About the Editor. Jan B Vermorken Future Medicine
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1 About the Editor Jan B Vermorken Jan B Vermorken is Emeritus Professor of Oncology at the University of Antwerp and Consultant at the Antwerp University Hospital in Edegem, Belgium. His main field of expertise is head and neck oncology and gynecologic oncology. He devotes a considerable amount of time to teaching, professional training and continuing medical education. As of 1 January 2009, he is Editor-in-Chief of Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology. For reprint orders, please contact: reprints@futuremedicine.com Future Medicine
2 Foreword Monoclonal antibodies targeting EGFR/HER2 and clinical outcomes in cancer treatment Jan B Vermorken Monoclonal antibodies in cancer therapy The use of monoclonal antibodies (mabs) in cancer therapy is focused on the idea of selectively targeting tumor cells that express tumor-associated antigens [1]. The aim of these mabs is to specifically antagonize receptor signaling pathways, which are essential for proliferation, survival and migration of tumor cells. Their use may lead to a more customized treatment prioritizing the attack of tumor cells over normal cells. At the same time, the high specificity to the target reduces cytotoxic side effects on normal tissues, as seen with the traditional chemotherapeutic agents, and has the potential of maintaining a high quality of life. The first experience of mab administration occurred in a patient suffering from non-hodgkin lymphoma [2]. Since then, several mabs against cancer-associated antigens have been developed, which over time have been introduced into the clinic. In fact, mabs have rapidly become one the largest classes of new drugs approved for the treatment of cancer. Currently, 14 mabs have been approved by the US FDA for cancer therapy (Table 1). Seven of the mabs have been approved for the treatment of hematologic malignancies: rituximab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, tositumomab, ofatumumab and brentuximab vedotin. Seven mabs have been approved for the therapy of solid tumors: trastuzumab, pertuzumab and trastuzumab emtansine (T-DM1) are used for the doi: /ebo Future Medicine 3
3 Vermorken treatment of HER2-positive breast cancer; cetuximab, bevacizumab and panitumumab have been approved for the treatment of metastatic colorectal cancer, while cetuximab and bevacizumab have also been approved for the treatment of head and neck cancer and non-small-cell lung cancer, respectively. Ipilimumab has been approved for the treatment of advanced melanoma. These solid-tumor mabs are most effective when combined with chemotherapy or radiotherapy. Although these mabs interfere mainly with signal transduction pathways by targeting growth factors or their receptors, most of the naked therapeutic mabs can also act by other effector mechanisms, such as antibody-dependent cellular toxicity (ADCC), complement-dependent cytotoxicity (CDC), induction of apoptosis and immunomodulation. Targeting of immune cells can be achieved by employment of mabs specific for surface receptors that can have suppressing or activating function. Examples of this are ipilimumab (Table 1) and catumaxomab, a monoclonal bispecific trifunctional antibody, with binding sites directed to human epithelial cell adhesion molecule (EpCAM) and the human T-cell antigen CD3, and approved by the EMA for intraperitoneal treatment of patients with malignant ascites. In a study by Reichert and Valge-Archer on 206 mabs in clinical trials during 1980 to 2005 by commercial companies worldwide for a variety of cancer indications they found that 91 mabs were specific for only ten targets, and for most of these targets approved mabs have now become available. Targets of highest interest included: EpCAM (17 mabs), epidermal growth factor receptor (EGFR; 12 mabs), mucin-1 (MUC1/ CanAg; ten mabs), cluster of differentiation 20 (CD20; ten mabs), carcinoembryonic antigen (CEA), human epithelial receptor 2 (HER2) (nine mabs each), and CD22, CD33, Lewis Y and prostate-specific membrane antigen (PSMA) (six mabs each) [3,4]. HER family The present book focuses on two of the HER family, EGFR and HER2. The HER family consists of four types of transmembrane tyrosine kinase receptors, HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3) and HER4 (ErbB4). The general structure of ErbB members includes an extracellular ligand-binding region, an α-helical transmembrane segment, a cytoplasmic tyrosine kinasecontaining domain, and a C-terminal phosphorylation tail [5]. ErbB members are widely expressed in epithelial, mesenchymal, and neuronal tissues and regulate cell division, proliferation, differentiation, and other normal cellular processes [6,7]. These membrane receptors receive extracellular signals from their ligands, including those preferentially binding to EGFR, such as EGF, epiregulin, betacellulin, TGF-α, as well as neuregulins, which only bind to 4
4 mabs targeting EGFR/HER2 & clinical outcomes in cancer treatment Table 1. US FDA-approved monoclonal antibodies for cancer therapy. Year approved Generic name (trade name) 1997 Rituximab (Rituxan, 1998 Trastuzumab (Herceptin, Target Type Indication CD20 Chimeric IgG 1 NHL HER2 Humanized IgG 1 Breast cancer CD33 Humanized IgG 2000 Gemtuzumab ozogamicin (Mylotarg, Pfizer) 4 conjugated to calicheamicin 2001 Alemtuzumab (Campath- 1H, Genzyme) Y-Ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) I-Tositumomab (Bexxar, GlaxoSmithKline) Bevacizumab (Avastin, Cetuximab (Erbitux, ImClone LLC) 2006 Panitumumab (Vectibix, Amgen Inc.) 2009 Ofatumumab (Arzerra, GlaxoSmithKline) 2011 Ipilimumab (Yervoy, Bristol-Myers Squibb) 2011 Brentuximab vedotin (Adcetris, Seattle Genetics) 2012 Pertuzumab (Perjeta, AML CD52 Humanized IgG 1 CLL CD20 CD20 90 Y-radiolabeld murine IgG I-radiolabeld murine IgG 2a NHL NHL VEGF Humanized IgG 1 Colorectal cancer, Nonsmall-cell lung cancer EGFR Chimeric IgG 1 Colorectal cancer, Head and neck cancer EGFR Human IgG 2 Colorectal cancer CD20 Human IgG 1 CLL CTLA-4 Human IgG 1 Melanoma CD30 Chimeric IgG 1, conjugated to MMAE drug Anaplastic large cell lymphoma, Hodgkin lymphoma HER2 Humanized IgG 1 Breast cancer HER2 Humanized IgG 2013 Trastuzumab emtansine (Kadcyla, 1 conjugated to mertansine (DM1) Breast cancer Conjugated antibodies. AML: Acute myeloid leukemia; CLL: Chronic lymphocytic leukemia; CTLA-4: Cytotoxic T-lymphocyte antigen; EGFR: Epidermal growth factor receptor; HER2/neu: Human EGF receptor 2; MMAE: Monomethyl auristatin E; NHL: Non-Hodgkin lymphoma. 5
5 Vermorken HER3 and HER4 [8,9]. Their normal physiologic expression and function are controlled by the spatial and temporal expression of these ligands. Binding of ligands to the receptors leads to receptor homodimerization (two of the same receptors) or heterodimerization (two different receptors) between the HER family of receptors, cross-activation of tyrosine kinase domains and auto phosphorylation [10 12]. No ligand is known for HER2, whereas HER3 contains an inactive tyrosine kinase. Phosphorylated tyrosine residues within the cytoplasmic tail serve as docking sites for adaptor proteins and tyrosine kinase substrates, initiating a cascade of phos phorylations. Within a few hours of activation, receptors are internalized into the cytoplasm where they are either degraded or recycled back to the membrane. EGFR activation can stimulate proliferation, angiogenesis, protection from apoptosis, loss of differentiation, migration and invasion all hallmarks of cancer. Receptor dimerization drives signal transduction; EGFR homodimers undergo degradation, whereas EGFR and HER2 heterodimerization are associated with recycling following endocytosis, which enhances mitogenic signaling. The activating ligand and receptor dimer formed drives different signaling cascades and ultimately different cellular processes. Homodimers are weaker effectors than heterodimers: EGFR and HER2 is the most common heterodimer; HER2:3 plus neuregulin is the most potent combination; HER2 decelerates the internalization of HER1; HER1 requires ligand binding before dimerization; and HER2 does not require a ligand to dimerize and is often expressed at a 100-fold higher concentration than HER1 [11]. The complex inter-related EGFR-stimulated signal transduction network includes different pathways. The two key signaling pathways activated by the ErbB family are the RAS/RAF/MAPK pathway, which stimulates proliferation, and the PI3K/Akt pathway, which promotes tumor cell survival [13]. Targeting the HER family with monoclonal antibodies Several approaches are currently being undertaken to inhibit HERsignaling that is, blocking of ligand binding to EGFR by mabs, blocking of EGFR and HER2 dimerization by mabs, blocking kinase activation by smallmolecule drugs such as tyrosine kinase inhibitors (TKIs), modulation of EGFR expression, either by inhibition of EGFR synthesis by sirna or by stimulation of EGFR degradation [14]. At present, the two main approaches being investigated in the laboratory and in the clinic are mabs and TKIs. The mabs are directed against the extracellular region of the receptors and block peptide binding and signal transduction, resulting in a cytotoxic effect on tumor cells as well as direct and indirect effects on angiogenesis, invasion and metastases [11,15]. As mentioned earlier, there is increasing evidence that immunological mechanisms contribute to the efficacy of 6
6 mabs targeting EGFR/HER2 & clinical outcomes in cancer treatment mabs. ADCC has been shown with mabs and also shown to correlate with the level of EGFR expression on target cells [16,17]. The use of EGFR-directed mabs was shown to downregulate PI3K/Akt, MAPK, SRC, and signal transducer and activator of transcription (STAT) signaling. EGFR-directed mabs also enhance the antitumor effects of routinely used chemotherapeutic agents and radiotherapy. mabs against EGFR are generally well tolerated by patients and the most common side effect are diarrhea and skin reactions, which are most probably dose related [6]. The present book focuses on mabs targeting EGFR and HER2 and summarizes information on the use of these mabs in colorectal cancer, breast cancer, lung cancer, genitourinary cancers, tumors of the skin, the CNS and the head and neck, and gynecologic malignancies. Financial & competing interests disclosure JB Vermorken has advisory function in Merck-Serono, Amgen and Genentech, and received honoraria for traveling and giving lectures at satellite symposia for Merck- Serono Bristol-Myers Squibb and Amgen. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. References 1 Oldham RK, Dillman RO. Monoclonal antibodies in cancer therapy: 25 years of progress. J. Clin. Oncol. 26, (2008). 2 Nadler LM, Stashenko P, Hardy R et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphomaassociated antigen. Cancer Res. 40, (1980). 3 Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nat. Rev. Drug Discov. 6, (2007). 4 Van Dongen GA, Vosjan MJV. Immuno-positron emission tomography: shedding light on clinical antibody therapy. Cancer Biother. Radiopharm. 25, (2010). 5 Olayioye MA, Neve RM, Lane HA, Hynes NE. The Erb signaling network: receptor heterodimerization in development and cancer. EMBO J. 19, (2000). 6 Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 5, (2005). 7 Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonist in the biology and treatment of cancer. J. Clin. Oncol. 21, (2003). 8 Riese DJ, Stern DF. Specificity within the EGF family/erbb receptor family signaling network. Bioassays 20, (1998). 9 Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat. Rev. Mol. Biol. 2, (2001). 10 Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 7(Suppl 4), (2002). 11 West CM, Joseph L, Bhana S. Epidermal growth factor receptor-targeted therapy. Br. J. Radiol. 81, S36 S44 (2008). 7
7 Vermorken 12 Jiang N, Saba NF, Chen ZG. Advances in targeting HER3 as an anticancer therapy. Chemother. Res. Pract. 2012, (2012). 13 Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9, (2009). 14 Harari PM. Epidermal growth factor receptor inhibition strategies in oncology. Endocr. Relat. Cancer 11, (2004). 15 Nyati MK, Morgan MA, Feng FY, Lawrence TS. Integration of EGFR inhibitors with radiochemotherapy. Nat. Rev. Cancer 6, (2006). 16 Kimura H, Sakai K, Arao T, Shimoyama T, Tamura T, Nishio K. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 98, (2007). 17 Kurai J, Chikumi H, Hashimoto K et al. Antibodydependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin. Cancer Res. 13, (2007). 8
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