From conventional chemotherapy to targeted therapy

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Ramucirumab. VEGFR-2 inhibitor na. Metastatic gastric or GEJ adenocarcinoma. Cetuximab. EGFR inhibitor. RAS. mCRC. Panitumumab. EGFR inhibitor. RAS.
From conventional chemotherapy to targeted therapy: use of monoclonal antibodies (moAbs) in gastrointestinal (GI) tumors Federica Zoratto, L. Rossi, E. Giordani, M. Strudel, A. Papa & S. Tomao

Tumor Biology Tumor Markers, Tumor Targeting and Translational Cancer Research ISSN 1010-4283 Tumor Biol. DOI 10.1007/s13277-014-2367-1

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Author's personal copy Tumor Biol. DOI 10.1007/s13277-014-2367-1

REVIEW

From conventional chemotherapy to targeted therapy: use of monoclonal antibodies (moAbs) in gastrointestinal (GI) tumors Federica Zoratto & L. Rossi & E. Giordani & M. Strudel & A. Papa & S. Tomao

Received: 21 May 2014 / Accepted: 15 July 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014

Abstract In recent years, significant progress has been made in the diagnosis and treatment of gastrointestinal cancers. Researches and clinicians however are still faced with challenges, not the least is the detection and management of tumors with varied gene mutation status. Clarification of the molecular pathology of gastrointestinal cancers may improve treatment options as well as quality of life and the long-term survival of this patient class. Therefore, molecular-targeted therapies have emerged as clinically useful drugs for gastrointestinal cancers cure, and predictive biomarkers have been heralded as the way to develop the right drug for the right patient. Moving from such appealing molecular background, we wrote an overview of the main targeted therapies, with particular interest to monoclonal antibodies that have already been approved in clinical practice or are being tested in gastrointestinal cancers treatment.

F. Zoratto (*) Oncology Unit 2, Azienda Ospedaliera-Universitaria Pisana, Ospedale Santa Chiara, Via Roma 67, 56126 Pisa, Italy e-mail: [email protected] L. Rossi : E. Giordani : M. Strudel : A. Papa : S. Tomao Oncology Unit, Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, ICOT, Via Faggiana 1668, 04100 Latina, Italy L. Rossi e-mail: [email protected] E. Giordani e-mail: [email protected] M. Strudel e-mail: [email protected] A. Papa e-mail: [email protected] S. Tomao e-mail: [email protected]

Keywords Gastrointestinal cancers . Monoclonal antibodies . Molecular biomarkers . Personalized treatment strategy

Introduction Gastrointestinal (GI) tumors constitute a major public health problem around the world. Last year, in the USA, the National Center for Health Statistics recorded 284,680 GI cancer new cases and 142,680 new deaths [1]. It is equally true that, nowadays, there was a decrease of their incidence and mortality due to earlier diagnosis through screening and better treatment modalities, respectively. Although mainstays of GI tumor treatment are represented by surgery, chemotherapy, and radiotherapy, moleculartargeted therapies have emerged as clinically useful drugs for their cure [2]. The concept of targeted therapy was born more than a century ago, but its practical application in cancer therapy took several decades [3]. Targeted therapies used in GI cancer treatment are monoclonal antibodies (mAbs) or multitargeted tyrosine kinase inhibitors (mTKIs) directed against three main signaling pathways, which are involved in tumor angiogenesis and cancer cells proliferation: (a) vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptors (VEGFR), (b) epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR), and (c) HER2neu (Fig. 1) [4]. Nowadays, many biologic agents have been approved by the US Food and Drug Administration (FDA) for clinical use in GI cancers, while many are in various phases of development. Traditionally, oncologists have relied on histopathological description and surrogates for the biological behavior of the tumor at clinical presentation. Currently, research in malignancies has expanded to analyze alterations in genomic and proteomic signal pathways that caused growth and migration of cancer cells. In this way, the understanding of these alterations has led to development

Author's personal copy Tumor Biol. Fig. 1 moAbs and signaling pathways in GI cancers

of drugs targeted specifically for abnormal pathways and that may replace or complement conventional chemotherapy. Furthermore, genomic and proteomic profile knowledge of an individual patient cancer has allowed discovery predictive factors of response to therapy. These advances at GI tumors molecular level permitted the emergence of personalized medicine [5, 6]. Moving from such appealing molecular background, we will discuss the relevant trials in GI cancers with regard the main moAbs most commonly used in clinical practice (Table 1) and with a short explanation about those in experimentation (Table 2).

Anti-angiogenic monoclonal antibodies Tumor angiogenesis Angiogenesis refers to the process by which a new blood supply is established from pre-existing blood vessels [7]. Tumor angiogenesis is known to be different from the physiological angiogenesis and has been shown to lead to the

development of abnormal vascular architecture, and it is recognized as an important aspect of tumorigenesis. Without angiogenesis, tumors are limited in size to the distance that oxygen can diffuse, namely 1–2 mm. Increased vascularity not only allows an expansion in tumor size but also leads to a greater probability of hematogenous embolization of the tumor and so metastatic spread happens [8, 9]. The tumor produces a series of angiogenic factors. The VEGF family is divided into five members having a homodimer structure: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF). VEGF-A is generally called VEGF because VEGFA is a key regulator of developmental vasculogenesis, angiogenesis, and differentiation of progenitor endothelial cells [10, 11]. VEGF interacts with cell membrane receptors, the VEGF receptor (VEGFR). VEGFRs consist of three subtypes, VEGFR-1, VGFR-2, and VEGFR-3. All subtypes possess seven immunoglobulin-like domains in the extracellular region and a tyrosine kinase domain in the intracellular region [12–15]. VEGFR-1 and VEGFR-2 are expressed in vascular endothelial cells and hematopoietic stem cells, while VEGFR3 is largely restricted to lymphatic endothelial cells. These

Table 1 moAbs approved in GI cancers treatment moAbs

Mechanism of action

Biomarkers

US FDA approval status

Bevacizumab Ziv-aflibercept

VEGF inhibitor binds VEGF-A, VEGF-B, PlGF

na na

mCRC mCRC

Ramucirumab Cetuximab Panitumumab Trastuzumab

VEGFR-2 inhibitor EGFR inhibitor EGFR inhibitor HER2neu inhibitor

na RAS RAS HER2neu

Metastatic gastric or GEJ adenocarcinoma mCRC mCRC Metastatic gastric or GEJ adenocarcinoma

moAbs monoclonal antibodies, VEGF vascular endothelial growth factor, PlGF placenta growth factor, VEGFR vascular endothelial growth factor receptor, EGFR epidermal growth factor, na not available, mCRC metastatic colorectal cancer, GEJ gastroesophageal junction

Author's personal copy Tumor Biol. Table 2 moAbs being tested in GI cancers treatment moAbs

Mechanism of action

GI cancers

Bevacizumab

VEGF inhibitor

Ziv-aflibercept Ramucirumab

binds VEGF-A, VEGF-B, PlGF VEGFR-2 inhibitor

Cetuximab

EGFR inhibitor

Panitumumab

EGFR inhibitor

Metastatic gastric or GEJ adenocarcinoma Advanced HCC Advanced/metastatic pancreatic cancer Advanced/metastatic pancreatic cancer mCRC Advanced HCC Advanced/metastatic EGC Advanced HCC Advanced/metastatic EGC biliary cancer mCRC

Trastuzumab

HER2neu inhibitor

Nimotuzumab

EGFR inhibitor

Clivatuzumab Conatumumab

Mucin antigen of pancreatic cancer Activator deaths receptor 5

Ganitumab

IGF I inhibitor

Matuzumab

EGFR inhibitor

Advanced/metastatic esophageal cancer Advanced/metastatic pancreatic cancer Advanced/metastatic pancreatic cancer mCRC Advanced/metastatic pancreatic cancer mCRC PNET Advanced/metastatic pancreatic cancer Advanced/metastatic EGC

moAbs monoclonal antibodies, VEGF vascular endothelial growth factor, PlGF placenta growth factor, VEGFR vascular endothelial growth factor receptor, EGFR epidermal growth factor, mCRC metastatic colorectal cancer, GEJ gastroesophageal junction, HCC hepatocarcinoma, EGC esophageal gastric cancer, IGF insulin growth factor, PNET carcinoid or pancreatic neuroendocrine tumor

VEGF members have different affinities for one of the three VEGFR subtypes. VEGF-A activates VEGFR-1 and VEGFR2, whereas VEGF-B and PlGF bind only to VEGFR-1. VEGFR stimulation with VEGF of PlGF causes receptor dimerization, leading to activation of intrinsic tyrosine kinase that induces tumor angiogenesis. When the number of capillaries per volume of tissue decreases, tumor cell proliferation is not affected, but the apoptotic fraction increases, leading to “dormant” tumors [16]. Since Folkman proposed that antiangiogenesis would be a novel anti-tumor strategy, angiogenesis has become an attractive drug target [17], especially that VEGF-A and VEGFR-2 are currently the main targets for antiangiogenic therapy. Anti-VEGF therapy inhibits tumor angiogenesis and promotes apoptosis of existing tumor blood vessels, thereby intercepting the supply of oxygen and nutrition essential for tumor growth and metastasis [18–20]. It was also suggested that anti-VEGF therapy effectively normalizes abnormal vascular permeability and thereby decreases the interstitial pressure [21, 22]. These drugs can be categorized into four groups: anti-VEGF antibodies, soluble receptors binding directly to VEGF ligand such as VEGF-Trap, anti-VEGFR antibodies, and VEGFR tyrosine kinase inhibitors. Bevacizumab Bevacizumab (bv) is a humanized monoclonal antibody that blocks the binding of VEGF to its receptors and results in

regression of immature tumor vasculature, normalization of remaining tumor vasculature, and inhibition of further tumor angiogenesis. To date, BV is approved in the first- and second-line treatment of metastatic colorectal cancer (mCRC) [23, 24]. In 2004, the FDA approved BV as a first-line treatment following a phase III study that compared bolus irinotecan/5fluorouracil/leucovorin (IFL) plus placebo vs IFL plus bevacizumab in previously untreated patients. In that pivotal trial, a longer overall survival (OS) was observed with the use of bevacizumab (OS, 20.3 months in IFL + bevacizumab group vs 15.6 months in IFL group; HR 0.66; P