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CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2017; 77(10): 1095-1103
DOI: 10.1055/s-0043-118907
GebFra Science
Review
Georg Thieme Verlag KG Stuttgart · New York

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

Bedeutung des PI3K/AKT/mTOR-Signalwegs für die Behandlung des Ovarialkarzinoms: Sind wir auf dem richtigen Weg?
Maria Luisa Gasparri
1   Department of Gynecology, Obstetrics and Urology, “Sapienza” University of Rome, Rome, Italy
2   Department of Obstetrics and Gynecology, University of Berne, Berne, Switzerland
,
Erlisa Bardhi
1   Department of Gynecology, Obstetrics and Urology, “Sapienza” University of Rome, Rome, Italy
,
Ilary Ruscito
1   Department of Gynecology, Obstetrics and Urology, “Sapienza” University of Rome, Rome, Italy
,
Andrea Papadia
2   Department of Obstetrics and Gynecology, University of Berne, Berne, Switzerland
,
Ammad Ahmad Farooqi
3   Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College, Lahore, Pakistan
,
Claudia Marchetti
1   Department of Gynecology, Obstetrics and Urology, “Sapienza” University of Rome, Rome, Italy
,
Giorgio Bogani
4   Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy
,
Irene Ceccacci
1   Department of Gynecology, Obstetrics and Urology, “Sapienza” University of Rome, Rome, Italy
,
Michael D. Mueller
2   Department of Obstetrics and Gynecology, University of Berne, Berne, Switzerland
,
Pierluigi Benedetti Panici
1   Department of Gynecology, Obstetrics and Urology, “Sapienza” University of Rome, Rome, Italy
› Author Affiliations
Further Information

Publication History

received 31 May 2017
revised 02 August 2017

accepted 25 August 2017

Publication Date:
26 October 2017 (online)

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Abstract

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents.

Zusammenfassung

Die hohe Rückfallquote und die allgemeine niedrige Gesamtüberlebensrate beim Ovarialkrebs weisen darauf hin, dass neben der herkömmlichen Behandlung zusätzlich eine spezifischere Therapie benötigt wird. In der translationalen und klinischen Forschung wird derzeit nach alternativen molekularen Zielstrukturen gesucht, die einerseits das Tumorwachstum aufhalten und andererseits die überlappende Toxizität von wachstumshemmenden Wirkstoffe minimieren könnten. Da PI3K/AKT/mTOR viele Zellfunktionen steuern, u. a. die Regulierung des Zellwachstums, Motilität, Überleben, Proliferation, Proteinsynthese, Autophagozytose, Transkription und Angiogenese, gehören sie zu den meist untersuchten intrazellulären Signalwegen. Eine Deregulierung dieses Signalweges wurde bei einigen Tumoren festgestellt, darunter auch für das Ovarialkarzinom. Vor diesem Hintergrund könnten mTor-Proteine potenzielle Ziele für Inhibitoren sein, die dann eine Schlüsselrolle bei der Hemmung der Zellproliferation spielen könnten. Vor Kurzem wurden mTor-Inhibitoren zur Behandlung von neuroendokrinen Tumoren der Bauchspeicheldrüse, Mantelzell-Lymphomen und Nierenkrebs zugelassen. Klinische Studien haben die Sicherheit dieser Medikamente in Patientinnen mit Eierstockkrebs untersucht. Aktuell werden Phase-I und -II-Studien durchgeführt, um die onkologischen Ergebnisse nach einer Behandlung mit mTOR-Inhibitoren und die Auswirkungen dieser Therapie in Kombination mit konventioneller Chemotherapie und Target-Wirkstoffen zu bewerten.

Key words

everolimus - mTOR inhibitors - ovarian cancer - target therapy - temsirolimus - PI3K/AKT/mTOR

Schlüsselwörter

Everolimus - mTOR-Inhibitoren - Ovarialkarzinom - gezielte Therapie - Temsirolimus - PI3K/AKT/mTOR
 

  • References

  • 1 Marchetti C, Gasparri ML, Ruscito I. et al. Advances in anti-angiogenic agents for ovarian cancer treatment: the role of trebananib (AMG 386). Crit Rev Oncol Hematol 2015; 94: 302-310
    CrossrefPubMedGoogle Scholar
  • 2 Leone Roberti Maggiore U, Bellati F, Ruscito I. et al. Monoclonal antibodies therapies for ovarian cancer. Expert Opin Biol Ther 2013; 13: 739-764
    CrossrefPubMedGoogle Scholar
  • 3 Bellati F, Napoletano C, Ruscito I. et al. Past, present and future strategies of immunotherapy in gynecological malignancies. Curr Mol Med 2013; 13: 648-669
    CrossrefPubMedGoogle Scholar
  • 4 Marchetti C, Imperiale L, Gasparri ML. et al. Olaparib, PARP1 inhibitor in ovarian cancer. Expert Opin Investig Drugs 2012; 21: 1575-1584
    CrossrefPubMedGoogle Scholar
  • 5 Bellati F, Napoletano C, Gasparri ML. et al. Monoclonal antibodies in gynecological cancer: a critical point of view. Clin Dev Immunol 2011; 2011: 890758
    PubMedGoogle Scholar
  • 6 Bellati F, Napoletano C, Gasparri ML. et al. Current knowledge and open issues regarding bevacizumab in gynaecological neoplasms. Crit Rev Oncol Hematol 2012; 83: 35-46
    CrossrefPubMedGoogle Scholar
  • 7 Attar R, Gasparri ML, Donato VD. et al. Ovarian cancer: interplay of vitamin D signaling and miRNA action. Asian Pac J Cancer Prev 2014; 15: 3359-3362
    CrossrefPubMedGoogle Scholar
  • 8 Musella A, Marchetti C, Gasparri ML. et al. PARP inhibition: a promising therapeutic target in ovarian cancer. Cell Mol Biol (Noisy-le-grand) 2015; 61: 44-61
    PubMedGoogle Scholar
  • 9 Marchetti C, De Felice F, Palaia I. et al. Efficacy and toxicity of bevacizumab in recurrent ovarian disease: an update meta-analysis on phase III trials. Oncotarget 2016; 7: 13221-13227
    CrossrefPubMedGoogle Scholar
  • 10 Ruscito I, Gasparri ML, Marchetti C. et al. Cediranib in ovarian cancer: state of the art and future perspectives. Tumour Biol 2016; 37: 2833-2839
    CrossrefPubMedGoogle Scholar
  • 11 Gasparri ML, Savone D, Besharat RA. et al. Circulating tumor cells as trigger to hematogenous spreads and potential biomarkers to predict the prognosis in ovarian cancer. Tumour Biol 2016; 37: 71-75
    CrossrefPubMedGoogle Scholar
  • 12 Gasparri ML, Attar R, Palaia I. et al. Tumor infiltrating lymphocytes in ovarian cancer. Asian Pac J Cancer Prev 2015; 16: 3635-3638
    CrossrefPubMedGoogle Scholar
  • 13 Klukovits A, Schally AV, Szalontay L. et al. Novel antagonists of growth hormone-releasing hormone inhibit growth and vascularization of human experimental ovarian cancers. Cancer 2015; 118: 670-680
    PubMedGoogle Scholar
  • 14 Papadia A, Schally AV, Halmos G. et al. Growth hormone-releasing hormone antagonists inhibit growth of human ovarian cancer. Horm Metab Res 2011; 43: 816-820
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Verri E, Guglielmini P, Puntoni M. et al. HER2/neu oncoprotein overexpression in epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. Clinical study. Oncology 2005; 68: 154-161
    CrossrefPubMedGoogle Scholar
  • 16 Papadia A, Morotti M. Diaphragmatic surgery during cytoreduction for primary or recurrent epithelial ovarian cancer: a review of the literature. Arch Gynecol Obstet 2013; 287: 733-741
    CrossrefPubMedGoogle Scholar
  • 17 Gasparri ML, Grandi G, Bolla D. et al. Hepatic resection during cytoreductive surgery for primary or recurrent epithelial ovarian cancer. J Cancer Res Clin Oncol 2016; 142: 1509-1520
    CrossrefPubMedGoogle Scholar
  • 18 Gasparri ML, Panici PB, Papadia A. Primary chemotherapy versus primary surgery for ovarian cancer. Lancet 2015; 386: 2142-2143
    CrossrefPubMedGoogle Scholar
  • 19 Kehoe S, Hook J, Nankivell M. et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet 2015; 386: 249-257
    CrossrefPubMedGoogle Scholar
  • 20 Papadia A, Remorgida V, Salom EM. et al. Laparoscopic pelvic and paraaortic lymphadenectomy in gynecologic oncology. J Am Assoc Gynecol Laparosc 2004; 11: 297-306
    CrossrefPubMedGoogle Scholar
  • 21 Papadia A, Ragni N, Salom EM. The impact of obesity on surgery in gynecological oncology: a review. Int J Gynecol Cancer 2006; 16: 944-952
    CrossrefPubMedGoogle Scholar
  • 22 Aletti GD, Dowdy SC, Gostout BS. et al. Quality improvement in the surgical approach to advanced ovarian cancer: the Mayo Clinic experience. J Am Coll Surg 2009; 208: 614-620
    CrossrefPubMedGoogle Scholar
  • 23 Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2015; 65: 5-29
    CrossrefPubMedGoogle Scholar
  • 24 Online: cancer.gov
    PubMed
  • 25 Jayson GC, Kohn EC, Kitchener HC. et al. Ovarian cancer. Lancet 2014; 384: 1376-1388
    CrossrefPubMedGoogle Scholar
  • 26 Miller DS, Blessing JA, Krasner CN. et al. Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol 2009; 27: 2686-2691
    CrossrefPubMedGoogle Scholar
  • 27 Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609-615
    CrossrefPubMedGoogle Scholar
  • 28 Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926-1945
    CrossrefPubMedGoogle Scholar
  • 29 Huang J, Zhang L, Greshock J. et al. Frequent genetic abnormalities of the PI3K/AKT pathway in primary ovarian cancer predict patient outcome. Genes Chromosomes Cancer 2011; 50: 606-618
    CrossrefPubMedGoogle Scholar
  • 30 Mabuchi S, Kuroda H, Takahashi R. et al. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol 2015; 137: 173-179
    PubMedGoogle Scholar
  • 31 Cheaib B, Auguste A, Leary A. The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. Chin J Cancer 2015; 34: 4-16
    PubMedGoogle Scholar
  • 32 Whitman M, Downes CP, Keeler M. et al. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 1988; 332: 644-646
    CrossrefPubMedGoogle Scholar
  • 33 Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13: 140-156
    CrossrefPubMedGoogle Scholar
  • 34 Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375-13378
    CrossrefPubMedGoogle Scholar
  • 35 Gewinner C, Wang ZC, Richardson A. et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 2009; 16: 115-125
    CrossrefPubMedGoogle Scholar
  • 36 Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274-293
    CrossrefPubMedGoogle Scholar
  • 37 Kunz J, Henriquez R, Schneider U. et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 1993; 73: 585-596
    CrossrefPubMedGoogle Scholar
  • 38 Delgoffe GM, Pollizzi KN, Waickman AT. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 2011; 12: 295-303
    PubMedGoogle Scholar
  • 39 Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet 2014; 290: 1067-1078
    CrossrefPubMedGoogle Scholar
  • 40 Bai H, Li H, Li W. et al. The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget 2014; 6: 25520-25532
    PubMedGoogle Scholar
  • 41 Levine DA, Bogomolniy F, Yee CJ. et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 2005; 11: 2875-2878
    CrossrefPubMedGoogle Scholar
  • 42 Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609-615
    CrossrefPubMedGoogle Scholar
  • 43 Kurman RJ, Shih IeM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol 2016; 186: 733-747
    CrossrefPubMedGoogle Scholar
  • 44 Kuo KT, Mao TL, Jones S. et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol 2009; 174: 1597-1601
    CrossrefPubMedGoogle Scholar
  • 45 Philp AJ, Campbell IG, Leet C. et al. The phosphatidylinositol 3ʼ-kinase p 85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 2001; 61: 7426-7429
    PubMedGoogle Scholar
  • 46 Tanwar PS, Zhang L, Kaneko-Tarui T. et al. Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/β-catenin and PTEN. PLoS One 2011; 6: e20715
    CrossrefPubMedGoogle Scholar
  • 47 Pritchard DI. Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today 2005; 10: 688-691
    CrossrefPubMedGoogle Scholar
  • 48 Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005; 11: 353-361
    CrossrefPubMedGoogle Scholar
  • 49 Liu P, Cheng H, Roberts TM. et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627-644
    CrossrefPubMedGoogle Scholar
  • 50 Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5: 671-688
    CrossrefPubMedGoogle Scholar
  • 51 Behbakht K, Sill MW, Darcy KM. et al. Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol 2011; 123: 19-26
    CrossrefPubMedGoogle Scholar
  • 52 Temkin SM, Yamada SD, Fleming GF. A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies. Gynecol Oncol 2010; 117: 473-476
    CrossrefPubMedGoogle Scholar
  • 53 Takano M, Kikuchi Y, Kudoh K. et al. Weekly administration of temsirolimus for heavily pretreated patients with clear cell carcinoma of the ovary: a report of six cases. Int J Clin Oncol 2011; 16: 605-609
    CrossrefPubMedGoogle Scholar
  • 54 Kollmannsberger C, Hirte H, Siu LL. et al. Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179). Ann Oncol 2012; 23: 238-244
    CrossrefPubMedGoogle Scholar
  • 55 Boers-Sonderen MJ, de Geus-Oei LF, Desar IM. et al. Temsirolimus and pegylated liposomal doxorubicin (PLD) combination therapy in breast, endometrial, and ovarian cancer: phase Ib results and prediction of clinical outcome with FDG-PET/CT. Target Oncol 2014; 9: 339-347
    CrossrefPubMedGoogle Scholar
  • 56 Piha-Paul SA, Wheler JJ, Fu S. et al. Advanced gynecologic malignancies treated with a combination of the VEGF inhibitor bevacizumab and the mTOR inhibitor temsirolimus. Oncotarget 2014; 5: 1846-1855
    CrossrefPubMedGoogle Scholar
  • 57 Emons G, Kurzeder C, Schmalfeldt B. et al. Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8). Gynecol Oncol 2016; 140: 450-456
    CrossrefPubMedGoogle Scholar
  • 58 Vlahovic G, Meadows KL, Uronis HE. et al. A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors. Cancer Chemother Pharmacol 2012; 70: 95-102
    CrossrefPubMedGoogle Scholar
  • 59 Guo H, Zhong Y, Jackson AL. et al. Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer. Oncotarget 2016; 7: 20338-20356
    CrossrefPubMedGoogle Scholar
  • 60 Perl A. mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann N Y Acad Sci 2015; 1346: 33-44
    CrossrefPubMedGoogle Scholar
  • 61 Zhang D, Xia H, Zhang W. et al. The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor. Tumour Biol 2016; 37: 1327-1336
    CrossrefPubMedGoogle Scholar
  • 62 Schrauwen S, Depreeuw J, Coenegrachts L. et al. Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models. Gynecol Oncol 2015; 138: 165-173
    CrossrefPubMedGoogle Scholar
  • 63 Bogani G, Chiappa V, Lorusso D. et al. Treatment of recurrent endometrial carcinoma: progress toward a more personalized approach. J Clin Oncol 2015; 33: 3516
    PubMedGoogle Scholar
  • 64 Hussain AR, Al-Romaizan M, Ahmed M. et al. Dual targeting of mTOR activity with Torin2 potentiates anti-cancer effects of cisplatin in epithelial ovarian cancer. Mol Med 2015; 21: 466-478 doi:10.2119/molmed.2014.00238
    PubMedGoogle Scholar
  • 65 Wang D, Wang M, Jiang N. et al. Effective use of PI3K inhibitor BKM120 and PARP inhibitor olaparib to treat PIK3CA mutant ovarian cancer. Oncotarget 2016; 7: 13153-13166
    CrossrefPubMedGoogle Scholar
  • 66 Taylor SE, Chu T, Edwards RP. et al. Phase II study of everolimus (EV) and bevacizumab (BEV) in recurrent ovarian, peritoneal, and fallopian tube cancer. J Clin Oncol 2016; 34 (Suppl.) Abstr.. 5552
    PubMedGoogle Scholar
  • 67 Chia S, Gandhi S, Joy AA. et al. Novel agents and associated toxicities of inhibitors of the pi3 k/Akt/mtor pathway for the treatment of breast cancer. Curr Oncol 2015; 22: 33-48
    CrossrefPubMedGoogle Scholar