Tyrosine Kinase Inhibitors (Tkis) in Human and Pet Tumours with Special

Home , Toceranib

Critical Reviews in Oncology/Hematology 88 (2013) 293–308

Tyrosine kinase inhibitors (TKIs) in human and pet tumours with special

reference to breast cancer: A comparative review

a,∗ b b b

Girolamo Ranieri , Marianna Pantaleo , Mariagrazia Piccinno , Maria Roncetti ,

b c d b

Maddalena Mutinati , Ilaria Marech , Rosa Patruno , Annalisa Rizzo ,

Raffaele Luigi Sciorsci

Interventional Radiology Unit with Integrated Section of Transational Medical Oncology National Cancer Research Centre,

Cancer Institute“Giovanni Paolo II”, Bari, Italy

Department of Emergencies and Organ Transplantation (DETO)-University of Bari “Aldo Moro”, Italy

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology,

University of Bari Medical School, Bari, Italy

Department of Prevention and Animal Ealth, ASL BAT, Barletta, Italy

Accepted 17 May 2013

Contents

1. Breast tumours in humans and pets ...... 294

2. Dysregulation of tyrosine kinase proteins in tumours ...... 295

3. The TKR type III family and breast cancer ...... 297

3.1. PDGFRs ...... 297

3.2. Colony stimulating factor-1 receptor (CSF-1R, c-fms) ...... 298

3.3. c-KitR ...... 298

4. Tyrosine kinase inhibitors (TKIs) in the treatment of cancer...... 298

4.1. EGFR and HER-2 inhibitors ...... 298

4.2. VEGFR, PDGFR, c-KitR and CSF-1R inhibitors ...... 299

5. Concluding remarks ...... 301

Conﬂict of interest statement ...... 301

Reviewers ...... 302

Acknowledgement ...... 302

References ...... 302

Biographies...... 307

Abstract

Tyrosine kinase receptors (TKRs) play a key role in tumour cell proliferation and survival since they are involved in endothelial cell

activation leading to tumour neoangiogenesis. In particular, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth

factor receptor (PDGFR), stem cell factor receptor (c-KitR), and colony-stimulating factor 1 (CSF-1) are overexpressed or constitutively

activated in human and pet malignancies. A variety of small molecule inhibitors targeting speciﬁc tyrosine kinases (known as tyrosine kinase

inhibitors or TKIs) have recently been approved, or are under investigation, for the treatment of human cancer. TKI application in animal

∗

Corresponding author at: Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre

“Giovanni Paolo II”, via Orazio Flacco 65, 70124, Bari, Italy. Tel.: +39 080 5555561; fax: +39 080 5555563.

E-mail addresses: [email protected], [email protected] (G. Ranieri).

294 G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308

cancer is however relatively recent. This review aims to illustrate the major aspects of tyrosine kinase dysfunctions, with special regard to

human and animal cancer of the mammary gland, providing an update on the background of the anti-angiogenic and anti-neoplastic properties

of TKIs in human and veterinary cancer.

Keywords: Tyrosine kinase receptors; Tyrosine kinase inhibitors; Angiogenesis; Breast cancer; Women; Pets; Comparative oncology; Bitch; Queen

1. Breast tumours in humans and pets which tends to be clinically HER-2 positive, and the basal-

like subtype, which tends to have a low expression of ER,

Breast cancer is the most commonly diagnosed malig- progesterone receptor (PR) and HER-2 [25,26,28]. This clas-

nancy and one of the major causes of mortality among women siﬁcation is clinically meaningful, leading to distinct tumour

worldwide [1]. It is diagnosed in about 1 million women every phenotypes and outcomes [26,27,29].

year, causing the death of over 400,000 of them [2]. In 2010, Moreover, a number of prognostic factors have been iden-

breast cancer was the most diagnosed cancer in the USA tiﬁed in human breast cancer [30].

(207,090 women) and showed the fourth highest death rate Humans and their pets share the same environment, and

(39,840 women) [3]. For this reason, it is one of the most this suggests pets may be considered as an “environmental

investigated diseases [1,4]. sentinel” [31], allowing for a much more timely evaluation of

Breast cancer is a heterogeneous disease in which genetic carcinogenicity and exposure risk for countless agents [32].

and environmental factors interact to initiate carcinogenesis It is well known that the biological behaviour of some malig-

[5]. Many of the breast cancer risk factors are well known: (1) nancies, including breast carcinoma, shares a similar biology

age [6,7], (2) early menarche (<12 years); (3) late menopause in dogs and humans [33]. In fact, in both species the tumour

(>55 years) [8,9]; (4) family history [6,10,11]; (5) genetic arises spontaneously over a number of years as a result of

factors [12]; (6) obesity; (7) use of combined oestrogen and multiple genetic alterations, and is frequently characterized

progestin hormones; (8) alcohol consumption; (9) repro- by microscopic metastases at the time of diagnosis [34]. In the

ductive behaviour; (10) sedentary lifestyle; (11) radiation canine species, tumour incidence increases around 6 years of

exposure; and (12) chronic accidental exposition to endocrine age and peaks in bitches aged 9–11 years [35]. In particular,

disrupters [13–15]. Nevertheless, the aetiology of this disease about 50% of all tumours in bitches are mammary tumours

remains unclear [16]. Moreover, since breast cancer is inﬂu- [36,37], which clearly show a steroid hormone-dependent

enced by hormonal status, its incidence increases with age development [38], as suggested by the protective effects of

and doubles every 10 years until menopause [17]. Conversely, early spaying [39]. Some authors have reported that bitches

it has been demonstrated that younger age at ﬁrst full-term spayed before their ﬁrst estrous cycle have an approximately

pregnancy (<30 years), and multiple births rather than no 0.5% chance of developing breast neoplasia which, con-

pregnancy, decrease the risk of breast cancer over the long versely, increases if spaying occurs after the ﬁrst estrus [40].

term [8,18,19]. The protective role against tumour develop- On the other hand, ovariohysterectomy, performed at later

ment provided by pregnancy on the mammary gland depends ages, does not seem to play a role in reducing the risk of devel-

on the permanent changes to the gland structure determined oping malignant mammary tumours in the canine species

by pregnancy itself [20,21]. Interestingly, some researchers [41]. Canine mammary neoplasms are commonly presented

have suggested that the increased risk of breast cancer may be as circumscribed nodules with variable size, consistency and

due to a decrease in melatonin levels which occurs as a result mobility to the skin and muscle [34].

of exposure to light at night. In fact, melatonin may affect As to the morfo-functional classiﬁcation system of mam-

oestrogen levels as well as acting as a tumour suppressor [22]. mary tumours, both human and animal malignancies are

With regard to human breast cancer classiﬁcation, this disease staged according to the Tumour Node Metastasis (TNM) sys-

can be subclassiﬁed into preinvasive and invasive stages [23]. tem established by the World Health Organization (WHO).

The preinvasive histological phases of common hyperplasia, This system assesses the size of the primary lesion (T), the

atypical hyperplasia, and ductal carcinoma in situ (DCIS) extent of its spread to regional lymph nodes (N) and the

usually precede neoplastic conversion to invasive cancer [24]. presence or absence of distant metastases (M) [42].

Another criterium of classiﬁcation of breast cancer is based The grading system most widely used currently in human

on gene expression proﬁles [25,26]. According to this classi- medicine to establish the histological grade of tumour differ-

ﬁcation, the two major subtypes of ER-positive malignancies entiation is the Nottingham system modiﬁed by Elston and

are luminal A and luminal B. These subtypes are biolog- Ellis [43]. This system is based on the evaluation of the tubule

ically distinct in that luminal A tumours tend to have a formation index.

higher expression of ER-related genes and a lower expres- In veterinary medicine this system is not frequently used

sion of proliferative genes than luminal B [26,27]. Among [44]. The systems proposed by Gilbertson et al. [45] and

the ER-negative tumours, the major subtypes are the human by Misdorp et al. [46] are two of the most popular criteria

epidermal growth factor 2 (HER-2) array subtype, most of proposed for the identiﬁcation of breast tumour type in

G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308 295

veterinary medicine. Both are based on the combined evalua- Table 1

Principal classiﬁcations of mammary gland tumours in human and pet.

tion of cellular and nuclear features as suggested by Misdorp

et al. [46]. They classify breast tumours as: (1) non-neoplastic Breast cancer Pet mammary gland tumours

epithelial lesions; (2) benign tumours; (3) malignant tumours. Histological Misdorp system

•

Non-neoplastic epithelial lesions consist of epithelial Preinvasive Non-neoplastic epithelial

- Common hyperplasia lesions

hyperplasia, ductal hyperplasia (when these lesions arise

- Atypical hyperplasia - Epithelial hyperplasia

in the extralobular ducts), lobular hyperplasia (when these

- Ductal carcinoma in situ (DCIS) - Ductal hyperplasia

lesions arise in the intralobular ducts), adenosis, and colum-

- Lobular hyperplasia

nar cell lesions (columnar cell alteration, columnar cell • Invasive - Adenosis

hyperplasia, atypical columnar cell lesions) [46]. Benign - Ductal carcinoma - Columnar cell lesions

- Lobular carcinoma • Benign tumours

tumours are adenoma, complex adenoma or adenomyoep-

- Tubular carcinoma - Adenoma

ithelioma, basaloid adenoma, ﬁbroadenoma, mixed benign

- Cribriform carcinoma - Complex adenoma

tumour and ductal papilloma [46]. Among the malignant

- Medullary carcinoma - Adenomyoepithelioma

canine breast tumours, which represent 80% of all breast - Mucinous carcinoma - Basaloid adenoma

tumours, malignant mixed tumours, complex carcinomas, - Fibroadenoma

- Mixed benign tumour

and carcinosarcomas are relatively common (approximately

- Ductal papilloma

30%) [47]. However, several authors have reported that •

Malignant tumours

malignant tumours account for approximately 50% of all

- Adenocarcinoma

tumours in the bitch [41,45,48], mainly carcinomas or sar- - Mixed tumours

comas [46]. Malignant breast tumours can also be associated - Complex carcinomas

- Carcinosarcomas

with skin ulceration and local inﬂammatory reactions. More-

over, these tumours affect the inguinal mammary glands with Based on gene expression proﬁles

•

Luminal A

a higher frequency than they do with thoracic glands [34].

• Luminal B None

Besides carcinomas and sarcomas, an uncommon and aggres- •

HER-2 enriched

sive neoplasm in bitches is inﬂammatory carcinoma (IMC)

• Basal-like

[42], which is characterized by an inﬂammatory process of

Morfo-functional according to TNM None

the breast gland [34]. As in humans [49,50], animal IMC is

Nottingham grading system modiﬁed None

characterized by a high rate of nodal and widespread metasta-

by Elston and Ellis

sis [34,41], particular aggressiveness [51], fulminant clinical

course, and unfavourable prognosis [52].

In the queen, mammary tumours represent about 17%

of all neoplasms, but in this species the protective role of alters cell function and may cause disease [59]. Uncon-

ovariohysterectomy is unfortunately not as well described trolled kinase activity leads to changes in gene transcription

[41]. and cell response. The loss of kinase inhibitory mediators

In cats, approximately 85% of mammary neoplasms are or activating mutations leads to subsequent cell prolifera-

malignant, and the most widespread is adenocarcinoma [45]. tion and is common in cancer [57]. Protein kinases can be

Feline breast tumours grow rapidly and easily metastasize to divided into two main classes, tyrosine kinases (TKs) and

regional lymphnodes and lungs [53–55]. serine–threonine kinases (STK), according to the phosphory-

The principal classiﬁcations of mammary gland tumours lation of tyrosine or serine–threonine residues, respectively.

in humans and pets are summarized in Table 1. Both protein kinases have a common catalytic core, which

contains a glycine-rich N-terminal ATP-binding pocket and

a central conserved aspartic acid residue, required for its cat-

2. Dysregulation of tyrosine kinase proteins in alytic activity [60]. TKs are key players in normal cell signal

tumours transduction, acting to tightly regulate cell growth and differ-

entiation, and are divided into two large classes: receptor and

Protein kinases are one of the largest families of pro- non-receptor TKs. TK receptors (TKRs) are transmembrane

teins. They catalyze a series of phosphorylation of target proteins with a ligand-binding extracellular domain and a

proteins, leading to the activation of signal-transduction path- catalytic intracellular kinase domain, whereas non-receptor

ways which are indispensable for many cellular processes TKs lack transmembrane domains and are found in the inner

[56–58]. It has been shown that protein phosphorylation reg- surface of the plasma membrane, the cytosol and the nucleus

ulates cellular proliferation, metabolism, motility, survival [61]. Of the 90 tyrosine kinases discovered [62], 58 are recep-

and apoptosis [58]. tor type, divided into 20 subfamilies according to their similar

Protein kinases are susceptible to a variety of stimuli gen- structure [63], while the 32 non-receptor tyrosine kinases

erated outside and inside the cell. It is not surprising that can be sorted into 10 subfamilies. Their products regulate

any alteration of the phosphorylation mechanism due to the cellular proliferation, survival, differentiation, functions, and

aberrant expression and/or activity of protein kinase receptors motility [61].

296 G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308

In recent years, great attention has been paid to TKRs. micro vessel density (MVD) in malignant neoplasia and a

In particular, strong emphasis has been given to the cancer- positive correlation between MVD and the expression of

related activity of these proteins [58,64]. The aberrant VEGF in breast tumours [80]. With regard to feline mam-

expression and activity of TKRs seem to be strongly deter- mary tumours, increased VEGF expression was correlated

mined by the occurrence of many DNA alterations, such as to tumour anaplasia and shorter survival times, but VEGF

point mutations or gene duplication/chromosome transloca- was not correlated with MVD [81]. In a more recent study

tion [62]. The process of ligand binding and activation of the investigating the role of VEGF in promoting tumour angio-

catalytic domain is well known in TKRs. Normally, the acti- genesis in both feline and canine mammary carcinomas, the

vation of the intracellular kinase domain, which is a result of same authors demonstrated VEGF expression in endothelial,

the binding of ligands to the external region of a TKR, leads to epithelial and stromal compartments, which did not show any

dimerization of the receptors and autophosphorylation of the correlation with poorer prognosis [82]. On the other hand,

tyrosine residues of the intracellular catalytic domain. This the results by Kato et al. [83], who measured blood concen-

results in an active receptor conformation and activation of a trations of VEGF in bitches with mammary gland tumours,

down-stream effect or pathway [65,66]. showed that the concentration of this factor was higher in

Examples of TKRs include epidermal growth factor recep- the bitches with malignant neoplasms than in those with

tor (EGFR), known to be dysregulated in particular forms of benign ones, suggesting that VEGF could represent a valid

cancer [67]. Other receptors, such as platelet-derived growth and reliable biomarker of malignancy of breast tumours in

factor receptor (PDGFR ␣ and ␤), colony stimulating factor the bitch, as well as an indicator of prognosis. In 2010, Mil-

receptor (CSF-1R, c-fms) and stem cell or steel factor recep- lanta et al. [84] found that VEGF expression was higher in

tor (c-Kit) [68] are members of the TKR type III family, and canine inﬂammatory breast carcinoma (IMC) than in carcino-

are implicated in highly malignant human tumours includ- mas without inﬂammation (non-IMC). These results suggest

ing breast cancer [69]. In addition to regulating normal cell that VEGF may contribute to the high angiogenic pheno-

function, certain TKRs are important in promoting tumour type of canine IMC and that its expression may relate to

angiogenesis. These include vascular endothelial growth fac- the high tendency of this tumour to metastasize. Moreover,

tor receptors (VEGFRs), PDGFR, ﬁbroblast growth factor ER and PR expression were detected in canine non-IMC,

receptor (FGFR), and TKRs Tie1/2 [70–72]. but not in IMC [85]. A study conducted by Al-Dissi et al.

Several speciﬁc biomolecular features, such as the over- [86] in samples of canine adenocarcinoma found a moderate

expression of human epidermal growth factor receptor-2 correlation between VEGF expression and proliferation, and

(HER-2) [73] and the activation of VEGFRs [74], are histologic grade. It has been found that a number of stimuli

involved in breast cancer. trigger VEGF production and secretion within the breast

In particular, VEGF and VEGFRs, the class III recep- cancer microenvironment. In particular, besides growth fac-

tor tyrosine kinases PDGFR and c-Kit receptor are key tors, cytokines or hormones, a key role is played by the

proangiogenic factors involved in breast cancer development overexpression of the c-erbB-2 proto-oncogene (also called

[58,75,76]. HER2 or neu receptor tyrosine kinase, HER2/neu, ErbB2)

In some cancer types, a frequent mechanism of TK acti- [87,88]. Some researchers have demonstrated that HER2/neu

vation is the fusion of a TKR or non-receptor TK with a is ampliﬁed up to 100-fold in the tumour cells of about

partner protein, which causes constitutive oligomerization of 30% of patients with invasive breast cancer. Furthermore,

the TKR in the absence of ligand binding or physiologic acti- a signiﬁcant clinical correlation has been shown between

vating signals thereby promoting autophosphorylation and HER2/neu gene ampliﬁcation and overexpression of malig-

activation [61]. A second important mechanism of TKR nancy parameters, including reduced survival and reduced

deregulation is a mutation disrupting the auto-regulation time to relapse, as compared to patients with normal receptor

of the kinase that renders TKR active in the absence of levels [61,65].

the ligand [61]. Thus, small deletions and point mutations Phosphorylation of the tyrosine kinase domain results in

in the kinase domain of EGFR increase the sensitiv- tumour and endothelial cell proliferation and survival via the

ity of the receptor to its ligand [77] and alter receptor PI3K- and Ras/MEK/MAPK-signalling pathways [89–91].

signalling [78]. Cellular transformation is also caused by a protein kinase

A third mechanism of TKR deregulation is increased that catalyzes the phosphorylation of tyrosine deriving from

expression of a TKR, its ligand, or both [61]. Increased a cellular gene (the proto-oncogene, c-Src). Src activity is reg-

TKR activity can increase the proliferation, survival, and ulated by intramolecular interactions, controlled by tyrosine

cytotoxic drug resistance of malignant cells, and it can phosphorylation, and domains of Src (SH2 and SH3) mediate

induce tumour angiogenesis, invasiveness, and metastatic protein–protein interactions [64,92]. Src is a membrane-

potential [61]. associated non-receptor TK, involved in several transduction

In human and veterinary oncology, angiogenesis is one signals [93–95]. Src plays a role in signal transduction and

of the key factors in the development of breast tumours cross-talk between growth-promoting pathways, such as the

[79]. Some studies, regarding both benign and malignant ER, HER2 [95] and EGFR family pathways, known to be

canine mammary neoplasia, have shown a statistically higher active in breast cancer [93,94].

G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308 297

Fig. 1. Fundamental tyrosine kinases’ pathways involved in tumour progression.

Many tumours, including breast cancer, exhibit elevated identiﬁed also in feline MCTs [105]. Dank et al. [106] iden-

expression of the Src family of protein tyrosine kinases tiﬁed c-Kit mutations in exon 8 which are believed to promote

(SFKs) [64]. Moreover, in breast cancer tissue, an increase in unregulated c-KitR activation in these tumour cells. There-

Src kinase activity (4-fold to 30-fold) as compared to normal fore, c-Kit is likely to be a relevant target for feline mast cell

breast tissue has been observed [95]. disease.

Although many studies have been conducted on the In conclusion, in both human and veterinary patients

involvement of TK dysfunction in human breast cancer, this TKRs are often abnormally activated in malignant tumours.

argument has been studied far less in veterinary oncology. This induces persistent cell signalling in the absence of

As previously mentioned, c-Kit, a receptor found on appropriate negative regulation/growth factor stimulation,

mast cells, is required for their differentiation, survival, thereby stimulating uncontrolled cell proliferation, survival

proliferation and degranulation [96,97]. Interestingly, c- and increased angiogenesis. The alterations in TKR acti-

Kit receptor (c-KitR) stimulates angiogenesis in mast cell vation depend on mutations, overexpression, generation of

tumours by degranulation of pro-angiogenic factors stored in fusion proteins from chromosomal translocation, or autocrine

their secretory granules. It has been demonstrated recently loops of activation through coexpression of growth factor and

that mast cell-depending angiogenesis is important in human TKRs [58], as described below.

and canine mammary cancer [98]. Several authors have Fundamental tyrosine kinase pathways involved in tumour

identiﬁed the presence of c-Kit mutations in canine mast progression are shown in Fig. 1.

cell tumours (MCTs), which are also angiogenesis-driven

tumours [99–101]. Mutations of this receptor have also been

found in canine gastrointestinal stromal tumours (GISTs) 3. The TKR type III family and breast cancer

which are nearly identical to those present in human GISTs

[102]. 3.1. PDGFRs

EGFR is another TKR currently being investigated for its

potential role in canine cancers. It has also been reported As mentioned above, PDGFRs belong to the TKR type

that malignant breast lines demonstrate enhanced chemo- III family. They are minimally expressed or undetectable

taxis and VEGF production in response to EGFR activation in normal tissues, since they are expressed only in ﬁbro-

[103]. Few data exist on TK dysfunction in feline cancers. In blasts, smooth muscle cells in lungs, airways and pericytes

this context, cell lines of vaccine-associated sarcoma (VAS) of the vascular wall [107]. Like other members of this

␤

were shown to express PDGFR- that was phosphorylated family, PDGFR has an extracellular domain, made up of

after PDGF exposure [104]. It was shown that PDGFR pro- ﬁve immunoglobulin-like repeats and a TK domain [58].

motes the growth and survival of these cancer cells and, PDGFRs ␣ and ␤ and their ligands, platelet-derived growth

consequently, that this receptor may be an appropriate target factors A and B (PDGFs), are important for stromal cell

for therapeutic intervention [104]. Mutations in c-Kit were migration and proliferation. Physiologically, they participate

298 G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308

in wound healing, inﬂammation and angiogenesis [108]. In 4. Tyrosine kinase inhibitors (TKIs) in the treatment

␤

particular, PDGFR- takes part in angiogenesis and blood of cancer

vessel maintenance whereas its ligand, PDGF-B, has been

shown to be an essential factor, indirectly, in the regulation In human medicine, the safety and efﬁcacy of new antineo-

of endothelial cell function [58,109]. The over-expression of plastic therapeutics for the treatment of malignant tumours

PDGFR has been reported in multiple malignancies, includ- have sometimes been studied previously on spontaneous

ing breast tumours [75,110,111], and aberrant expression malignancies in the canine population [128]. In some human

of PDGFR receptors appear to deregulate growth of these and canine malignant tumours, similar TKR dysregulation

tumours [58]. These factors are mainly associated with a poor occurs [128], and for this reason TKs represent an attractive

prognosis and a poor response to systemic chemotherapy in target for selective pharmacologic inhibitors. A most success-

advanced breast cancer patients [112]. ful approach is the use of a class of recent drugs termed “small

molecule tyrosine kinase inhibitors” which block intracel-

3.2. Colony stimulating factor-1 receptor (CSF-1R, lular signalling pathways, inducing deregulation of cellular

c-fms) proliferation and differentiation [61,103].

In particular, these small molecules block the ATP binding

The c-fms proto-oncogene encodes the only known recep- site of kinases, acting as competitive inhibitors, and their

tor (CSF-1R) for colony stimulating factor 1 (CSF-1 or action may be reversible or irreversible [58,129,130]. The

M-CSF) [113]. CSF-1 and its receptor (CSF-1R) regulate binding of TKIs to TKRs causes a conformational change,

breast gland development [114]. Activation of CSF-1R by or the competitive inhibition of the link to ATP and to other

its ligand triggers a series of rapid events, including CSF-1R molecules necessary for signal transduction to the nucleus,

tyrosine phosphorylation that creates binding sites for a vari- providing a targeted approach for the treatment of many types

ety of cytoplasmic proteins (such as ERK1/2) which activate of human and mammalian cancers [131].

signal transduction pathways [115]. CSF-1 and CSF-1R are Alternatively, a second mechanism exists, usually referred

expressed in normal breast tissue during puberty, pregnancy to a monoclonal antibody, binding to the extracellular ligand

and lactation. However, several studies indicate that CSF- domain of TKRs to induce a block in the intracellular signal-

1R and CSF-1 are expressed in breast cancer cell lines, too, transduction pathways [66]. The inhibition of angiogenesis,

demonstrating the relevance of CSF-1/CSF-1R signalling in especially through VEGFR-2, FGFR-2 and PDGFR, is an

the invasiveness of these cancerous cells [114,116–118]. The important focus area in breast cancer research. Many TKIs,

expression of CSF-1R and/or CSF-1 has been documented directed towards angiogenic pathways, are currently being

in breast carcinomas [119–121]. It has been demonstrated studied in clinical trials on patients with metastatic breast

that this pathway strongly correlates with poor prognosis, cancer [132].

and it is predictive of ipsilateral recurrence in breast cancer The introduction of TKIs as anti-cancer drugs in human

patients [114,117]. Furthermore, in mouse models, CSF-1 cancer treatment is fairly recent [61,133,134], but these

promotes metastasis, stimulates angiogenesis and with EGF it inhibitors are often easy to synthesize in large quantities, are

is involved in a paracrine loop to promote tumour cell invasion orally bioavailable, and can readily enter cells to gain access

[122–124]. to the intended target [103]. In particular, targeting TKRs with

kinase inhibitors has recently led to a new era in the treatment

3.3. c-KitR of hematologic malignancies and solid tumours, including

breast cancer [135–137]. Substantial preclinical and indirect

The TK transmembrane receptor c-KitR is involved in clinical evidence has shown that TKIs add potential value

normal cell physiology and is expressed in different tissues. to current treatment regimens for advanced breast cancer,

Initially, it was identiﬁed as a product of a viral oncogene in such as chemotherapy, antioestrogen drugs, and antibody-

the Hardy-Zuckerman IV feline sarcoma virus (HZ4-FeSV) mediated therapies [132].

and it was associated with its transforming activity [125]. The targets for therapeutic intervention are not clearly

Later on, c-Kit gene product was shown to be expressed in a deﬁned for most canine or feline cancers, therefore limited

number of cells, including mast cells, epithelial breast cells data exist on the clinical efﬁcacy of TKIs in these species.

and some human and canine tumours [126,127]. The ligand Additionally, many of the human TKIs are currently cost-

for c-KitR has been identiﬁed as Steel Cell Factor (SCF). prohibitive, preventing their widespread use in veterinary

Both sporadic mutations of c-Kit and autocrine/paracrine oncology [103].

activation mechanisms of the SCF/c-KitR pathway are impli-

cated in a variety of malignancies, leading to tumour growth, 4.1. EGFR and HER-2 inhibitors

increased cell proliferation, mast cell degranulation and

angiogenesis, which in turn lead to apoptosis reduction. Trastuzumab is a monoclonal antibody that targets the

Several experimental data suggest that c-Kit mutation and extracellular domain of HER-2. It has been used in breast

activation may be involved in the pathogenesis of breast can- cancer [138], in combination with or after standard adju-

cer [75]. vant chemotherapy [139]. Trastuzumab shows an attractive

G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308 299

response rate and outcome in treating HER-2 positive 4.2. VEGFR, PDGFR, c-KitR and CSF-1R inhibitors

metastatic breast cancer (MBC) patients [132,140–143].

However, Nahta and Esteva [144] reported that resistance Several scientists and clinical investigators have estab-

to trastuzumab may develop within one or two years, even in lished the essential nature of tumour angiogenesis in cancer

patients that initially respond to treatment. [154]. In this regard, antiangiogenic strategies have attractive

Lapatinib is an oral reversible TKI that targets the kinase advantages for different types of cancer, preventing tumour

domain of both HER-2 and EGFR; it has been demonstrated neovascularization [155,156].

to provide clinical beneﬁt in patients with HER-2-positive About one third of the molecular therapeutics in clini-

breast cancer [132]. This agent has also been tested in cal development are directed against VEGF or its principal

metastatic breast cancer [132]. Other authors [145] have receptor, the receptor TK VEGFR2 (KDR) [157,158]. VEGF

investigated lapatinib monotherapy in second-line MBC, inhibitors can yield a survival beneﬁt when added to cytotoxic

evaluating the efﬁcacy and safety of lapatinib in patients chemotherapy in solid tumours [159].

with HER-2-positive breast cancer that progressed during Pazopanib is a small TKI molecule that acts as an antian-

or after trastuzumab therapy. Overall, single-agent lapatinib giogenic drug via inhibition of the intracellular domains

in these patients showed clinical activity with manage- VEGFR, PDGFR and c-KitR. It is efﬁcacious in metastatic

able toxic effects, such as rash, diarrhoea, nausea, and renal cell cancer and soft tissue sarcomas [160,161]. Sla-

fatigue [145,146]. mon et al. [162] have shown that the administration of

Another small oral TKI EGFR selective molecule, geﬁt- pazopanib plus lapatinib to patients with untreated HER-2-

inib [132], was found to have little antitumour activity in positive advanced breast cancer or MBC lowers the rate of

breast cancer when administered as a single agent [147]. disease in the combination group compared to the lapatinib

In a phase II study however, in combination with docetaxel alone group.

active and generally well-tolerated in chemotherapy naïve Other authors have demonstrated the safety and efﬁcacy

MBC patients [148]. Herbst et al. [149] reported the adverse of pazopanib, emphasizing its effects on disease stabiliza-

events associated with geﬁtinib as diarrhoea and an acne- tion and demonstrating the cytostatic activity of this drug

like rash [148]. Ciardiello et al. [148] found a statistically [163]. The side effects of pazopanib are in keeping with those

signiﬁcant correlation between clinical response to geﬁtinib reported for other drugs causing VEGF inhibition (such as

plus docetaxel treatment and ER status. In this study, the hypertension or gastrointestinal haemorrhage), c-KitR inhi-

clinical data may be explained by the ﬁnding that human bition (such as skin hypopigmentation), and transaminitis

breast cancer cells, chronically cultured in the presence of (increase in hepatic transaminases) and gastrointestinal tox-

tamoxifen, generally become antioestrogen-resistant in 3–6 icity. Although pazopanib did not demonstrate efﬁcacy in

months [150,151]. The interesting results of Ciardiello et al. inducing response as a single agent, these authors suggest

[148] suggest that a clinically relevant issue is the identi- that it may be useful in studies of combination therapy and

ﬁcation of potential predictive factors which could help to that the dose may need to be reduced, when used in combina-

select breast cancer patients who could respond to anti-EGFR tion, to improve tolerability [163]. Pazopanib appears to have

targeted therapies. Women with ER-positive tumours have single-agent activity similar to that of other targeted inhibitors

higher response rates and are most likely to be the patients of angiogenesis in advanced pretreated breast cancer, such as

who could beneﬁt from a combination of docetaxel plus sunitinib or sorafenib [164–166].

geﬁtinib. However, in postmenopausal breast cancer patients In particular, sunitinib is an oral multitargeted TKI that

with ER-positive and EGFR-positive tumours before cura- inhibits VEGFR, PDGFR, c-KitR and CSF-1R, showing

tive surgery it has been demonstrated that a short treatment promising activity as a single agent for advanced breast can-

with geﬁtinib monotherapy, or with geﬁtinib plus anastrozole, cer [167].

determines a direct antiproliferative effect [152]. Geﬁtinib, Some experimental breast cancer cell lines and breast can-

in association with anastrozole, improves the progression- cer xenograft models showed that sorafenib, an oral Raf-1

free survival (PFS) and the clinical beneﬁt rate in women kinase, PDGFR and VEGFR kinase inhibitor, has antitu-

with hormone receptor-positive MBC when compared with mour effects [168,169]. Interestingly, a study conducted by

placebo [147]. Wilhelm et al. [170] reported that sorafenib signiﬁcantly

In addition, neratinib, an oral irreversible pan-ErbB recep- inhibited neovascularization in xenograft models of human

tor TKI, in combination with trastuzumab, shows a good breast cancer.

objective response rate (ORR) when administrated in patients Another agent, axitinib, an orally active TKI that blocks

with Her-2 positive MBC. The most common adverse advents VEGFR 1–2, PDGFR and c-KitR, when administrated in

were diarrhoea, nausea, anorexia, vomiting, and asthenia. No combination with docetaxel, is tolerable and has potential

cardiac events were reported [153]. Therefore, on the basis of antitumour activity for MBC in the ﬁrst-line setting. This

these results by Swaby et al. [153], it was suggested that ner- association shows a signiﬁcant ORR and time to progression

atinib plus trastuzumab is well tolerated with no signiﬁcant in favour of the axitinib group as compared to placebo [171].

or unexpected toxicities and demonstrates clinical activity Preclinical data have shown that dasatinib, a potent

[153]. oral inhibitor of multiple tyrosine kinases including the

300 G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308

Src family, c-KitR, and PDGFR-␤, is active against mul- as reported in canine breast carcinomas [184], and also to the

tiple breast cancer cell lines, especially the basal subtype inhibition of the aberrant expression of VEGFR and PDGFR

[172,173]. Dasatinib, when administered at higher doses, in women with breast cancer [185]. Toceranib acts on VEGFR

induces adverse events in HER2-ampliﬁed, ER+ and/or PgR+ and PDGFR, promoting an antiangiogenic effect that con-

resistant breast cancer patients who had prior chemotherapy tributes to tumour regression [128]. It has been suggested that

[174]. On the other hand, results obtained in patients with nor- toceranib might act through two separate and complementary

mal HER-2 but ER+ breast cancer who received dasatinib mechanisms: the direct inhibition of cell signalling pathways,

demonstrated some beneﬁt in 70% of these patients when necessary for sustained tumour cell growth and survival, and

this drug was administered in combination with hormonal the inhibition of growth and survival of neovessels [128]. Fur-

therapies [172–174]. thermore, in canine species, the administration of toceranib

With regard to the use of TKIs in animals, toceranib implies a signiﬁcant and selective decrease in the percentage

is an oral novel TKI that shows activity against various of regulatory T-lymphocytes (Treg) in the blood [186]. Con-

receptors [128]. In vitro studies on mouse tumour mod- versely, Treg are present in increased numbers in the blood

els and in human malignancies have demonstrated that and regional lymph nodes of dogs with various malignancies,

toceranib seems to be a potent antitumour and antiangio- therefore the evaluation of their level may be useful as a pro-

genic drug [133,175–178]. Toceranib is characterized by an gnostic factor [187,188]. The data reported by Yancey et al.

indolinone chemical structure and acts as a selective inhibitor [178] regarding the distribution, metabolism, and excretion

of VEGFRs, PDGFR, and c-KitR [128,179,180]. Although of toceranib in dogs showed that this drug has a moderate

this small, orally bioavailable molecule was designed and is clearance and a large volume of distribution. These ﬁndings

currently approved for the treatment of mast cell tumours suggest that toceranib, in combination with other drugs, may

(MCTs) in dogs, it appears to exert biological activity also represent an attractive treatment option for dogs with can-

against breast carcinoma in this species [103,128]. This cer based on potential antitumour and immunomodulatory

molecule is involved in the stimulation of tumour growth effects [186].

as well as mutations leading to ligand-independent receptor Masitinib is a TKI that primarily targets c-KitR, PDGFRs

TK signalling through autocrine and paracrine mechanisms and members of Src family kinases (SFKs) [128]. Masitinib

[181–183]. Furthermore, toceranib directly competes with has already been approved for use in the United States of

ATP at the intracellular kinase domain of the TKR, therefore America and Europe to treat MCTs in dogs [189–191]. This

preventing tyrosine phosphorylation and subsequent signal inhibitor is indirectly efﬁcient in controlling tumour growth

transduction [171,175]. In a study performed in 2003, London through the modulation of proliferation, differentiation and

et al. [128] investigated the safety and efﬁcacy of toceranib, degranulation of mast cells [192,193]. In 2012, Thamm et al.

using dogs with spontaneous tumours in which standard [194] examined the ability of masitinib to inhibit the growth

treatment regimens had failed. The study was conducted on of a panel of canine cancer cells, including two breast carci-

companion dogs with spontaneous malignancies. noma cell lines (CMT12 and CMT27), through a bioreductive

Toceranib, administered at a dose of 3.25 mg/kg on alter- ﬂuorometric cell proliferation assay. Furthermore, Daly et al.

nate days, was safe and well tolerated. In addition, in most [189] observed that masitinib mesylate was well tolerated in

dogs enrolled in these study, the levels of toxicity were gen- the majority of healthy cats.

erally mild in severity and amenable to minimal supportive Imatinib was the ﬁrst commercially available TKI used on

care. Clinical laboratory tests showed an increase in liver human patients with chronic myelogenous leukaemia (CML)

transaminases or creatinine levels. On the other hand, spo- [195], but showed remarkable results also in patients affected

radic hind limb weakness and the development of neutropenia by other cancers such as GISTs [196,197] amongst others

of ﬁrst grade were observed in some dogs. Additionally, it was [198,199].

reported that toceranib may induce localized muscle cramp- Imatinib in dogs and cats, reversibly, competes with ATP

ing. Interestingly, dogs that develop this toxicity do not appear for binding to the kinase domain of protein tyrosine kinases,

to be predisposed to further episodes once therapy is reini- including PDGFR and c-KitR [66,132].

tiated after its interruption [128]. Moreover, it was shown Imatinib is known to inhibit CSF-1R activity [200].

that toceranib may induce anorexia, vomiting, diarrhoea, and Morandi et al. [114] demonstrated that the exposition of

gastrointestinal bleeding in some treated patients [103,128]. breast cancer cell lines to imatinib induces a reduction in

Antitumour responses, determined on the basis of radiologi- cell number in the presence of CSF-1. Furthermore, imat-

cal assessment or tumour-marker evaluations, showed partial inib was in part able to prevent the activation of ERK1/2

responses (PRs) in dogs with MBC [128]. Additionally, PRs induced by CSF-1, conﬁrming the involvement of ERK1/2

were observed in pulmonary metastases, encouraging the use in the proliferative effect of CSF-1 in breast cancer cells.

of toceranib, also in dogs with breast carcinoma [128]. On On the other hand, imatinib treatment alone did not decrease

the other hand, London et al. [128] reported that although ERK1/2 phosphorylation [114].

the mechanisms of breast tumour regression induced by As to PDGFR, conﬂicting data exist. It has been found

toceranib are not known, the action of this drug could be that the inhibition of the PDGFR pathway by imatinib can

linked to the inhibition of the aberrant expression of c-KitR enhance drug delivery to the tumour. In vitro evidence

G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308 301

Table 2

Main biologic drugs in use or in development in breast cancer.

Drug Class Targets Administration Types of cancer

a b c

Trastuzumab Humanized m.a. HER-2 e.d. I.v. Breast and gastric

Lapatinib Dual receptor tyrosine kinase EGFR i.d. , HER-2 i.d. Oral Breast

inhibitor (TKI)

Geﬁtinib TKI EGFR Oral NSLC, breast

Neratinib Dual receptor TKI EGFR i.d., HER-2 i.d. Oral Breast

␣ ␤

Pazopanib Multi-targeted receptor TKI VEGFR-1/2/3, PDGFR / , KIT Oral Kidney, sarcomas, breast

Sunitinib Multi-targeted receptor TKI VEGFR-1/2/3, PDGFR-␤, RET, FLT3 Oral Kidney, GIST, breast

Sorafenib Multi-targeted receptor TKI VEGFR-1/2/3, PDGFR-␤, Raf-1,c-KitR, ERK Oral Hepatocellular, kidney, breast

Axitinib Multi-targeted receptor TKI VEGFR-1/2/3, PDGFR, c-KitR Oral Kidney, breast

Dasatinib Multi-targeted receptor TKI BCR/ABL, Src, PDGFR, c-KitR Oral CML, Ph + LLA, breast

Toceranib Multi-targeted receptor TKI VEGFRs, PDGFR, c-KitR Oral Mast cell tumour (in dogs), breast

Masitinib Multi-targeted receptor TKI Src, c-KitR, PDGFRs Oral Mast cell tumour (in dogs), GIST, breast

Imatinib Multi-targeted receptor TKI ABL, PDGFR, c-KitR Oral CML, Ph + LLA, GIST, sarcomas, breast a Monoclonal antibody. b Extracellular domain. c Intravenous. d

Intracellular domain.

has suggested that the inhibition of this pathway could from clinical trials on imatinib in dogs, the recent intro-

decrease the concentration of VEGF and other proangiogenic duction of toceranib and masitinib for the treatment of pets

molecules [147]. demonstrated the importance of pet spontaneous tumour

Moreover, it has been reported that in patients with MBC models for the development of novel targeted therapies

and in whom PDGFR was overexpressed, treatment with [206–208].

imatinib, until disease progression, demonstrated no ORR It is intriguing that toceranib and masitinib were particu-

[132]. The data from Mundhenke et al. [132] are conﬁrmed larly developed for pets affected by MCTs [179,207]. Based

to be similar to those of Cristofanilli et al. [147], indicating on recent in vitro experimental data, the use of toceranib and

that targeting PDGFR with imatinib monotherapy treatment masitinib to treat dog mammary tumours [186,194] has also

is ineffective in MBC. been suggested. Up to now, masitinib has been under eval-

The main biologic drugs in use or in development in breast uation in human clinical trials and the ﬁrst data from these

cancer are summarized in Table 2. studies are already available [209–211].

On the other hand, the use of TKIs is encouraged for

the control of tumour angiogenesis. The molecular targets

of TKIs demonstrate that angiogenic growth factor recep-

5. Concluding remarks

tors such as VEGF, PDGF, FGF, and also c-KIT are of

shared prominence in human and veterinary research, and

William Osler focused his interest on comparative pathol-

that there is scope for leveraging trials involving novel

ogy, advocating the following view: “one medicine, one

TKIs from veterinary to human oncology and vice versa

pathology” [201]. He would like to encourage advances [212,213].

in public health and increase understanding of human

Interestingly, most TKIs are formulated to be orally

and veterinary disease [201]. The understanding that pets

administrated, which represents a great advantage during

develop similar tumours to humans initiated the concept of

therapy in terms of both quality of life for patients and of

“comparative oncology” which aims to speed up the devel-

compliance for pets and their owners.

opment of anti-cancer therapies in human and veterinarian

Further studies will be necessary to establish the efﬁcacy

medicine simultaneously [202]. It has therefore been sug-

of multitarget TKIs on speciﬁc deﬁned molecular targets,

gested recently that clinical trials in dogs may bear close

based on biogenetics of the tumour cells, with a view to select-

resemblance to clinical scenarios in humans [203].

ing patients more sensitive to the therapy. This could enhance

Tyrosine kinase dysfunctions frequently occur in human

the development and standardization of TKI-based therapies,

cancer and, in a similar manner, also in pet malignancies

endowed with a greater efﬁcacy focused on molecular targets,

[60,61,204]. It is interesting to note that the development of

and a better tolerability.

TKIs is the most important therapeutic advance in the ﬁeld

of targeted anticancer agents in both veterinary and human

oncology [205].

Imatinib was the ﬁrst TKI approved in human oncol- Conﬂict of interest statement

ogy [195], and it was later translated for the therapy of

pet tumours [66,105]. As well as promising data coming None of the authors has any conﬂict of interest to declare.

302 G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308

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[194] Thamm DH, Rose B, Kow K, Humbert M, Mansﬁeld CD, Moussy with locally advanced or metastatic gastro-intestinal stromal tumour

A, et al. Masitinib as a chemosensitizer of canine tumor cell lines: a (GIST). European Journal of Cancer 2010;46(8):1344–51.

proof of concept study. Veterinary Journal 2012;191:131–4. [212] Bavcar S, Argyle DJ. Receptor tyrosine kinase inhibitors: molec-

[195] Druker BJ. Imatinib and chronic myeloid leukemia: validating the ularly targeted drugs for veterinary cancer therapy. Veterinary and

promise of molecularly targeted therapy. European Journal of Cancer Comparative Oncology 2012;10(3):163–73.

2002;38(5):S70–6. [213] Airley R. Lab reports and cat scans: can veterinary oncology guide

[196] Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisen- our way to new treatments for human cancers? Future Medicinal

berg B, Roberts PJ, et al. Efﬁcacy and safety of imatinib mesylate in Chemistry 2012;4(11):1391–4.

advanced gastrointestinal stromal tumors. New England Journal of

Medicine 2002;347:472–80.

[197] van Oosterom AT, Judson IR, Verweij J, Stroobants S, Dumez H,

Donato di Paola E, et al. Update of phase I study of imatinib (STI571)

in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a

report of the EORTC Soft Tissue and Bone Sarcoma Group. European Biographies

Journal of Cancer 2002;38(5):S83–7.

[198] McArthur GA, Demetri GD, van Oosterom A, Heinrich MC, Debiec-

Rychter M, Corless CL, et al. Molecular and clinical analysis of Girolamo Ranieri is a medical oncologist and vice director

locally advanced dermatoﬁbrosarcoma protuberans treated with imat- of the Interventional Radiology Unit with Integrated Section

inib: Imatinib Target Exploration Consortium Study B2225. Journal

of Translational Medical Oncology at the National Can-

of Clinical Oncology 2005;23:866–73.

cer Research Centre “Giovanni Paolo II” in Bari, Italy.

[199] Marosi C, Vedadinejad M, Haberler C, Hainfellner JA, Dieck-

His research interests include: tumour angiogenesis, targeted

mann K, Rössler K, et al. Imatinib mesylate in the treatment of

patients with recurrent high grade gliomas expressing PDGF-R. therapies, pet animal models in translational oncology, and

ASCO Annual Meeting Proceedings. Journal of Clinical Oncology loco-regional therapies in the liver and lung. He has been

2006;24(18S):1526.

a principal and co-investigator on several national research

[200] Dewar AL, Cambareri AC, Zannettino AC, Miller BL, Doherty KV,

cancer projects.

Hughes TP, et al. Macrophage colony-stimulating factor receptor c-

fms is a novel target of imatinib. Blood 2005;105:3127–32.

Marianna Pantaleo is a veterinary medical doctor with

[201] Cardiff RD, Ward JM, Barthold SW. ‘One medicine—one pathology’:

a PhD in “Human and Animal Biology” at the University

are veterinary and human pathology prepared? Laboratory Investiga-

of Bari Veterinary Medical School, Valenzano (BA), Italy.

tion 2008;88(1):18–26.

[202] Paoloni M, Khanna C. Translation of new cancer treatments from pet Her research interests include oxidative stress and physio-

dogs to humans. Nature Reviews Cancer 2008;8(2):147–56. pathologic effects in animal obstetrics and gynaecology.

[203] Gordon I, Paoloni M, Mazcko C, Khanna C. The Comparative Oncol-

Recently, she has been involved in comparative studies of

ogy Trials Consortium: using spontaneously occurring cancers in

breast cancer in pets and humans.

dogs to inform the cancer drug development pathway. PLoS Medicine

2009;6(10):e1000161.

Mariagrazia Piccinno is a veterinary medical doctor and

[204] Singer J, Weichselbaumer M, Stockner T, Mechtcheriakova D,

PhD student in “Human and Animal Biology” at the Uni-

Sobanov Y, Bajna E, et al. Comparative oncology: ErbB-1 and ErbB-

versity of Bari Veterinary Medical School, Valenzano (BA),

2 homologues in canine cancer are susceptible to cetuximab and

trastuzumab targeting. Molecular Immunology 2012;50(4):200–9. Italy. Her research interests include oxidative stress and

[205] London CA. Kinase dysfunction and kinase inhibitors. Veterinary physio-pathologic effects in animal obstetrics and gynaecol-

Dermatology 2013;24(1):181–240.

ogy. Recently, she has been involved in comparative studies

[206] Isotani M, Ishida N, Tominaga M, Tamura K, Yagihara H, Ochi S,

of breast cancer in pets and humans.

et al. Effect of tyrosine kinase inhibition by imatinib mesylate on

mast cell tumors in dogs. Journal of Veterinary Internal Medicine

Maria Roncetti is a veterinary medical doctor and PhD

2008;22(4):985–8.

student in “Human and Animal Biology” at the University

[207] Hahn KA, Legendre AM, Shaw NG, Phillips B, Ogilvie GK, Prescott

of Bari Veterinary Medical School, Valenzano (BA), Italy.

DM, et al. Evaluation of 12- and 24-month survival rates after treat-

ment with masitinib in dogs with nonresectable mast cell tumors. Her research interests include oxidative stress and physio-

American Journal of Veterinary Research 2010;71(11):1354–61. pathologic effects in animal obstetrics and gynaecology.

308 G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308

Recently, she has been involved in comparative studies of Her research interests include pet tumour angiogenesis and

breast cancer in pets and humans. comparative oncology.

Maddalena Mutinati is aveterinary medical doctor and Annalisa Rizzo is a veterinary medical doctor, PhD in

PhD in “Human and Animal Biology” at University of “Human and Animal Biology” and aggregate professor at

Bari Veterinary Medical School, Valenzano (BA), Italy. the University of Bari Veterinary Medical School, Valenzano

Her research interests include oxidative stress and physio- (BA), Italy. Her research interests include the involvement

pathologic effects in animal obstetrics and gynaecology. of the opioidergic system in the modulation of reproduc-

Recently, she has been involved in comparative studies of tive activity. Recently, she has been involved in comparative

breast cancer in pets and human. studies of breast cancer in pets and humans as well as the

application of experimental therapies with GnRH analogue.

Ilaria Marech is a medical oncologist in the Department of

Biomedical Sciences and Human Oncology, Section of Inter- Raffaele Luigi Sciorsci is a veterinary medical doctor, PhD

nal Medicine and Clinical Oncology at the University of Bari and full professor in “Veterinary Obstetrics and Gynaecol-

Medical School of Bari, Italy. Her research interests include: ogy” at the University of Bari Veterinary Medical School,

tumour angiogenesis, targeted therapies and ultrasonography. Valenzano (BA), Italy. His research interests include oxidative

stress and its physio-pathologic effects in animal obstetrics

Rosa Patruno is a veterinary medical doctor specialized

and gynaecology. Recently, he has been involved in compara-

in infectious disease and veterinary prophylaxis and also

tive studies of breast cancer in pets and humans as well as the

in veterinary public health. She works at the Department

application of experimental therapies with GnRH analogue.

of Prevention and Animal Ealth, ASL BAT, Barletta, Italy.