Prostate cancer cell lines under hypoxia exhibit greater stem-like properties. PloS ONE 6, e29170 (2011).
Tan, Y. et al. Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression. Nat. Commun. 5, 4619 (2014).
Doldi, V. et al. Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation. Oncotarget 6, 31441–31460 (2015).
Lee, G. T. et al. Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. Prostate 71, 1525–1537 (2011).
Li, M. et al. Hypoxia inducible factor-1alpha-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells. Oncol. Rep. 36, 521–527 (2016).
Smith, P. C. & Keller, E. T. Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice. Prostate 48, 47–53 (2001).
Wallner, L. et al. Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. Cancer Res. 66, 3087–3095 (2006).
Dorff, T. B. et al. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin. Cancer Res. 16, 3028–3034 (2010).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT00433446 (2013).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT00401765 (2014).
Hudes, G. et al. A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. Invest. Drugs 31, 669–676 (2013).
Tang, Y. et al. Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia 13, 108–119 (2011).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01949519 (2018).
van den Hoogen, C. et al. High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 70, 5163–5173 (2010).
Liu, P. et al. Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells. Br. J. Cancer 109, 1876–1885 (2013).
Nechushtan, H. et al. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist 20, 366–367 (2015).
Liu, X. et al. Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells. Oncotarget 7, 58516–58530 (2016).
Triscott, J. et al. Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. Oncotarget 3, 1112–1123 (2012).
Ketola, K., Kallioniemi, O. & Iljin, K. Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells. PloS ONE 7, e51470 (2012).
Safi, R. et al. Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 74, 5819–5831 (2014).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02963051 (2017).
Otto, T. et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15, 67–78 (2009).
Meulenbeld, H. J. et al. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int. 111, 44–52 (2013).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT00766324 (2014).
Richards, M. W. et al. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. Proc. Natl Acad. Sci. USA 113, 13726–13731 (2016).
Gustafson, W. C. et al. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26, 414–427 (2014).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/study/NCT01799278 (2017).
Puissant, A. et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 3, 308–323 (2013).
Wyce, A. et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4, 2419–2429 (2013).
Asangani, I. A. et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510, 278–282 (2014).
Rickman, D. S., Beltran, H., Demichelis, F. & Rubin, M. A. Biology and evolution of poorly differentiated neuroendocrine tumors. Nat. Med. 23, 1–10 (2017).
Rudin, C. M. et al. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC) [abstract]. J. Clin. Oncol. 34 (Suppl.), LBA8505 (2016).
Puca, L. et al. Rovalpituzumab tesirine (Rova-T) as a therapeutic agent for Neuroendocrine Prostate Cancer (NEPC) [abstract]. J. Clin. Oncol. 35 (Suppl.), 5029 (2017).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02709889 (2017).
Antonia, S. J. et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 17, 883–895 (2016).
Graff, J. N. et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 7, 52810–52817 (2016).
Warrell, R. P. Jr. et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N. Engl. J. Med. 324, 1385–1393 (1991).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02395601 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02875548 (2018).
Mantovani, F., Walerych, D. & Sal, G. D. Targeting mutant p53 in cancer: a long road to precision therapy. FEBS J. 284, 837–850 (2017).
Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).
Helpap, B., Kollermann, J. & Oehler, U. Neuroendocrine differentiation in prostatic carcinomas: histogenesis, biology, clinical relevance, and future therapeutical perspectives. Urol. Intern. 62, 133–138 (1999).
Nadal, R., Schweizer, M., Kryvenko, O. N., Epstein, J. I. & Eisenberger, M. A. Small cell carcinoma of the prostate. Nat. Rev. Urol. 11, 213–219 (2014).
Aparicio, A., Logothetis, C. J. & Maity, S. N. Understanding the lethal variant of prostate cancer: power of examining extremes. Cancer Discov. 1, 466–468 (2011).
Wang, W. & Epstein, J. I. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am. J. Surg. Pathol. 32, 65–71 (2008).
Beltran, H. et al. Aggressive variants of castration-resistant prostate cancer. Clin. Cancer Res. 20, 2846–2850 (2014).
Guo, C. C. et al. TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate. Hum. Pathol. 42, 11–17 (2011).
Wang, H. T. et al. Neuroendocrine Prostate Cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis. J. Clin. Oncol. 32, 3383–3390 (2014).
Aparicio, A. M. et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin. Cancer Res. 19, 3621–3630 (2013).
Lotan, T. L. et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Modern Pathol. 24, 820–828 (2011).
Russo, M. V. et al. SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis. Oncotarget 7, 12372–12385 (2016).
Clarke, M. F. et al. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).
Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J. & Maitland, N. J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).
Collins, A. T., Habib, F. K., Maitland, N. J. & Neal, D. E. Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J. Cell Sci. 114, 3865–3872 (2001).
Davies, A. H. & Zoubeidi, A. The androgen receptor bridges stem cell-associated signaling nodes in prostate stem cells. Stem Cells Int. 2016, 4829602 (2016).
Maitland, N. J., Frame, F. M., Polson, E. S., Lewis, J. L. & Collins, A. T. Prostate cancer stem cells: do they have a basal or luminal phenotype? Hormones Cancer 2, 47–61 (2011).
Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).
Chaffer, C. L. et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. Sci. USA 108, 7950–7955 (2011).
Flavahan, W. A. et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat. Neurosci. 16, 1373–1382 (2013).
Bluemn, E. G. et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 32, 474–489.6 (2017).
Don-Doncow, N. et al. Galiellalactone is a direct inhibitor of the transcription factor STAT3 in prostate cancer cells. J. Biol. Chem. 289, 15969–15978 (2014).
Hellsten, R., Johansson, M., Dahlman, A., Sterner, O. & Bjartell, A. Galiellalactone inhibits stem cell-like ALDH-positive prostate cancer cells. PloS ONE 6, e22118 (2011).
Attwell, S. et al. Preclinical characterization of ZEN-3694, a novel BET bromodomain inhibitor entering phase I studies for metastatic castration-resistant prostate cancer (mCRPC) [abstract]. Cancer Res. 76 (Suppl.), LB-207 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02711956 (2017).
Antonarakis, E. S., Armstrong, A. J., Dehm, S. M. & Luo, J. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostat. Dis. 19, 231–241 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02607228 (2018).
Yap, T. A. et al. A phase I, open-label study of GSK2816126, an enhancer of zeste homolog 2 (EZH2) inhibitor, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), other non-Hodgkin's lymphomas (NHL), multiple myeloma (MM) and solid tumor. J. Clin. Oncol. 34 (Suppl.), TPS2595 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02082977 (2017).
Knutson, S. K. et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13, 842–854 (2014).
Vaswani, R. G. et al. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J. Med. Chem. 59, 9928–9941 (2016).
Constellation Pharmaceuticals. Constellation pharmaceuticals announces first patient dosed in phase 1b/2 PROSTAR combination study of CPI-1205 in advanced form of prostate cancer. Constellation Pharmaceuicals https://www.constellationpharma.com/constellation-pharmaceuticals-announces-first-patient-dosed-phase-1b-2-prostar-combination-study-cpi-1205-advanced-form-prostate-cancer/ (2017).