We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Future perspectives for mTOR inhibitors in renal cell cancer treatment

    Anna M Czarnecka

    *Author for correspondence:

    E-mail Address: anna.czarnecka@gmail.com

    Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland

    ,
    Anna Kornakiewicz

    Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland

    Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

    ,
    Fei Lian

    Emory School of Medicine Atlanta, GA 30322, USA

    &
    Cezary Szczylik

    Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland

    Published Online:https://doi.org/10.2217/fon.14.303

    ABSTRACT 

    Everolimus is a mTOR inhibitor that demonstrates antitumor and antiangiogenic activities. In a randomized Phase III trial, patients with metastatic renal cell carcinoma who progressed on sunitinib/sorafenib were treated with everolimus and showed significant improvement in progression-free survival compared with best supportive care. Novel approaches in treatment are expected to ensure less toxic therapies and increase efficacy of everolimus. To provide a new perspective for mTOR inhibitor research and therapy, we discuss renal cell carcinoma cancer stem cells as a potential target for mTOR inhibitors and present new concepts on emerging antiangiogenic therapies. Finally, we point why systems biology approach with reverse molecular engineering may also contribute to the field of drug discovery in renal cell carcinoma.

    Papers of special note have been highlighted as: •• of considerable interest

    References

    • 1 Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP. A Phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 115(11), 2438–2446 (2009).
    • 2 Garcia JA, Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol. Cancer Ther. 7(6), 1347–1354 (2008).
    • 3 Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 18(16), 1926–1945 (2004).
    • 4 Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 12(1), 9–22 (2007).
    • 5 Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov. 5(8), 671–688 (2006).
    • 6 Patel PH, Chadalavada RS, Chaganti RS, Motzer RJ. Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin. Cancer Res. 12(24), 7215–7220 (2006).
    • 7 Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 80(7), 883–889 (2005).
    • 8 Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a Phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol. 26(10), 1603–1610 (2008).
    • 9 Stein A, Wang W, Carter AA et al. Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the Phase 3 RECORD-1 trial. BMC Cancer 12, 311 (2012).
    • 10 Anandappa G, Hollingdale A, Eisen T. Everolimus - a new approach in the treatment of renal cell carcinoma. Cancer Manag. Res. 2, 61–70 (2010).
    • 11 Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled Phase III trial. Lancet 372(9637), 449–456 (2008).
    • 12 Motzer RJ, Escudier B, Oudard S et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116(18), 4256–4265 (2010).
    • 13 Calvo E, Escudier B, Motzer RJ et al. Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the Phase III RECORD-1 study. Eur. J. Cancer 48(3), 333–339 (2012).•• This is the first and only Phase III – RECORD-1 – trial demonstrated clinical benefit of everolimus over placebo in treatment-resistant patients with metastatic RCC. It was underlined that the Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate was low. The study shows that the benefit and the safety of the drug are independent of the age of patients. Moreover, regardless of response on prior TKI therapy, the percentage of patients with stable disease who received everolimus was about two-times higher than those who received placebo.
    • 14 Oudard S, Thiam R, Fournier LS et al. Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study. Eur. J. Cancer 48(10), 1512–1518 (2012).
    • 15 Bracarda S, Hutson TE, Porta C et al. Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis. Br. J. Cancer 106(9), 1475–1480 (2012).
    • 16 Grunwald V, Seidel C, Fenner M, Ganser A, Busch J, Weikert S. Treatment of everolimus-resistant metastatic renal cell carcinoma with VEGF-targeted therapies. Br. J. Cancer 105(11), 1635–1639 (2011).
    • 17 Di Lorenzo G, Buonerba C, Federico P et al. Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma. Eur. Urol. 58(6), 906–911 (2010).
    • 18 Heng DY, Mackenzie MJ, Vaishampayan UN et al. Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy. Ann. Oncol. 23(6), 1549–1555 (2012).
    • 19 Porta C, Calvo E, Climent MA et al. Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial. Eur. Urol. 61(4), 826–833 (2012).
    • 20 White DA, Camus P, Endo M et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J. Respir. Crit. Care Med. 182(3), 396–403 (2010).
    • 21 Beaumont JL, Butt Z, Baladi J et al. Patient-reported outcomes in a Phase III study of everolimus versus placebo in patients with metastatic carcinoma of the kidney that has progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy. Oncologist 16(5), 632–640 (2011).
    • 22 Grunwald V, Karakiewicz PI, Bavbek SE et al. An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. Eur. J. Cancer 48(3), 324–332 (2012).
    • 23 Van Den Eertwegh AJ, Karakiewicz P, Bavbek S et al. Safety of everolimus by treatment duration in patients with advanced renal cell cancer in an expanded access program. Urology 81(1), 143–149 (2013).
    • 24 Bergmann L, Goebell PJ, Kube U et al. Everolimus in metastatic renal cell carcinoma after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: results of an interim analysis of a non-interventional study. Onkologie 36(3), 95–100 (2013).
    • 25 Czarnecka A, Sobczuk P, Bogusz K, Spychalska M, Szczylik C. Survival, safety and treatment response duration in “real world” patients with metastatic clear cell renal cancer – an update from clinical practice. BJU International 112(s3), 1–17 (2013).
    • 26 Poprach A, Bortlicek Z, Buchler T et al. Patients with advanced and metastatic renal cell carcinoma treated with targeted therapy in the Czech Republic: twenty cancer centres, six agents, one database. Med Oncol. 29(5), 3314–3320 (2012).
    • 27 Tsukamoto T, Shinohara N, Tsuchiya N et al. Phase III trial of everolimus in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from RECORD-1. Jpn. J. Clin. Oncol. 41(1), 17–24 (2011).
    • 28 Maraz A, Bodoky G, Dank M et al. Experience with everolimus therapy for patients with metastatic renal cancer in Hungary. Magy Onkol 58(1), 4–9 (2014).
    • 29 Guo J, Huang Y, Zhang X et al. Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label Phase 1b study. BMC Cancer 13, 136 (2013).
    • 30 Koh Y, Lim HY, Ahn JH et al. Phase II trial of everolimus for the treatment of nonclear-cell renal cell carcinoma. Ann. Oncol. 24(4), 1026–1031 (2013).
    • 31 Escudier BJ, Bracarda S, Maroto JP et al. Open-label Phase II trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. Ann. Oncol. 23(9), 264 (2013).•• The first Phase II study to investigate the use of everolimus for the initial treatment of advanced papillary kidney cancer. It has shown that everolimus is successful in slowing or preventing the spread of the disease. This study is unique as it was the first study of an mTOR inhibitor to enroll patients only with advanced papillary RCC and diagnosis was also confirmed by an independent group of pathologists experienced in the classification of RCC to prevent any patients being enrolled incorrectly.
    • 32 Vrdoljak E, Ciuleanu T, Kharkevich G et al. Optimizing treatment for patients with metastatic renal cell carcinoma in the Central and Eastern European region. Expert Opin. Pharmacother. 13(2), 159–174 (2012).
    • 33 Porta C, Szczylik C, Escudier B. Combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: a critical review. Crit. Rev. Oncol. Hematol. 82(3), 323–337 (2012).•• In this manuscript, few questions about the optimal sequence of RCC treatment have been answered. Both everolimus and axitinib have been suggested as standard of care after failure of first-line TKI treatment. Sorafenib has been proposed as an additional option in such clinical situation. It was shown that in clinical practice, several factors may influence the choice of subsequent treatment. Considerations on appropriate drug exposure in first-line, gained insights on prognostic and predictive factors as well as mechanisms of resistance are shown. The decision schema of second-line therapy has been shown and challenges of what to offer in third- and later lines are suggested.
    • 34 Porta C, Bellmunt J, Eisen T, Szczylik C, Mulders P. Treating the individual: the need for a patient-focused approach to the management of renal cell carcinoma. Cancer Treat. Rev. 36(1), 16–23 (2012).
    • 35 Buczek M, Escudier B, Bartnik E, Szczylik C, Czarnecka A. Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: from the patient's bed to molecular mechanisms. Biochim. Biophys. Acta 1845(1), 31–41 (2014).
    • 36 Vickers MM, Choueiri TK, Rogers M et al. Clinical outcome in metastatic renal cell carcinoma patients after failure of initial vascular endothelial growth factor-targeted therapy. Urology 76(2), 430–434 (2010).
    • 37 Busch J, Seidel C, Kempkensteffen C et al. Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors. Eur. Urol. 60(6), 1163–1170 (2011).
    • 38 Signorovitch JE, Vogelzang NJ, Pal SK et al. Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: synthesis of findings from two multi-practice chart reviews in the United States. Curr. Med. Res. Opin. 30(11), 2343–2353 (2014).
    • 39 Iacovelli R, Santoni M, Verzoni E et al. Everolimus and temsirolimus are not the same second-line in metastatic renal cell carcinoma. A systematic review and meta-analysis of literature data. Clin. Genitourin. Cancer 8(3-4), E121–E125 (2014).
    • 40 Motzer RJ, Barrios CH, Kim TM et al. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 31(Suppl.), Abstract 4504 (2013).
    • 41 Blesius A, Beuselinck B, Chevreau C et al. Are tyrosine kinase inhibitors still active in patients with metastatic renal cell carcinoma previously treated with a tyrosine kinase inhibitor and everolimus? Experience of 36 patients treated in France in the RECORD-1 Trial. Clin. Genitourin. Cancer 11(2), 128–133 (2013).
    • 42 Maj-Hes A, Medioni J, Scotte F et al. Rechallenge with mTOR inhibitors in metastatic renal cell carcinoma patients who progressed on previous mTOR inhibitor therapy. Oncology 85(1), 8–13 (2013).
    • 43 Maj-Hes A, Elaidi R-T, Medioni J et al. What is the benfit of mTOR inhibitors (mTORi) rechallenge in metastatic renal clear cell carcinoma (mRCC) patients (pts) initially treated with TKI. J. Clin. Oncol. 30(Suppl. 5), Abstract 442 (2012).
    • 44 Goebell PJ, Kube U, Staehler MD et al. Everolimus as second-line therapy for metastatic renal cell carcinoma (mRCC) after one previous VEGF-targeted therapy: final results of the noninterventional change study. J. Clin. Oncol. 32(Suppl. 4), Abstract 469 (2014).
    • 45 Sun M, Shariat SF, Trinh QD et al. An evidence-based guide to the selection of sequential therapies in metastatic renal cell carcinoma. Ther. Adv. Urol. 5(2), 121–128 (2013).
    • 46 Ryan CW, Vuky J, Chan JS, Chen Z, Beer TM, Nauman D. A Phase II study of everolimus in combination with imatinib for previously treated advanced renal carcinoma. Invest. New Drugs 29(2), 374–379 (2011).
    • 47 Hainsworth JD, Spigel DR, Burris HA 3rd, Waterhouse D, Clark BL, Whorf R. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J. Clin. Oncol. 28(13), 2131–2136 (2010).
    • 48 Harshman LC, Barbeau S, Mcmillian A, Srinivas S. A Phase II study of bevacizumab and everolimus as treatment for refractory metastatic renal cell carcinoma. Clin. Genitourin. Cancer 11(2), 100–106 (2013).
    • 49 Harzstark AL, Small EJ, Weinberg VK et al. A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer 117(18), 4194–4200 (2011).
    • 50 Amato RJ, Flaherty AL, Stepankiw M. Phase I trial of everolimus plus sorafenib for patients with advanced renal cell cancer. Clin. Genitourin. Cancer 10(1), 26–31 (2012).
    • 51 Hainsworth JD, Waterhouse DM, Penley WC et al. Sorafenib and everolimus in advanced clear cell renal carcinoma: a Phase I/II trial of the SCRI Oncology Research Consortium. Cancer Invest. 31(5), 323–329 (2013).
    • 52 Molina AM, Feldman DR, Voss MH et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 118(7), 1868–1876 (2012).
    • 53 Powles T, Foreshew SJ, Shamash J et al. A Phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. Eur. J. Cancer 50(12), 2057–2064 (2014).
    • 54 Molina AM, Hutson TE, Larkin J et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother. Pharmacol. 73(1), 181–189 (2014).
    • 55 Feala JD, Cortes J, Duxbury PM, Piermarocchi C, Mcculloch AD, Paternostro G. Systems approaches and algorithms for discovery of combinatorial therapies. Wiley Interdiscip. Rev. Syst. Biol. Med. 2(2), 181–193 (2010).
    • 56 Calderwood SK. Tumor heterogeneity, clonal evolution, and therapy resistance: an opportunity for multitargeting therapy. Discov. Med. 15(82), 188–194 (2013).
    • 57 Lehar J, Zimmermann GR, Krueger AS et al. Chemical combination effects predict connectivity in biological systems. Mol. Syst. Biol. 3, 80 (2007).
    • 58 Nelander S, Wang W, Nilsson B et al. Models from experiments: combinatorial drug perturbations of cancer cells. Mol. Syst. Biol. 4, 216 (2008).
    • 59 Liu YN, Wan RZ, Liu ZP. Recent developments of small molecule PI3K/mTOR dual inhibitors. Mini. Rev. Med. Chem. 13(14), 2047–2059 (2013).
    • 60 Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat. Rev. Clin. Oncol. 10(3), 143–153 (2013).
    • 61 Gedaly R, Galuppo R, Musgrave Y et al. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J. Surg. Res. 185(1), 225–230 (2013).
    • 62 Zhang H, Berel D, Wang Y et al. A comparison of Ku0063794, a dual mTORC1 and mTORC2 inhibitor, and temsirolimus in preclinical renal cell carcinoma models. PLoS ONE 8(1), e54918 (2013).
    • 63 Bussolati B, Brossa A, Camussi G. Resident stem cells and renal carcinoma. Int. J. Nephrol. 2011, 286985 (2011).
    • 64 Zhang Y, Sun B, Zhao X et al. Clinical significances and prognostic value of cancer stem-like cells markers and vasculogenic mimicry in renal cell carcinoma. J. Surg. Oncol. 108(6), 414–419 (2013).
    • 65 Sehl ME, Sinsheimer JS, Zhou H, Lange KL. Differential destruction of stem cells: implications for targeted cancer stem cell therapy. Cancer Res. 69(24), 9481–9489 (2009).
    • 66 Smith KM, Datti A, Fujitani M et al. Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens. EMBO Mol. Med. 2(9), 371–384 (2010).
    • 67 Azzi S, Bruno S, Giron-Michel J et al. Differentiation therapy: targeting human renal cancer stem cells with interleukin 15. J. Natl Cancer Inst. 103(24), 1884–1898 (2011).
    • 68 Thoreen CC, Kang SA, Chang JW et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284(12), 8023–8032 (2009).
    • 69 Wang K, Li Z, Chen Y, Su C. The pharmacokinetics of a novel anti-tumor agent, beta-elemene, in Sprague-Dawley rats. Biopharm. Drug Dispos. 26(7), 301–307 (2005).
    • 70 Zhan YH, Liu J, Qu XJ et al. Beta-Elemene induces apoptosis in human renal-cell carcinoma 786-0 cells through inhibition of MAPK/ERK and PI3K/Akt/mTOR signalling pathways. Asian Pac. J. Cancer Prev. 13(6), 2739–2744 (2012).
    • 71 Chen G, Zhang W, Li YP et al. Hypoxia-induced autophagy in endothelial cells: a double-edged sword in the progression of infantile haemangioma? Cardiovasc. Res. 98(3), 437–448 (2013).
    • 72 Csermely P, Korcsmaros T. Cancer-related networks: a help to understand, predict and change malignant transformation. Semin. Cancer Biol. 23(4), 209–212 (2013).
    • 73 Kubisch J, Turei D, Foldvari-Nagy L et al. Complex regulation of autophagy in cancer – integrated approaches to discover the networks that hold a double-edged sword. Semin. Cancer Biol. 23(4), 252–261 (2013).
    • 74 Kim KW, Paul P, Qiao J, Chung DH. Autophagy mediates paracrine regulation of vascular endothelial cells. Lab. Invest. 93(6), 639–645 (2013).
    • 75 Heuser M, Schlott T, Schally AV et al. Expression of gastrin releasing Peptide receptor in renal cell carcinomas: a potential function for the regulation of neoangiogenesis and microvascular perfusion. J. Urol. 173(6), 2154–2159 (2005).
    • 76 Kim KW, Paul P, Qiao J, Lee S, Chung DH. Enhanced autophagy blocks angiogenesis via degradation of gastrin-releasing peptide in neuroblastoma cells. Autophagy 9(10), 1579–1590 (2013).
    • 77 Liu Y, Zhang X, Liu J, Hou G, Zhang S, Zhang J. Everolimus in combination with letrozole inhibit human breast cancer MCF-7/Aro stem cells via PI3K/mTOR pathway: an experimental study. Tumour Biol. 35(2), 1275–1286 (2014).
    • 78 Siejka A, Barabutis N, Schally AV. GHRH antagonist MZ-5–156 increases the expression of AMPK in A549 lung cancer cells. Cell Cycle 10(21), 3714–3718 (2011).
    • 79 Sustarsic EG, Junnila RK, Kopchick JJ. Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment. Biochem. Biophys. Res. Commun. 441(1), 144–150 (2013).
    • 80 Block M, Grundker C, Fister S et al. Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. Int. J. Oncol. 41(5), 1845–1854 (2012).
    • 81 Brewer C, Yeager N, Di Cristofano A. Thyroid-stimulating hormone initiated proliferative signals converge in vivo on the mTOR kinase without activating AKT. Cancer Res. 67(17), 8002–8006 (2007).
    • 82 Bishop JD, Nien WL, Dauphinee SM, Too CK. Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells. J. Endocrinol. 190(2), 307–312 (2006).
    • 83 Rapley J, Oshiro N, Ortiz-Vega S, Avruch J. The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution to mTOR complex 1 signaling. J. Biol. Chem. 286(44), 38043–38053 (2011).
    • 84 Kang JW, Cho HI, Lee SM. Melatonin inhibits mTOR-dependent autophagy during liver ischemia/reperfusion. Cell Physiol. BioChem. 33(1), 23–36 (2014).
    • 85 Guo X, Zhou CY, Li Q et al. Rapamycin sensitizes glucocorticoid resistant acute lymphoblastic leukemia CEM-C1 cells to dexamethasone induced apoptosis through both mTOR suppression and up-regulation and activation of glucocorticoid receptor. Biomed. Environ. Sci. 26(5), 371–381 (2013).
    • 86 Polman JA, Hunter RG, Speksnijder N et al. Glucocorticoids modulate the mTOR pathway in the hippocampus: differential effects depending on stress history. Endocrinology 153(9), 4317–4327 (2012).
    • 87 Hou X, Zhao M, Wang T, Zhang G. Upregulation of estrogen receptor mediates migration, invasion and proliferation of endometrial carcinoma cells by regulating the PI3K/AKT/mTOR pathway. Oncol. Rep. 31(3), 1175–1182 (2014).
    • 88 Barone I, Cui Y, Herynk MH et al. Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway. Cancer Res. 69(11), 4724–4732 (2009).
    • 89 Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat. Rev. Urol. 7(5), 277–285 (2010).
    • 90 Halmos G, Schally AV, Varga JL, Plonowski A, Rekasi Z, Czompoly T. Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone. Proc. Natl Acad. Sci. USA 97(19), 10555–10560 (2000).
    • 91 Schmidinger M, Vogl UM, Bojic M et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 117(3), 534–544 (2011).
    • 92 Cardillo TM, Trisal P, Arrojo R, Goldenberg DM, Chang CH. Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro. BMC Cancer 13, 170 (2013).
    • 93 Park EJ, Woo SM, Min KJ, Kwon TK. Transcriptional and post-translational regulation of Bim controls apoptosis in melatonin-treated human renal cancer Caki cells. J. Pineal Res. 56(1), 97–106 (2014).
    • 94 Yakirevich E, Matoso A, Sabo E et al. Expression of the glucocorticoid receptor in renal cell neoplasms: an immunohistochemical and quantitative reverse transcriptase polymerase chain reaction study. Hum. Pathol. 42(11), 1684–1692 (2011).
    • 95 Yu CP, Ho JY, Huang YT et al. Estrogen inhibits renal cell carcinoma cell progression through estrogen receptor-beta activation. PLoS ONE 8(2), e56667 (2013).
    • 96 Gaiser T, Ruschoff J, Schally AV, Keller G, Engel JB. Receptors for luteinizing hormone releasing hormone expressed on melanoma, renal cell carcinoma and non Hodgkin lymphoma can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone analogues. Verh. Dtsch Ges. Pathol. 90, 186–192 (2006).
    • 97 Malaguarnera R, Belfiore A. The emerging role of insulin and insulin-like growth factor signaling in cancer stem cells. Front. Endocrinol. (Lausanne) 5, 10 (2014).
    • 98 Quek R, Wang Q, Morgan JA et al. Combination mTOR and IGF-1R inhibition: Phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin. Cancer Res. 17(4), 871–879 (2011).
    • 99 Guttilla IK, Adams BD, White BA. ERalpha, microRNAs, and the epithelial–mesenchymal transition in breast cancer. Trends Endocrinol. Metab. 23(2), 73–82 (2012).
    • 100 Janakiram NB, Mohammed A, Brewer M et al. Raloxifene and antiestrogenic gonadorelin inhibits intestinal tumorigenesis by modulating immune cells and decreasing stem-like cells. Cancer Prev. Res. (Phila) 7(3), 300–309 (2014).
    • 101 Jung YS, Lee SJ, Yoon MH, Ha NC, Park BJ. Estrogen receptor alpha is a novel target of the Von Hippel–Lindau protein and is responsible for the proliferation of VHL-deficient cells under hypoxic conditions. Cell Cycle 11(23), 4462–4473 (2012).
    • 102 Neradugomma NK, Subramaniam D, Tawfik OW et al. Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERK manner. Carcinogenesis 5(4), 795–806 (2013).
    • 103 D'angelo G, Struman I, Martial J, Weiner RI. Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin. Proc. Natl Acad. Sci. USA 92(14), 6374–6378 (1995).
    • 104 Martin V, Sanchez-Sanchez AM, Herrera F et al. Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells. Br. J. Cancer 108(10), 2005–2012 (2013).
    • 105 Kim KJ, Choi JS, Kang I, Kim KW, Jeong CH, Jeong JW. Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF-1 in a mouse tumor model. J. Pineal Res. 54(3), 264–270 (2013).
    • 106 Schally AV, Varga JL, Engel JB. Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer. Nat. Clin Pract Endocrinol. Metab 4(1), 33–43 (2008).
    • 107 Cowey CL, Rathmell WK. VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy. Curr. Oncol. Rep. 11(2), 94–101 (2009).
    • 108 Koh MY, Darnay BG, Powis G. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation. Mol. Cell Biol. 28(23), 7081–7095 (2008).
    • 109 Tabruyn SP, Sorlet CM, Rentier-Delrue F et al. The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-kappaB. Mol. Endocrinol. 17(9), 1815–1823 (2003).
    • 110 Kinet V, Nguyen NQ, Sabatel C et al. Antiangiogenic liposomal gene therapy with 16K human prolactin efficiently reduces tumor growth. Cancer Lett. 284(2), 222–228 (2009).
    • 111 Surazynski A, Miltyk W, Wolczynski S, Palka J. The effect of prolactin and estrogen cross-talk on prolidase-dependent signaling in MCF-7 cells. Neoplasma 60(4), 355–363 (2013).