Receptor tyrosine kinase-like orphan receptor 1 (ROR-1): An emerging target for diagnosis and therapy of chronic lymphocytic leukemia

Biomedicine & Pharmacotherapy 88 (2017) 814–822

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Receptor tyrosine kinase-like orphan receptor 1 (ROR-1): An emerging target for diagnosis and therapy of chronic lymphocytic leukemia Leili Aghebati-Malekia,b,c,d , Mahdi Shabanie, Behzad Baradarana,b , Morteza Motallebnezhada,b , Jafar Majidia,b,* , Mehdi Yousefib,c,* a

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran d Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran e Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran b c

A R T I C L E I N F O

Article history: Received 29 November 2016 Received in revised form 4 January 2017 Accepted 12 January 2017 Keywords: CLL Diagnosis ROR-1 Therapy Tyrosine kinase

A B S T R A C T

Chronic lymphocytic leukemia (CLL) is characterized by reposition of malignant B cells in the blood, bone marrow, spleen and lymph nodes. It remains the most common leukemia in the Western world. Within the recent years, major breakthroughs have been made to prolong the survival and improve the health of patients. Despite these advances, CLL is still recognized as a disease without definitive cure. New treatment approaches, based on unique targets and novel drugs, are highly desired for CLL therapy. The Identification and subsequent targeting of molecules that are overexpressed uniquely in malignant cells not normal ones play critical roles in the success of anticancer therapeutic strategies. In this regard, ROR family proteins are known as a subgroup of protein kinases which have gained huge popularity in the scientific community for the diagnosis and treatment of different cancer types. ROR1 as an antigen exclusively expressed on the surface of tumor cells can be a target for immunotherapy. ROR-1 targeting using different approaches such as siRNA, tyrosine kinase inhibitors, cell therapy and antibody induces tumor growth suppression in cancer cells. In the current review, we aim to present an overview of the efforts and scientific achievements in targeting ROR family, particularly ROR-1, for the diagnosis and treatment of chronic lymphocytic leukemia (CLL). © 2017 Elsevier Masson SAS. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ROR-1 structure and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ROR-1 expression profile in normal and malignant tissues . . . . . . . . . ROR-1 and CLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ROR-1 post-translational modifications in CLL . . . . . . . . . . . . . . . . . . . ROR-1 and its importance in CLL diagnosis . . . . . . . . . . . . . . . . . . . . . ROR1 targeting in CLL therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting ROR1 using mAbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting ROR1 using cell therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting ROR1 using small-molecule tyrosine kinase inhibitors (TKI) Viewpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding authors at: Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail addresses: [email protected] (J. Majidi), yousefi[email protected] (M. Yousefi). http://dx.doi.org/10.1016/j.biopha.2017.01.070 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

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Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820

1. Introduction Identification and targeting molecules that are overexpressed uniquely in malignant but not normal cells are critical points for the success of cancer therapy. In recent years, growing interest has been towards the application of tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) as therapeutic, diagnostic and screening targets for cancers [1]. Such antigens have a vital role in the growth and survival of cancer cells and targeting them may lead to inhibiting the growth and survival of malignant cells. As Weinstein stated, tumor cells may be dependent on the activated oncogenic pathways for survival and accumulation, a phenomenon known as “oncogenic addiction” [2]. Phosphorylation of signaling proteins has a major role in regulating cellular activity and hence the protein kinases that are critical determinants of phosphorylation processes are of particular importance in tumorigenesis as well as natural evolution [3,4]. Protein kinases catalyze the transfer of a phosphate group from adenosine triphosphate (ATP) to specific amino acid residues in proteins involved in signaling pathways. These residues include tyrosine and serine/threonine. Tyrosine kinases (TKs) are considered a group of protein kinases and a class of TAAs which contribute to the most central cellular processes such as cell cycle, migration, metabolism, accumulation, survival and differentiation. Therefore, the activity of tyrosine kinases must be under strict control [5–8]. Among TKs, receptor tyrosine kinases (RTKs) are structurally transmembrane proteins with an intracellular kinase domain. The aberrant regulation of RTKs has been observed in a

variety of cancer cells in the form of overexpression, abnormal expression, mutations and translocations which lead to constant kinase activity independent of ligand binding [9,10]. Receptor tyrosine kinase-like orphan receptor (ROR) as a member of RTK family has been recently brought into the focus of researchers in different fields of medical sciences due to its unique expression profile and other properties. Compatible with altered expression and activity of TKs in different cancers, overexpression of ROR protein has been observed in different malignancies such as chronic lymphocytic leukemia (CLL) [11]. CLL is one of the most common malignancies across the globe. CLL is histologically identified by the accumulation of small mature B lymphocytes in the blood, bone marrow, lymph nodes, and other lymphoid tissues. With an overview of cancer epidemiology in the Western societies, it can be concluded that CLL is the most frequent leukemia in these populations such that only in the United States of America this cancer is responsible for the death of about 5000 people yearly [12]. Unfortunately, there is no available efficient therapy for CLL patients and many research works are being conducted to find standard and effective therapeutic modalities for CLL. CLL diagnosis is performed based on clinical and laboratory findings, but there is major challenges for introducing a specific diagnostic marker that individually can be applied to diagnose CLL. Considering ROR1 expression profile in CLL, it can be used as a potential attractive target for CLL diagnosis, prognosis and treatment. In the current article, we try to review the efforts and scientific achievements on ROR family, particularly ROR-1 in the diagnosis and treatment of CLL.

Fig. 1. Structure of the ROR-1 receptor tyrosine kinase. Human ROR-1 consists of an immunoglobulin-like domain (IG), two cysteine-rich domain (CRD), frizzled (FZD) and kringle domain (KRD) at extracellular part. In the intracellular portion, ROR-1 possesses a tyrosine kinase domain (TKD), two serine/threonine-rich domains (Ser/Thr), and a proline-rich domain (PRD). Complete ROR-1 protein encompasses 937 amino acids.

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2. ROR-1 structure and biology ROR-1 and ROR-2 RTK proteins were first discovered about 20 years ago in neuroblastoma cell lines and initially named as neurotrophic tyrosine kinase receptor-related protein [13]. These two proteins have 58% similarity in amino acid sequence in human and are closely related to the Trk and MUSK receptor family [13,14]. Corresponding genes of ROR-1 and ROR-2 encode 104 kDa proteins; however, ROR-1 undergoes a variety of posttranslational modifications in partiuclar glycosylation, which lead to variation of its molecular weight up to 130 kDa. Importantly, such regions of glycosylation are involved in ROR-1 transport to the membrane as well as its function [15]. The structure of ROR proteins includes an extracellular portion at N-terminus comprised of immunoglobulin-like domain, a cysteine rich domain (CRD) called Frizzled domain (FZD) and a Kringle domain (KRD), followed by transmembrane and cytoplasmic sections with the last section containing tyrosine kinase, serine/threonine-rich and proline rich domains (Fig. 1). It has recently been predicted that the ROR-1 juxtamembrane domain of cytoplasmic region mediates its translocation to the nucleus to act as a transcription factor [16,17]. Accumulation of the cytoplasmic domain in the nuclei can be associated with cell migration and cytoskeleton restructuring that mediates this process through the activation of genes involved in regulating actin skeleton, including RDX, EZR, SOS2 and CALD1 [17]. One of the remarkable features of these two proteins is that although both fall into tyrosine kinase family, they lack several highly conserved amino acids present in other TKs [18]. Considering the replacement of at least three highly conserved amino acids in the ROR-1 kinase domain, it can be concluded that ROR-1 is a false kinase with absence or very little kinase activity [19–22]. Therefore, despite the weak evidence reported by some studies about autocatalytic kinase activity of ROR-1 kinase [19,20], the activity of ROR-1 kinase domain is still a matter of discussion. Gentile et al. in their study suggested that ROR-1 is a false kinase with no internal catalytic activity and is also transphosphorylated by the Met oncogene [19,23]. Despite these reports, Yamaguchi et al. revealed that ROR-1 interacts with c-Src in transfected COS-7 and HEK293-T cell lines and shows also high kinase activity in the phosphorylation of c-Src [24]. This finding became controversial when Bainbridge et al. reported that ROR-1 and ROR-2 kinase domains have no catalytic activity and ROR-1 kinase activity is due to contamination with cofactors or other kinases [25]. According to

the these conflicting reports, the activity of ROR-1 kinase domain has not been approved yet and needs further investigation. The investigation of ROR biological function was initially performed using in situ hybridization and detection of mutant knockouts in mice. These studies proposed that ROR family proteins play important roles in the development of skeletal, cardio-respiratory and nervous systems in the early stages of embryonic development [21]. In this context, ROR proteins have different functions in cell aggregation, differentiation, angiogenesis, and migration [18], the processes involved in metabolism and cell signaling during embryogenesis [18,22,26]. In general, it can be concluded that the ROR family proteins are mostly activated in the nerve and skeletal tissues [27–29]. In this regard, Paganoni and Ferreira demonstrated that ROR-1 controls the neurite growth along with branching pattern in the hippocampal neurons [30]. Other studies tried to suppress ROR molecules by interfering with the function of RNA (RNA interference) or antisense oligonucleotides to assess the effectiveness of these proteins in cell survival [31]. These studies revealed that ROR-1apparently plays a vital role in the survival of normal cells of infant rats not only on the first day after birth, but also in later days. Infants with mutations in ROR-1 develop breathing problems followed by death, however, mutations in ROR-2 leads to dwarfism, shortening of limbs and tail, breathing difficulties and consequently death 6 h after birth. Additionally, mice with both ROR mutations die shortly after birth due to severe respiratory failure [31–35]. 3. ROR-1 expression profile in normal and malignant tissues The expression patterns of mouse ROR-1 and ROR-2 molecules in the fetus partially overlap each other. For example, different expression patterns of these molecules have been observed in the evolution of pharyngeal arches, processing nose and many neuronal membranes of derivative cells [21,26]. In general, during mouse evolution ROR-1 expression is limited to mesenchymal cells and neuronal cell membranes in the brain while ROR-2 is expressed at higher levels in neural and non-neural cells [21,26]. In organs of the body, low level of ROR-1 has been identified in the proximal portion of the limb bud while ROR-2 expression has been detected in the mesenchymal limb of mouse. In the later stages of development, the strong expression of ROR-2 is seen in evolving Perichondrium finger while ROR-1 expression is observed in the interdigital necrotic areas [36,37]. In human, the expression of ROR-1 is predominantly limited to embryo and fetus and it is not

Table 1 The expression of ROR-1 and its association with disease progression in different malignancies. Malignancy

Overexpression

Disease progression

References

CLL CML AML B-ALL Pancreatic cancer Bladder carcinoma Hairy cell leukemia Mantle cell lymphoma Prostate Cancer Ovarian cancer Testicular Cancer Adrenal carcinoma Breast Cancer Lung cancer Melanoma Colon cancer

+ ?

+ NI NI + + NI NI NI NI + NI NI + + NI NI

Baskar et al. [38], and Daneshmanesh et al. [40] Shabani et al., Daneshmanesh et al. [11,45,46], and Shabani et al. [47] Shabani et al., [11] and Daneshmanesh et al. [46] Shabani et al. [11], Daneshmanesh et al. [46], and Bicocca et al. [23] Zhang et al. [48], Daneshmanesh et al. [49], and Cui et al. [50] Zhang et al. [48] Daneshmanesh et al. [46] Daneshmanesh et al. [46] Zhang et al. [48] Zhang et al. [48] Zhang et al. [48] Zhang et al. [48] Zhang et al. [48] Yamaguchi et al. [24], and Zhang et al. [48] Farsangi et al. [53], and O’connell et al. [95] Zhang et al. [48]

/+ + + ? + + + + ? + + + + +

ROR-1: Receptor tyrosine kinase-like orphan receptor 1, CLL: chronic lymphocytic leukemia, CML: chronic myeloid leukemia, AML: acute myeloid leukemia, B-ALL: B-cell acute lymphoblastic leukemia, and NI: no information

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observed in adult tissues; however, the low level of expression of ROR-1 has been found in adipose tissue and in much lower levels in the pancreas, lung and some B-cell intermediate subtypes [23,38,39]. In addition, ROR-1 mRNA expression has been observed in heart, lung and kidney of adults and to a lesser extent in placenta, pancreas and skeletal muscle [40]. ROR-1 overexpression has been reported in many human cancers [38,40–42]. The expression profile of ROR-1 and its association with progression in different malignancies are presented in Table 1. In an elegent study, RNAi based silencing of 650 known kinases in cervical Hela carcinoma cells revealed that 73 genes are involved in the survival of Hela cells. ROR-1 was among 4 genes out of 73 genes with the most critical role in cell survival. It is interesting that ROR-1 turns off after 72 h and the rate of apoptosis in these cell lines increases to four times the throughput [43,44]. Most studies have suggested that ROR-1 might stimulate different signaling pathways in various malignancies by recruiting different signaling proteins and activating several transcription factors (Fig. 2). The final outcome of different signaling pathways is increased tumor survival, proliferation and metastasis [45]. In the following parts we will focus on important findings highlighting the role of ROR-1 in the diagnosis and treatment of CLL as a common leukemia in Western countries. 4. ROR-1 and CLL For the first time, the increased expression of ROR-1 in a malignancy was identified using microarray technique in B-CLL [39]. In CLL, ROR-1 overexpression is seen uniformly on the surface of leukemic cells and there is not a special feature in terms of distribution [38,39,45]. Interestingly, Baskar et al. reported that ROR-1 protein is selectively expressed only on the surface of leukemic B-cells in CLL patients while it is not expressed in normal B-cells derived from healthy individuals as well as in other normal tissues. Moreover, their findings indicated that ROR-1, regardless of having any biological characteristics, has uniform expression on the leukemic cells of B-CLL [46–48]. Antibody binding to

817

transmembrane ROR-1 results in partly internalization of this molecule [49,50]. Many other studies have confirmed overexpression of ROR-1 in CLL patients [40,48]. Investigations for understanding the mechanism underlying ROR-1 overexpression have lead to the finding that structural phosphorylation of Stat3, one of the most important features of CLL, is observed in different areas of the ROR-1 promoter. It has also been exhibited that IL-6 can induce the expression of ROR-1 through Stat3 [51,52]. 5. ROR-1 post-translational modifications in CLL There are 7 asparagine residues with the potential of N-linked glycosylation and 24 serine-threonine residues with O-linked glycosylation capabilities in the structure of ROR-1 that can provide a variety of patterns for protein glycosylation [53]. The presence of 100 to 130 kDa glycosylation forms of ROR-1 have been identified in CLL which most notably are 105 and 130 kDa isoforms accumulated in the cytoplasm and nucleus of leukemic cells [15,40]. Farsangi et al. using specific antibodies against ROR-1 revealed that two forms of this protein are expressed in CLL with molecular weights of 105 and 130 kDa. These isoforms are probably representatives of glycosylated and non-glycosylated forms of ROR-1 [53]. Furthermore, another form of ROR-1 with 260 kDa molecular weight has been recognized that could be considered as ROR-1 dimer. It has been stated that this dimer can exist as heteroor homo- dimer [54–56]. Interestingly, a 64 kDa fragment of ROR1 which is probably a piece of its C-terminal portion is only observed in the nucleus of cells [53]. The post-translational modifications of ROR-1 have functional importance in CLL. It has been demonstrated that blocking ROR-1 glycosylation in different ways such as treatment of ROR-1 expressing cells with the drug tunicamycin, as an N-linked glycosylation inhibitor, leads to the inhibition of ROR-1 expression in CLL cells [15,53]. As mentioned above, ROR-1 has different scenarios and a variety of glycosylation patterns [15,53]. In this regard, different states of ROR-1 glycosylation have been detected among diverse CLL patients and even different cell clones of one

Fig. 2. A schematic suggested model for ROR-1 signalingpathways.

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patient [53]. Interestingly, the non-glycosylated ROR-1 protein has higher frequency in non-progressive CLL patients compared with progressive ones. This highlights the contribution of glycosylation patterns of ROR1 in disease state [57]. In addition to glycosylation patterns, it has been shown that phosphorylation of the mature ROR-1 protein in the progressive CLL case is higher than non-progressive states [53]. Also, the expression of ROR-1 in the progressive leukemic cells is significantly higher than the non-progressive leukemic cells [46]. It seems that there are relationships among the maturity of ROR-1, its phosphorylation, and activity in CLL cells [58]. 6. ROR-1 and its importance in CLL diagnosis Currently, flow cytometry is routinely used in CLL diagnosis for investigating the cell surface and cytoplasmic markers of malignant cells. However, the lack of specific markers for the recognition of leukemic cells in CLL does not allow for definite diagnosis of CLL using single marker detection. For this reason, the process of CLL diagnosis using flow cytometry requires the exploitation of multiple markers that altogether can improve the success rate of detection, even though the use of several markers increases the cost and uncertainty of diagnosis [59]. Now, efforts are being made to introduce reliable markers for the diagnosis of CLL. Such markers should have specific features to be accepted for diagnosis such as constant and uniform expression on CLL cells with no expression on normal cells as well as independence from the disease stage [60,61]. To use ROR-1 as a diagnostic target, it should be noted that one of the characteristics of each diagnostic marker is its capability to distinguish healthy from transformed tissue. In this regard, preliminary studies indicated that ROR-1 molecule has a low level of expression in normal blood cells [62]. Subsequent investigations revealed that ROR-1 expression on normal cells does not interfere with the process of CLL diagnostic because ROR-1 is expressed at very low levels on normal blood cells. It has been indicated that 3.7% of B-cells, 0.3% of T-cells, 1.4% of monocytes, 1.6% of granulocytes, and 1.9% of NK-cells naturally expresee ROR-1 [62]. Considering the expression level of ROR-1 protein in CLL in comparison with normal blood cells as well as the capacity of flowcytometry technique to define the threshold of sensitivity and reading system, ROR-1 can still be applied for CLL diagnosis. In flow cytometry protocol, threshold can be adjustable to exclude the low expression of ROR-1 in normal PBMCs as negative value. Keeping this in mind, it was thought that ROR-1 is itself an appropriate target for the early diagnosis of CLL using flow cytometry [59,62]. In terms of specificity of the expression of ROR-1 in CLL as another standard for diagnostic marker, it has recently been figured out that ROR-1 is not only expressed in CLL, but also in Bcell non-Hodgkin's lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia [11,41]. In other words, studies have shown that ROR-1 is overexpressed on B-cells non-Hodgkin's lymphoma with expression of CD19 such as mantle cell lymphoma and follicular lymphoma, as 94.8% of CD19 positive cells in mantle cell lymphoma have high expression of ROR-1 [63]. Furthermore, in

marginal zone lymphoma patients variable levels of ROR-1 expression from 33.7% to 99.3% is observed.ROR-1 expression has also been observed in some patients with immunocytoma [62,63]. It is worthy to note that ROR1 expression is not detected in myeloid malignancies such as AML [47]. Due to the high expression of ROR-1 in other malignancies e.g. B-NHL, this marker alone does not seem to be enough for the early diagnosis of CLL. But less than 10% expression of ROR-1 protein can be used as an indicator of the disease absence. According to the current panel of antibodies for the diagnosis of CLL, it is proposed that ROR-1 can be used as a complement to improve the performance of the panel [64]. Further studies on CLL patients who were treated using various approaches have also demonstrated the consistent ROR-1 expression during treatment and confirmed its potential use as a diagnostic marker [62]. It was observed that ROR-1 expression after each stage of chemotherapy remains high in CLL patients [62]. It has become clear that due to the lack of being affected by therapeutic procedures, ROR-1 can be used as a marker not only in the newly diagnosed patients, but also in treated patients. Based on current data, although ROR-1 cannot be used to diagnose CLL alone, but it can be considered as a marker for the detection of malignant conditions such as non-Hodgkin lymphoma and CLL. After ROR-1 detection, more complete panels of CD markers are required to reach a differential diagnosis. On the other hand, monoclonal antibody (mAb) against the ROR-1 can also be used in combination with other antibodies that are currently included in a diagnostic panel, thereby increasing the specificity and sensitivity of detection. Additionally, the lack of ROR-1 overexpression in blood cells can be considered as an exclusion factor for B-cell malignancies such as CLL and non-Hodgkin's syndrome. 7. ROR1 targeting in CLL therapy Currently, the preferred drug used to treat B-CLL is Fludarabine that in combination with different compounds such as cyclophosphamide and anti-CD20 mAbs have increased the efficiency and effectiveness of treatment; however, these drugs are only effective for disease control not treatment [65]. Accordingly, much effort has been made to overcome the current shortcomings of CLL therapy. Many investigations have tried to present new modalities for CLL treatment using different approaches including specific mAbs, small tyrosine kinase inhibitors, immunotoxines, and cell therapy [66–68]. All of these therapeutic modalities can potentially target ROR-1 molecules especially for CLL therapy as summarized in Table 2 and Fig. 3. 8. Targeting ROR1 using mAbs The important point in tumor targeting by mAbs is that proposed targets should have consistent, persistent, and unique expression on the surface of malignant cells [69,70]. The application of mAbs such as rituximab (chimeric mAb to CD20) and alemtuzumab (humanized mAb to CD52) combined with first and second lines of treatment for B-CLL has been evaluated in

Table 2 Different approaches are being investigated and used for the treatment of cancer using ROR-1 targeting. Strategies

Malignancy type

References

Monoclonal antibody against ROR-1 Anti-ROR-1 immunotoxin Tyrosine kinase inhibitory small molecules Immunotherapy using ROR-1 targeting

Pancreatic carcinoma, melanoma, metastatic breast cancer and leukemia CLL and MCL CLL and pancreatic adenocarcinoma CLL and breast cancer

[49,53,70] [66] [72] [77,67,68]

ROR-1: Receptor tyrosine kinase-like orphan receptor 1, CLL: chronic lymphocytic leukemia, and MCL: Mantle cell lymphoma.

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Fig. 3. Strategies to target the receptor tyrosine kinase ROR-1. Monoclonal antibodies (mAbs), small-molecule tyrosine kinase inhibitors (TKI), their combination and antiROR-1 siRNA may interfere with cell proliferation, differentiation, migration, metastasis and invasion and induction of cell death by apoptosis.

different studies [71,72]. It should be mentioned that in various studies none of the target antigens have restricted expression on BCLL cells and hence lead to the reduced activity and increased toxicity of mAbs. For instance, it should be considered that approved therapeutic mAbs target B-CLL cells as well as other CD20 + or CD52 + B-cells, NK-cells, and monocytes [73]. This leads to immune suppression in treated patients as the side-effects of mAb-based immunotherapy. Therefore, it is necessary to target antigens expressed exclusively on malignant cells. Therapeutic mAbs against ROR-1, which is almost exclusively expressed on BCLL cells, can result in specific targeting of B-cells, and reduce side effects, thereby providing better management of the disease. Baskar et al. showed that ROR-1 expression levels on the cell surface of cells derived from B-CLL vary among different B-cells ranging from 1000 to 10,000 molecules per cell in various patients and ROR-1 is distributed homogenously and uniformly on the cell surface [69]. The density of ROR-1 molecules on the cell surface is lower compared with other therapeutic targets which provides the possibility to reduce immune responses, including cytotoxicity mediated by antibodies, and complement system [69]. However, other studies have indicated that specific mAb binding to the extracellular part of ROR1, including KRD and CRD domains results in the rapid dephosphorylation of ROR-1 and apoptosis in cells through a mechanism independent of the complement system. This phenomenon can be triggered by molecular conformational changes that eventually lead to the stimulation of downstream biological pathways [53,63,74–76]. Interestingly, ROR1-specific mAbs are not able to induce apoptosis in none of PBMCs isolated from healthy people implying on the effectiveness of ROR-1 targeting on CLL cells [63]. In addition, Yang et al. have shown that rabbit Fab specific to ROR1 can also bind to this molecule on human and mouse cells and activate antibody mediated cellular response (ADCC), complement mediated cytotoxicity (CDC), the ingestion of antigens as well as apoptosis induction [73].

Since the internalization of immunological drugs is an important feature for their effectiveness, researchers have evaluated the internalization capacity of ROR-1 molecule and came to the conclusion that this phenomenon is seen in 30 to 45% of cases. ROR-1 internalization is initiated within 30 min after incubation with mAb and increases to maximum level within 2 h [66,69]. Recently, Fukuda et al. provided evidence indicating that ROR-1 may act as a receptor for Wnt5a signaling pathway in CLL cells. The survival of CLL cells cultured with Wnt5a-expressing CHO cells was significantly higher than those cultured along with CHO cells. This survival rate disappeared after using antisera against ROR-1 which indicates the importance of ROR-1 in CLL cells [77]. All of these findings support the notion that specific anti-ROR1 mAbs could be appropriate tools for CLL targeted therapy. 9. Targeting ROR1 using cell therapy Modified T-cells that express recombinant receptors or a chimeric antigen receptor (CAR) against a tumor antigen have received huge attention as one of the efficient approaches for cancer immunotherapy [78–82]. CARs are synthetic receptors composed of a single variable chain (scFV) of a mAb specific for tumor antigen, a transmembrane domain and one or more intracellular signaling systems e.g. CD3z [83–85]. T-cells transduced for CAR expression can recognize target antigen on the surface of tumor cells without the help of MHC molecules. Autologous CD19-CAR T-cells have exhibited a long-term response against B-cell malignancies [86]. In this group of patients, the highest toxicity is related to tumor cell destruction, release of cytokines, and long-term decrease in the number of normal B-cells [79,80,87]. CAR T-cell specific for ROR-1 has been introduced by Hudecek et al. in 2013. They applied modified CAR T-cells specific for ROR-1 that efficiently recognize and lyse ROR-1+ tumor cells leading to an improved performance of T-cell antitumor activity

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[88]. This preliminary finding opens up new frontiers for ROR-1 targeting using T-cell therapy in clinical trials. 10. Targeting ROR1 using small-molecule tyrosine kinase inhibitors (TKI) One of the effective approaches for cancer treatment is targeting RTKs using small anti-TK molecules that directly influence kinase catalytic activity by interfering with ATP binding or substrate to the enzyme [89,90]. Within the past years, extensive efforts have been made to find small molecule inhibitors for RTKs [91]. Many of these inhibitors have been developed for cancer therapy including canertinib (EGFR inhibitor), crizotinib (MET inhibitor), ibrutinib (BTK inhibitor) and Tivozanib (VEGFR inhibitor) [92,93]. However, tumor resistance to mAbs is a challenge for these powerful tools and does not allow for continuing therapy course [91]. The combination of mAbs with other anticancer drugs such as small molecules targeting the kinase domain may overcome resistance to mAb. Targeting colon cancer cell lines which express EGFR with cetuximab and gefitinib has been demonstrated to prevent proliferation and induce apoptosis [92]. Similarly, treatment of HER-2 by trastuzumab and lapatinib in combination has shown better clinical activity than their use alone in HER-2 positive breast cancer patients [92]. ROR1 tyrosine kinase inhibitor could represent huge potential in the specific treatment of CLL. ROR1-specific small molecules might inhibit downstream signaling and induce leukemic cell death. Recently, Mellstedt et al. have reported that three small molecule compounds (KAN0173631, KAN0438063, KAN0438175T) could induce specific apoptosis in CLL cells [94,95]. It should be noted that there are conflicting views on using specific small molecules for targeting the catalytic kinase activity of ROR-1. 11. Viewpoints CLL is still a hard to treat disease but multiple therapeutic approaches are being used to control symptoms and prolong the survival of patients. Lately, a number of new agents have shown promising clinical activity and some have been approved for CLL therapy. This can pave the way for reaching long-term control of the disease in the future. Based on present data, ROR1 is recommended to be involved in recruiting several signaling proteins and transcription factors as well as activating signaling pathways, all of which can finally result in high proliferation, metabolism, metastasis and survival of malignant cells. Targeting ROR1 might be considered as a new approach for anticancer therapy which improves prognosis for several types of malignancies, hematological diseases as well as solid tumors. ROR1 has an interesting structure for targeted therapy. This may be attributed to some important characteristics of ROR1 including unique expression in malignant cells compared with normal ones, and its importance for several essential functions of malignant cell such as survival, proliferation, metabolism and metastasis. Despite producing some promising drug candidates, we need to obtain a deeper insight into the molecular and cellular biology of ROR1 in order to develop innovative therapeutic approaches. It can be concluded that due to ROR-1 overexpression in CLL cells and dramatic differences in its expression between normal cells, this marker can be considered a valuable target for the diagnosis and treatment of CLL. Based on the current data, the difference of ROR1 expression between normal and CLL cells can not hamper its exploitation for CLL diagnosis. Although, considering ROR-1 expression in other B-cell malignancies e.g. B-NHL, this marker alone does not seem to be sufficient for the early diagnosis of CLL, and less than 10% expression of ROR-1can be used as an

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