Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
konferencijos medžiaga ROLE OF INTEGRINS IN CANCER DEVELOPMENT – THERAPEUTIC IMPLICATIONS Integrinų vaidmuo vėžio atsiradime ir jo gydYme Jerzy Lazowski Polish Society of Oncology Pharmacists, Warsaw (Poland) Lenkijos onkologijos farmacininkų draugija, Varšuva (Lenkija) SANTRAUKA Reikšminiai žodžiai: integrinai, vežio gydymas, solidiniai tumorai, ląstelių adhezijos molekulės Integrinai yra heterodimerinės transmembraninės molekulės, kurios priklauso ląstelių adhezijos molekulių gupei. Be adhezijos funkcijos integrinai taip pat pasižymi signalo perdavimu ląstelėms. Šis signalas yra susijęs su ląstelės augimu, dauginimusi, migracija ir apoptoze. Pastebėta, kad piktybiniai navikai turi aktyvuotus integrinus ar padidintą jų ekspresiją. Taip pat jų sąveika su onkogeniniais signalo perdavimo keliais yra būtina vėžio migravimui-invazijai, metastazėms ir angiogenezei. Dėl savo vaidmens naviko vystymesi integrinai tapo patrauklūs taikiniai vėžio gydyme. Etaracizumab – pirmasis integrinų, antagonistas parodęs priešangiogenezinį poveikį, mažą toksiškumą ir ligos stabilizavimą gydant pažengusius solidinius navikus ir inkstų ląstelių karcinomą. CNTO 95 žmogaus integrinams specifinis antikūnis pirmos fazės klinikiniuose tyrimuose pasižymėjo priešvėžiniu veikimu ir mažu toksiškumu. ATN-161 peptidas, kuris inhibuoja integriną α5β1, buvo aktyvus prieš solidinius navikus ir stabilizavo ligą trečdaliui pacientų. E7820 – sulfonamidų junginys antros fazės klinikinuose tyrimuose taikomas storosios žarnos vėžio gydymui. Volociximab monokloninis antikūnis skirtas solidinių tumorų gydymui šiuo metu antroje klinikinių studijų stadijoje. Cilengitide sintetinis peptidas specifiškai jungiasi prie endotelyje esančių integrino receptorių, taip sukeldamas apoptozę ir yra plačiausiai tyrinėtas integrinų antagonistas. Integrinai yra daug žadantys vėžio gydyme, tačiau reikia daugiau klinikinių studijų norint įsitvirtinti standartinėje klinikinėje praktikoje. ABSTRACT Key words: integrins, cancer therapy, solid tumors, cell adhesion molecules Integrins are heterodimeric transmembrane molecules that belongs to group of cell adhesion factors. Apart from adhesion integrins regulate signal transduction pathways for cell growth, proliferation, migration and apoptosis. Recently it has been noticed that several human malignancies have up-regulated or activated integrins and their interaction with oncogenic signal transduction pathways are crutial in cancer migration – invasion, metastasis and angiogenesis. Integrin role in tumor progression has made them attractive target. Etaracizumab first integrin antagonist showed anti-angiogenic activity, low toxicity and disease stabillization in some patients with advanced solid tumors and renal cell cancer. CNTO 95 human integrin specific monoclonal antibody in Phase I clinical in patients with solid tumors was well tolerated and prolonged stable disease in one third of the patients. E7820 is a sulfonamide derivative currently undergoing Phase II clinical trials for treatment of the colon cancer. Volociximab is monclonar antibody that is currently in Phase II clinical trials for solid tumors. Cilengitide is synthetic peptide specifically binds to integrin receptors in endothelium and induce apoptosis it is most extensively studied integrin antagonist hitherto. Integrins are promising targets in cancer therapy, however more clinical trials are needed to introduce them to standard clinical practice. Introduction Throughout its life, a cell must constantly sense physiological changes in the microenvironment and respond by making critical decisions regarding process of proliferation, division, motility and death. In multicellular organisms different cell types coordinate function to facilitate tissue homeostasis by exchanging signals, such as growth factors or other cytokines, and secreting, assembling, and remod- eling an insoluble network of proteins termed the extracellular matrix (ECM) [1]. The ECM provides a structural framework that enables cells to anchor for stationary existence, or to migrate. It also influences cell seize, shape, and interaction with other cells and tissue formation. All these processes are mediated by cell adhesion molecules (CAM). Thanks to them cells are losing their ability to division after reaching a certain level of intracellular contact, as Jerzy Lazowsk ul. Mikolajczyka 12 m. 72, Warszawa 03984, Polska [email protected] 204 teorija ir praktika 2012 - T. 18 (Nr. 2), 204–207 p. konferencijos medžiaga well as adhere to ECM. This is an indispensable condition of replication of many types of cells and their proliferation. Disturbances in CAM function may negatively interfere in the process of cell proliferation and influence their transformation. CAM are divided into four essential groups: - cell adhesion molecules with immunoglobulin-like domains which take part in the intracellular connections communicating with other CAMs, - integrins which are active in the intracellular communication and communication between cells and ECM, - adherins which mediate adherence and proliferation of the same type of cells, - selectins which are mediators of initial interaction between leukocytes, blood platelets and activated cells of endothelium. [2] The role of CAMs is not only adhesion to themselves. They are also acting as sensors and effector factors in intracellular signal transduction which enables modification of adherence in response to phosphorylation phenomena in the cell. Cell adhesion to ECM is predominantly mediated by integrins, the most structurally and functionally diverse family of CAMs which regulate cell-cell and cell-ECM interaction . Closer look of integrins Integrins are heterodimeric transmembrane molecules consisting of two non-covalently bond α and β subunits. In mammals, eighteen α and eight β subunits have been characterized. The ectodomains of these receptors binds specific components of the ECM. At the same time, the cytoplasmic domain (largely that of β subunit) is linked, via intermediary proteins, to the cyclosceleton (largely that constructed by actin fibers); in addition, the cytoplasmic domains may attract a variety of signal-transducing proteins that become activated when the ectodomain binds an ECM ligand. In the binding of both chains participate calcium and magnesium ions which are necessary to maintain correct spatial structure and guarantee ligands binding [3]. Subunit α is responsible for the specificity of the binding. Different α subunits are binding one type of β subunit only, and that is why integrin subgroups are defined on the basis of common β subunit. In this way integrins β1, β2, β3 etc. have been classified. Integrins β1 and β2 binds ECM proteins while integrin β3 are binding immunoglobulinlike opposite receptors. Extracellular domains of integrins binds to 3 different types of ligands: ECM proteins (e.g. fibronectin, laminin, tenascin) - integrin bonds participate in cell adhesion to ECM, circulating proteins originating from ECM (e.g. fiteorija ir praktika 2012 - T. 18 (Nr. 2) bronectin, von Willebrand factor) – integrin binding results in platelet aggregation, opposite receptors – integrins binding causes strong adherence of cells. Activity of different integrins partially overlap. For instance integrins α4β1 and α1β2 participate in homotypical adhesion (between cells of the same type) and cytotoxicity of T cells. Similarly α4β1 and α3β1 can be receptors for fibronectin [4]. Extensive research over the past two decades has shown that integrins not only “glue” cells to ECM, but also regulate important signal transduction pathways for cell growth, proliferation, migration and apoptosis. One of the most important features of surface integrins is their role in cell migration. Cells adhere to substrate through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by endocytosis; they are transported through the cell to its front by endocytic cycle where they are cycled for reuse, enabling the cell to make fresh attachments at its leading front [5]. Integrins recognize in ligands common place of binding – tripeptide arginin-glycine-asparaginic acid called also RGD sequence. Binding with RGD sequence stabilizes ligand-integrin complex and synthetic peptides containing this sequence may block integrin-ligand complex. Integrins are most unusual in one other respect. Normally, we think that receptors are passing information from outside the cell into the cytoplasm. Integrins surely do this. But in addition, it is clear that signals originating in the cytoplasm are used to control the binding affinities to integrins for the ECM ligands. Such “inside-out” signaling enables cells to modulate their association with various types of ECM or with various points of contact with an ECM, breaking existing contacts and forging new ones in their place. Rapid modulation of extracellular contacts enables cells to free themselves from one microenvironment within a tissue and move into another, and to traverse a sheet of ECM at least in vitro. The significance of integrins in cellular physiology and body homeostasis is reflected by an increasing number of diseases states, ranging from hematologic, dermatologic, and musculoskeletal that have been associated with altered expression or activation of integrins. Does integrin play role in cancer development? In the cancer setting interest has been fueled by recent advances in our understanding that integrins are upregulated and/or activated in several human malignancies that are critical of almost all critical phase of tumorgenesis, 205 konferencijos medžiaga that they interact with major oncogenic signal transduction pathways, and that they regulate important cancer phenomena, such as migration-invasion, metastasis and angiogenesis [6, 7]. As the main link between a cell and the EM, integrins have an essential role in the invasion process . The cellular integrin expression pattern is highly variable between cancer types, in individual tumors, and even in separate tumor cells inside a single tumor. Thus, it is difficult to estimate the involvement of an individual adhesion receptor. The data that have accumulated with respect to integrin expression in various types of human cancer allow some conclusions to be drawn. Some integrins, especially αvβ3 seem to promote tumor progression and metastasis. The fact that some aggressive cells are negative for this integrin indicates that none of the adhesion receptors are irreplaceable. It is also obvious that some integrins have distinct functions depending on cell type. For example, α2β1 integrin may participate in the maintenance of differentiated cell phenotype in breast epithelial cells, and therefore it is often down-regulated in breast cancer. However in melanoma, prostate and gastric carcinoma, α2β1 expression is associated with tumor progression and invasion. In addition, many experimental models support the idea that α2β1 integrin is essential for cancer cell migration, invasion and metastasis formation. Studies correlating integrin expression levels in human tumors with pathological outcomes, such as patient survival and metastasis, have identified several integrins that might have an important role in cancer progression. Tumor cells expression of the integrins αvβ3, αvβ5,α6β4, α4β1 and αvβ6 is correlated with disease progression in various tumor types, therefore, these are the most studied integrins in cancer. However, this is by no means a complete list and other integrins certainly contribute to cancer progression, particularly on some of the host cell types in the primary tumors. It is also important to remember that down-regulation of an integrin subunit in cancer cells does not necessarily mean that the receptor is unimportant for malignant phenotype or that it has tumor suppressor function. Maximum cell migration speed is dependent on optimal ligand concentration, integrin expression, and ligand-integrin affinity. Therefore, a decrease in integrin expression may actually promote cell migration. The role of the integrins is not limited to their function as a mechanical bond in cell-matrix contact sites, but after binding extracellular ligands, integrins are also capable of sending signals into the cell. The cancer-related genomic instability leads to variable changes in the expression of cellular signaling molecules and most probably affects also integrin-linked pathways. Thus, the function of an integrin may change during tumor progression. The integrin may be down-regulated during transfor206 mation because it supports a normal phenotype or inhibits cell growth. However, it may also play an essential role in invasive cancer [8]. Current therapeutic approaches targeting integrins in cancer treatment The importance of integrins in several cell types that affect tumor progression has made them an appealing target for cancer therapy [9]. The first integrin antagonist which was admitted to clinical trials was etaracizumab (Vitaxin, MEDI-522). It is humanized derivative of mouse antibody LM609 against integrin α1β3, an antibody which was used in the studies on the role of this adhesive molecule in the process of neoplasia. Etaracizumab showed in Phase I clinical trials antiangionetic activity, low toxicity and disease stabilization in some patients with advanced solid tumors and renal cell cancer. A Phase II clinical study showed also some efficacy in metastatic melanoma[10]. CNTO 95, human αv integrin specific monoclonal antibody, which targets both αvβ3 and αvβ5 integrins, also has anti-tumor and anti-angiogenic effect on xerograft tumor models. In Phase I trial CNTO-95 was non-toxic and showed signs of anti-tumor activity [11, 12]. Both etaracizumab and CNTO 95 are being further evaluated in additional clinical trials. ATN-161 is non RGD-based peptide inhibitor of integrin α5β1 that blocks breast cancer growth and metastasis in vivo. In mouse model of colon cancer metastasis to the liver, combination therapy with ATN-161 and fluouracil significantly reduced tumor burden and liver metastases compared with either treatment alone. ATN-161 was tested in patients with advanced solid tumors and was well tolerated and prolonged stable disease in one-third of the patients [13, 14]. E7820 is sulphonamid derivative. Its mechanism of action depends on modulation of integrin expression on the surface of cells. It is the only integrin inhibitor used orally and has good safety profile. Currently Phase II clinical studies are carried in which E7820 and cetuximab are evaluated in the treatment of the colon cancer [15, 16]. Volociximab, a function-blocking monoclonal antibody against integrin α5β, inhibits angiogenesis and impedes tumor growth. Phase I trial with patients with advanced solid malignancies showed that volociximab was well tolerated and may have clinical efficacy. During ASCO Conference in 2007 results of Phase II clinical trials with volocoximab have been presented. During this study 40 patients with recurrent, disseminated clear cell carcinoma of kidney were receiving 10 mg/kg of volociximab every two weeks till the progression. Stabilization of the disease was observed in teorija ir praktika 2012 - T. 18 (Nr. 2) konferencijos medžiaga 32 (80 %) patients. Mean time to the progression was 4 months. Most often adverse effects were mild and included fatigue, nausea, dyspnoe and joint pain. Authors concluded that to full evaluation of volociximab effectiveness further, randomized trial are necessary [17]. Cilengitide is synthetic peptide containing sequence RGD which specifically binds to αvβ3 and αvβ5 integrin receptors in endothelium and in the consequence causes apoptosis, disturbing process of creating new blood vessels and eventually inhibition of tumor growth. Cilengitide is the most extensively studied integrin antagonist hitherto. In three Phase I clinical trials effectiveness of cilengitide had been evaluated: (1) in monotherapy of metastatic solid tumors, (2) in combination with gemcitabine in pancreas cancer and (3) in glioblastoma. In all these trials toxicity of cilengitide was low and side effects included nausea, anorexia, fatigue and vomiting. Hematologic toxicity has not been observed. The best result were obtained in the third study. Objective response was observed in 9 % of patients, and in 50 % of them stabilization of the disease lasted for 5 months (range 3–11 months). In 2007, during ASCO Conference, results of two Phase II clinical studies on cilengitide effectiveness in monotherapy of (1) glioblastoma and (2) melanoma were presented. The primary end point of the first trial was progression free survival at 6 months. In patients treated with 500 mg i.v. of cilengitide two times a week mean overall survival was 6,5 month and in patients receiving 2000 mg i.v. twice in a week it was 9,9 months. The drug was well tolerated and dose-limiting toxicity was not observed. The same dosing schedule was used in the second trial, but effectiveness of cilengitide in melanoma was minimal. The favorable results obtained from earlier clinical studies provided impetus for a Phase III trial with cilengitide that began in October 2008. The trial under the acronym CENTRIC will enroll approximately 500 patients and measure effect of cilengitide on survival of patients with glioblastoma [18-20]. In 2004 Committee for Orphan Medicinal Products enlisted cilengitide as an orphan dug in the treatment of glioblastoma. Conclusions Integrin inhibitors may become an important tool in the treatment of malignancies in the future. Hitherto trials has proven that they are medicines with low toxicity, and two of them, vitaxin and cilengitide have shown efficacy in palliative treatment of melanoma and glioblastoma. Integrins are promising group in respect of targeted therapy, however introducing them to standard clinical practice still need intensive trials. teorija ir praktika 2012 - T. 18 (Nr. 2) References 1. Moschos SJ, Drogowski LM, Reppert SL, Kirkwood JM. Integrins and cancer. Oncology (Williston Park) 2007 Aug;21(9 Suppl 3):13-20. 2. Weinberg RA. Integrin receptors sense association between the cell and the extracellural matrix. In: The Biology of Cancer. New York: Garland Science, 2007. 3. Stupack DG. The biology of integrins. Oncology (Williston Park) 2007 Aug, 21(9 Suppl 3):6-12. 4. Gille J, Swerlick RA. Integrins: role in cell adhesion and communication. Ann N Y Acad Sci 1996 Oct 25;797:93-106. 5. Pozzi A, Zent R. Integrins: sensors of extracellular matrix and modulators of cell function. Nephron Exp Nephrol 2003;94(3):e77-e84. 6. Rupp PA, Little CD. Integrins in vascular development. Circ Res 2001 Sep 28;89(7):566-72. 7. Stupack DG, Cheresh DA. Integrins and angiogenesis. Curr Top Dev Biol 2004;64:207-38. 8. Desgroseller JS CD. Integrins in cancer: biological implications and therapeutic opportunities. 10 ed. 2010. p. 9-22. 9. Rolski J NM. Integrin inhibitors in cancer treatment. 12 ed. 2008. p. 374-9. 10. Hersey P, Sosman J, O’Day S, Richards J, Bedikian A, Gonzalez R, et al. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage IV metastatic melanoma. Cancer 2010 Mar 15;116(6):1526-34. 11. Chen Q, Manning CD, Millar H, McCabe FL, Ferrante C, Sharp C, et al. CNTO 95, a fully human anti alphav integrin antibody, inhibits cell signaling, migration, invasion, and spontaneous metastasis of human breast cancer cells. Clin Exp Metastasis 2008;25(2):139-48. 12. Ning S, Nemeth JA, Hanson RL, Forsythe K, Knox SJ. Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo. Mol Cancer Ther 2008 Jun;7(6):1569-78. 13. Cianfrocca ME, Kimmel KA, Gallo J, Cardoso T, Brown MM, Hudes G, et al. Phase 1 trial of the antiangiogenic peptide ATN161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours. Br J Cancer 2006 Jun 5;94(11):1621-6. 14. Khalili P, Arakelian A, Chen G, Plunkett ML, Beck I, Parry GC, et al. A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol Cancer Ther 2006 Sep;5(9):2271-80. 15. Funahashi Y, Sugi NH, Semba T, Yamamoto Y, Hamaoka S, Tsukahara-Tamai N, et al. Sulfonamide derivative, E7820, is a unique angiogenesis inhibitor suppressing an expression of integrin alpha2 subunit on endothelium. Cancer Res 2002 Nov 1;62(21):6116-23. 16. Keizer RJ, Zamacona MK, Jansen M, Critchley D, Wanders J, Beijnen JH, et al. Application of population pharmacokinetic modeling in early clinical development of the anticancer agent E7820. Invest New Drugs 2009 Apr;27(2):140-52. 17. Kuwada SK. Drug evaluation: Volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr Opin Mol Ther 2007 Feb;9(1):92-8. 18. Bradley DA, Daignault S, Ryan CJ, Dipaola RS, Cooney KA, Smith DC, et al. Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest New Drugs 2011 Dec;29(6):1432-40. 19. Lombardi G, Zustovich F, Farina P, Polo V, Farina M, Puppa AD, et al. Cilengitide in bevacizumab-refractory high-grade glioma: two case reports and critical review of the literature. Anticancer Drugs 2012 Feb 29. 20. Lomonaco SL, Finniss S, Xiang C, Lee HK, Jiang W, Lemke N, et al. Cilengitide induces autophagy-mediated cell death in glioma cells. Neuro Oncol 2011 Aug;13(8):857-65. Gautas 2012 m. sausio 24 d., aprobuotas 2012 m. balandžio 20 d. Submitted January 24, 2012, accepted April 20, 2012 207