Aurora kinase A inhibitors: promising agents in antitumoral therapy.

Review

Aurora kinase A inhibitors: promising agents in antitumoral therapy 1.

Aurora A: more than a mitotic kinase

2.

†

Aurora A is a cancer-associated gene

3.

Consequences of Aurora A depletion/inhibition in vitro and in vivo

4.

Preclinical and clinical studies using Aurora inhibitors

5.

Conclusions

6.

Expert opinion

Marcos Malumbres & Ignacio Perez de Castro† Centro Nacional de Investigaciones Oncolo´gicas (CNIO), Cell Division and Cancer Group, Madrid, Spain

Introduction: Aurora proteins are serine/threonine kinases with critical functions during mitosis. Aurora A, one of the members of this family, participates in crucial processes including mitotic entry, DNA damage checkpoint recovery and centrosome and spindle maturation. Aurora A is frequently overexpressed in human cancers and, when inhibited, impairs cell proliferation. Areas covered: Here, we review the preclinical studies that support the use of Aurora A inhibitors in antitumoral strategies. We also discuss past or current clinical trials using Aurora A inhibitors in multiple tumor types. We pay special attention to Alisertib, a potent and selective Aurora A inhibitor currently in Phase III. Expert opinion: The potential of Aurora A inhibitors in the treatment of cancer depends on many factors, mainly related with the molecular status of tumor cells. Yet, we still need to find proper biomarkers to select those patients that better react to Aurora A inhibitors. Furthermore, their effect could significantly improve when used in combination with other drugs. Although some clinical trials are already testing the cooperative effect of different antitumoral drugs, additional preclinical studies are necessary to establish the best combinations. Here, we discuss some possibilities that could be explored in future studies. Keywords: Alisertib, Aurora A, cancer, clinical trials, kinase inhibitors, mitosis, MLN8237 Expert Opin. Ther. Targets (2014) 18(12):1377-1393

1.

Aurora A: more than a mitotic kinase

Among the different stages of the cell cycle, mitosis has attracted significant attention, not only because many mitotic regulators have been linked to tumorigenesis [1] but also because the success of microtubule (MT) poisons in cancer therapy [2,3]. Aurora family kinases are of special relevance during mitosis because they play essential roles in centrosome maturation and chromosome segregation [4]. The increasing trend of scientific publications (> 1600), patents (> 400) and clinical trials (> 90) on Aurora kinases during the last 16 years (Figure 1) demonstrates the importance of this family of mitotic kinases. The founding member of the Aurora family, Ipl1 (Increase in ploidy 1), was described in 1993 in a screen for Saccharomyces cerevisiae mutants that failed to undergo normal chromosome segregation [5]. Two Ipl1-like proteins (Aurora kinases A and B) have been found in Drosophila melanogaster, Caenorhabditis elegans and Xenopus laevis. Three members of this family of serine-threonine kinases, Aurora A, B and C are encoded in humans by the genes AURKA, AURKB and AURKC. Although they are highly conserved at the protein level, Aurora kinases have very distinct expression and localization patterns as well as functions [4]. Aurora A is upregulated at G2 and localizes to the centrosomes during interphase and to both spindle poles and spindle MTs during early mitosis. As expected by its expression and subcellular localization, Aurora 10.1517/14728222.2014.956085 © 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 All rights reserved: reproduction in whole or in part not permitted

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rez de Castro M. Malumbres & I. Pe

Article highlights. . . .

.

Aurora kinase A is a key mitotic protein frequently amplified and over-expressed in human cancers. Aurora kinase inhibitors have shown promising results in clinical trials. A total of forty clinical trials have been initiated to test Alisertib in monotherapy or in combination with other drugs. The identification of good biomarkers and effective combination therapies will improve the clinical use of Aurora inhibitors.

This box summarizes key points contained in the article.

Publications Patents

No. of publications/patents/trials

260

Clinical trials

200 140 80 80 60 40 20 20 10

13

11

20

09

20

07

20

05

20

03

20

01

20

20

19

99

0

Year

Figure 1. Number of scientific publications, clinical trials and patents related to Aurora kinases. Data were obtained from 1998 to 2013 using ‘Aurora kinase’ as the searching text. P u b M e d ( h t t p : / / w w w. n c b i . n l m . n i h . g o v / p u b m e d ? cmd=search), from the US National Library of Medicine, the U. National Cancer Institute and EU Clinical Trials Register web pages (http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/ctr-search/search) and PATENTSCOPE (http://patentscope.wipo.int/search/en/ search.jsf), from the World International Property Organization, were used as searching tools.

A regulates mitotic entry, centrosome maturation and spindle formation. Aurora B is expressed in proliferating cells during G2 and mitosis, shows a chromosomal-passenger localization (centromeric in early mitosis, central spindle in anaphase and mid-body during cytokinesis) and plays critical roles in chromosome condensation and cohesion, chromosome biorientation and cytokinesis. The importance of their functions make Auroras A and B required for mouse embryo development [6-9]. Aurora C is mainly expressed in testis, has 1378

a localization pattern similar to Aurora B and is required for spermatogenesis and the first divisions of mouse embryogenesis [9,10]. Aurora kinase A (AURKA) has many aliases, including serine/threonine kinase 15, serine/threonine kinase 6, breast tumor amplified kinase, Aurora-related kinase 1, Homo sapiens Aurora/IPL1-related kinase, Eg2 and Ipl- and Aurora-related kinase 1. Originally described in a screening for mutations that affect the centrosome cycle in Drosophila [11], Aurora A has been mainly associated with cell cycle regulation, specifically in the G2/M phases (Figure 2). The regulation of Aurora A activity is complex and is mainly associated with the phosphorylation of a threonine residue within the activation loop (Thr288 in human Aurora A) [12,13] and its proteolytic degradation. Although different molecules might function as AURKA-positive regulators (Figure 2) [14-22], the best-known activator is TPX2 [23]. Binding to TPX2 induces a conformational change that promotes autophosphorylation and prevents the action of its inhibitor, the phosphatase PP1 [24]. Recently, it has been shown in vitro that Aurora A autophosphorylation occurs in a long-lived dimer and that binding to TPX2 induces the activation of Aurora A molecules un-phosphorylated at Thr288 [25]. Aurora A is a target of the E3-ubiquitin ligase anaphase-promoting complex/ cyclosome, which in conjunction with its specificity cofactor Cdh1 targets this protein for destruction during mitotic exit [26]. Other molecules negatively regulate AURKA activity by dephosphorylation, SUMOylation or induction of its degradation (Figure 2) [27-34]. Several functions have also been reported for Aurora A in addition to its typical mitotic roles (Figure 2). Aurora A is essential for DNA damage-induced checkpoint recovery [35,36]. Aurora A has been involved in the regulation of p53 because it phosphorylates p53 at Ser315, leading to its Mdm2-mediated ubiquitination and subsequent proteolysis [37]. Another important non-mitotic function of Aurora A is the regulation of translation of RNAs that contain cytoplasmic polyadenylation elements at their 3¢ untranslated region, which has been shown in the regulation of meiosis [38,39]. Aurora A also modulates the function of alphaCamKII synthesis at synapses [40], calcium signaling in nonproliferative cells [41], Akt [42] and the cell cycle regulators Myc, cyclin B1 and Cdk1 [43,44]. Different reports have pointed out a role of Aurora A in development and pluripotency through the regulation of cell polarity and p53 activity. More specifically, Aurora A regulates cell polarity by determining mitotic spindle orientation through the Par complex [45-47] and p53 by inhibiting its transcriptional activity in mouse embryonic stem cells through direct phosphorylation at Ser212 [48]. Aurora A is also a major regulator of Nanog activity in epithelial tissues [49]. Other studies have pointed out to possible roles of Aurora A in angiogenesis [50], inflammation [51] and pro-oncogenic signaling pathways [42]. Finally, Aurora A has also been connected to the regulation of neurite elongation [52], cilia disassembly [22], cell motility [53], DNA replication [54] and NF-kB signaling [55].

Expert Opin. Ther. Targets (2014) 18(12)

Aurora kinase A inhibitors

Regulators PP1 / PP6 APCCdh1 P53 GADD45A

GSK3β FBXW7 USP2A AIP

TPX2 CDK1 AJUBA BORA CEP192 PUM2

SUMO1 HEF1 PAK1 MYC NPM CaM

Aurora A

Mitotic functions • Mitotic entry (BRCA1, PLK1, CDC25B) • Centrosome function (NDEL1, CENTRIN, LATS2, CENPA, CENPE, CEP192, SKI, LIMK1/2)

Non-mitotic functions • DNA damage/repair (PLK1, BRCA1) • DNA replication (GEMININ) • P53/P73 activity • RNA Poly-adenylation (CPEB) • Pluripotency (P53) • Cell polarity (PAR3, PAR6) • Cilium stability (HDAC6)

• Spindle dynamics

• NF-κB signaling (IκBα)

(KIF2A, TACC3, MCAK, HURP, TPX2, EG5, P150GLUED)

• Calcium signaling (PC2) • Cell migration/motility (RAL)

Figure 2. Regulation and cellular functions of Aurora A. Negative and positive modulators of AURKA activity are shown in red and blue, respectively. Effectors for the AURKA-dependent mitotic and non-mitotic functions are indicated. AURKA: Aurora kinase A.

2.

Aurora A is a cancer-associated gene

Aurora A is amplified and/or overexpressed in primary tumors of the breast, ovary, colon, pancreas, prostate, as well as in neuroblastoma among others (Table 1). High levels of Aurora A are associated with poor prognosis (Table 1) and Aurora A overexpression may also promote resistance to gefitinib, taxol and cisplatin in cancer cells [56-58]. Different Aurora A mutations are associated with cancer. The most frequently reported mutations consists on a single-nucleotide polymorphism T91A (Phe31Ile) that was originally proposed as a low-penetrance susceptibility allele in multiple human cancers [59]. However, a massive study performed with > 32,000 patients discarded the association between the T91A polymorphism and breast cancer [60]. Different studies demonstrated a determinant role of Aurora A in tumor development. First, overexpression of Aurora-A-induced malignant transformation in focus formation and xenograft assays [61,62], and elevated levels of Aurora A cooperated with oncogenic RAS in the

transformation of mouse fibroblasts [63]. Furthermore, transgenic mouse models for the overexpression of Aurora A showed hyperplasia in mammary glands and tumor development [64,65]. Importantly, Aurora A haploinsufficient mice are also prone to spontaneous tumor development [7], which points out a tumor suppressor role of this kinase. This antitumoral property of Aurora A has also been shown in Drosophila [66]. Therefore, both the overexpression and the downregulation of Aurora A are causally related with tumorigenesis. What are the mechanisms by which an abnormal expression of Aurora A triggers the malignant phenotype? Among the different ideas proposed during the last years, two hypotheses can be highlighted. The first one is based on the induction of chromosome instability and the generation of aneuploidy, which in turn, have been recognized as tumor drivers. The aneuploid phenotype induced by Aurora A abnormal expression has been associated to centrosome amplification, mitotic abnormalities and cytokinesis failure [58,62] and Aurora A has been included in the top-70 list of genes of the cancer-associated


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Table 1. Aurora A amplification/over-expression in human cancers. Tumor type

Amplification/overexpression*

Bad prognosis

Breast Colorectal Gastric Head and neck Leukemias, lymphomas Lung Neuronal Ovarian and endometrial Pancreatic Prostate Skin Urothelial and bladder

DNA, mRNA and protein DNA, mRNA and protein DNA, mRNA and protein mRNA and protein mRNA and protein mRNA and protein DNA, mRNA and protein DNA, mRNA and protein DNA, mRNA and protein mRNA and protein Protein mRNA and protein

Yes Yes Yes Yes Yes Yes Yes Yes n.r. Yes n.r. Yes

Ref. [147-150] [61,62,151,152] [153,154] [155-157] [20,158-160] [161-163] [119,164-166] [167-171] [172,173] [174,175] [176] [177-179]

*Amplification: DNA; Overexpression: mRNA and or protein. n.r.: Not reported.

Table 2. Main phenotypes observed in cells upon Aurora A depletion or inhibition. Phenotype

Inactivation mechanism

Organism/system

Ref.

Pupal lethality; mitotic arrest, monopolar spindle Lack of centrosome maturation, embryo lethality Delayed mitotic entry, lack of bipolar spindle Embryo lethality; lack of proliferation; mitotic defects; DNA damage; apoptosis; senescence

Genetic inactive mutants

D. melanogaster

[11,180]

RNAi and lack of function mutants mAb

C. elegans

[77,79,181]

X. laevis

[76,78,182]

RNAi, specific inhibitors, conditional KO

Mammalian cell lines; mouse embryos/tissues

[6-8,16,80-82,113,183],

RNAi: RNA interference.

chromosome instability signature [67]. The second possibility is based in the Aurora A-p53 crosstalk described during the last years [33,37]. Interestingly, induction of aneuploidy by Aurora A is p53-dependent [68,69], which connects the two hypotheses described above. In summary: i) Aurora A overexpression induces p53 degradation; ii) loss of p53 eliminates the checkpoints that arrest the polyploid and aneuploid cells generated upon Aurora A overexpression; and iii) the resulting cells are prone to become transformed. The mitotic regulator TPX2, which binds and stabilizes Aurora A [70], is also overexpressed in cancer, and the possible relevance of the Aurora A-TPX2 holoenzyme in cancer has been previously reviewed [71,72]. Both mitotic and nonmitotic, Aurora A partners could play a role in the AuroraA-induced malignant phenotype. The fact that Aurora A is mainly located at the nucleus of non-tumoral, interphasic cells, whereas overexpressed, tumor-associated Aurora A can also be found at cytoplasm [73], makes more complicated the characterization of the mechanisms by which Aurora A participates in tumorigenesis. So far, the relevance of Aurora A in the regulation of other major oncogenic partners such as Akt, Ras or Myc [44,57,74,75] is not well established, despite 1380

the interest of these interactions in the identification of possible biomarkers of clinical use.

Consequences of Aurora A depletion/ inhibition in vitro and in vivo

3.

Interfering with Aurora A expression or activity by siRNA expression, immunodepletion or specific inhibitors induces mitotic alterations that impair cell cycle progression (Table 2). The first functional assays demonstrated that its disruption in D. melanogaster, C. elegans and X. laevis causes defects in mitotic entry, centrosome maturation and spindle formation [11,76-79]. Similar results were obtained in mammalian cell lines when Aurora A expression was reduced using RNA interference technology [16,80,81]. Monopolar spindles, prometaphase arrest, promotion of tetraploid cells are the most commonly features cited in these works. Recently, three different groups have shown that Aurora A is necessary for mouse embryo development [6-8]. Specifically, its genetic ablation results in lethality at the morula stage mainly due to spindle assembly defects, pronounced cell proliferation failure and mitotic arrest. Aurora A depletion in adult tissues



A.

AurkaΔ/Δ

Aurka+/+ I

I

II

II

B.

C.

III

III

IV

IV

Aurka+/+

AurkaΔ/Δ

Aurka+/+

AurkaΔ/Δ

D. Aurka+/+

AurkaΔ/Δ

Figure 3. Cellular defects induced by Aurora A depletion. A. Upper panels show representative pictures of the mitotic progression (I to IV) in wild type (Aurka+/+) and Aurora A null (AurkaD/D) mouse fibroblasts that express EGFP-tagged Histone H2B. Arrows indicate abnormal chromosome segregation and DNA bridges. Mitotic abnormalities are also common in Aurora A null tissues. Lower panels show esophagous of wild type and Aurora A defective mice. Normal anaphase in the wild type tissue and abnormal monopolar spindles in Aurora A null cells are highlighted. B. The defects in chromosome segregation lead, with time, to the accumulation of giant nuclei, micronuclei and lobulated nuclei. Pictures are mouse fibroblasts stained with DAPI to visualize DNA. C. Senescence induced by Aurora A depletion. Images show representative cases for mouse fibroblasts (upper panels) and mouse splenocytes (lower panels). D. Aurora A null proliferative tissues show severe defects. Images are representative of wild type and Aurora A null mouse skin. Aurora A null mice show a thinner characterized by hair follicles at the catagen--telogen stage.

is characterized by a significant increase in mitotic abnormalities and DNA damage markers and with the presence of aneuploid cells, eventually resulting in impaired proliferation and senescence (Figure 3) [82]. Conditional deletion of Aurora A in adult tissues induces premature aging and prevents tumor growth in vivo. In normal or tumor cells, lack or inhibition of Aurora A results in defective chromosome segregation and the generation of tetraploid or aneuploid cells, which is subsequently accompanied by a stress response characterized by DNA damage and the induction of antiproliferative proteins such as p53 and p21Cip1. As a final consequence, cells arrest and enter into apoptosis or senescence.

Preclinical and clinical studies using Aurora inhibitors

4.

A significant number of compounds and procedures related with the use of Aurora kinase inhibitors have been patented during the last decade (Table S1). Different reviews summarizing the information about Aurora kinase inhibitors have been published in the last five years [83-86]. The number of clinical trials performed with Aurora kinase inhibitors has kept constant, and the results published from these preclinical and clinical studies have significantly increased (Figure 1).


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Pan or A/B 32%

A. AURKA 53%

AURKB 15%

B. Aurora A

Number of clinical trials

20 15

Phase I Phase II Phase III Aurora B

10 Pan or dual A/B 4 3 2 1

D

To

sa

ze

rti

b

(V

X-

K 68 W an 0/ -24 M 4 us K- 9 er 04 tib (P X 57) H L A- 22 73 8 93 AS 70 A 58 35 T9 ) 69 28 /R 3 -7 C YC 63 -1 1 PF SN 6 S -0 -3 38 14 14 AM 73 5 M E GK- NM 90 51 D 0 08 -2 /V 07 Al X 6 is er M -68 tib L 9 (M N-8 LN 05 -8 4 BI 237 81 ) 1 AZ 28 3 G SK D11 10 52 70 91 6

0

Figure 4. Clinical trials testing agents with anti-Aurora A activity. A. Chart shows the percentage of trials for Pan-Aurora kinase or Aurora kinase A/B dual inhibitors, Aurora kinase B selective inhibitors and Aurora-kinase--A-specific inhibitors. B. Bar graph shows the number of clinical trials started for up to 17 drugs with Pan-Aurora kinase activity (10), Aurora A selectivity (4) and specific for Aurora kinase B (3).

Most Aurora kinase inhibitors are small molecule compounds designed to bind to the ATP-binding pocket in a competitive and reversible manner. Around 10 pan-Aurora inhibitors without a clear preference for a single family member have been reported in clinical trials or in preclinical stages for the treatment of cancer (Supplementary Table S2 [184-191]). Although Aurora-B-specific compounds or Pan-Aurora inhibitors have been used in 15 and 34% of the clinical trials testing Aurora kinase inhibitors, most clinical trials (53%) have focused to Aurora A selective agents (Figure 4). In the next sections, we will describe the preclinical and clinical studies reported for the four developed AURKAspecific inhibitors used in clinical trials (Table 3). ENMD-2076 Originally developed by Miikana in 2006, this EntreMed product is the L(+) tartrate salt of ENMD-981693. 4.1

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ENMD-2076 selectively inhibits Aurora A (IC50 = 14 nM) instead of Aurora-B (IC50 = 700 nM) and has also potent activity (ranging 0.04 -- 21 µM IC50 in some cases) inhibiting other kinases (FGFR3, PDGFR, VEGFR1 and FLT3). A number of preclinical studies have shown the antitumoral potential of ENMD-2076. ENMD-2076 has shown significant cytotoxicity against multiple myeloma cell lines and primary cells, with minimal cytotoxicity to hematopoietic progenitors [87]. Similar results have been described in cell line-derived human colorectal cancer xenografts [88]. Interestingly, its activity against tumor cells both in vitro and in vivo takes places through several pathways and molecules (Aurora kinases A and B, PI3K/AKT and FGFR3) [87,89]. The results from one Phase I clinical trial in patients with advance solid tumors [90] showed that ENMD-2076 is well tolerated, has a linear pharmacokinetic profile and has as the most common drug-related adverse events hypertension, nausea/vomiting



Table 3. Aurora-A-kinase-specific inhibitors in clinical trials. Inhibitor (source) Preclinical data

Specificity (IC50 in nM) Clinical trial information (status and identifier)*

ENMD-2076 (EntreMed)

Aurora-A-specific inhibitor AurkA = 14; AurkB = 700; AurkC = NA [88]

Phase I Relapsed or refractory hematological malignancies and multiple myeloma (completed: NCT00904787) Advanced cancer (active: NCT00658671 [90]) Phase II Advanced or metastatic triple negative breast cancers (recruiting: NCT01639248 and NCT00806065) Advanced/metastatic soft tissue sarcoma (recruiting; NCT01719744) Ovarian clear cell cancers (recruiting; NCT01914510 [91]) MK-5108/ VX-689 (Merk/Vertex)

Aurora-A-specific inhibitor AurkA = 0.064; AurkB = 14; AurkC = 12 [94]

Phase I Alone or in combination with docetaxel in patients with advanced solid tumors (completed; NCT00543387 [100]) MLN-8054 (Millennium Pharmaceuticals)

Aurora-A-specific inhibitor AurkA = 0.064; AurkB = 14; AurkC = 12 [101]

Phase I Advance malignancies, breast, colon, pancreatic and bladder neoplasms (terminated: NCT00249301 and NCT00652158) [107,108] Alisertib (MLN-8237) (Millennium Pharmaceuticals)

Aurora-A-specific inhibitor AurkA = 1; AurkB > 200; AurkC = NA [113]

Phase I Advanced malignancies, solid tumors and lymphomas (completed: NCT01512758, NCT00962091, NCT01154816 [133], NCT00651664 [132], NCT00697346 [134], NCT00500903 [131], NCT01714947 and 2008-006981-27; recruiting: NCT01898078) In combination with: Esomeprazole and Rifampicin in advanced solid tumors and lymphomas (recruiting: NCT01844583) Vorinostat in treating patients with relapsed or recurrent Hodgkin lymphoma, B-cell non-Hodgkin lymphoma or peripheral T-cell lymphoma (recruiting: NCT01567709) Rituximab and Bortezomib in treating patients with relapsed or refractory mantle cell lymphoma or B-cell low grade non-Hodgkin lymphoma (recruiting: NCT01695941) Cytarabine and Idarubicin in acute myelogenous leukemia (recruiting: NCT01779843) Gemcitabine hydrochloride in treating patients with solid tumors or advanced pancreatic cancer (recruiting: NCT01924260) Romidepsin in patients with relapsed or refractory B-cell or T-cell lymphomas (recruiting: NCT01897012) Irinotecan hydrochloride in treating patients with advanced solid tumors or colorectal cancer (recruiting: NCT01923337) Pazopanib in patients with advanced, previously treated non-hematologic solid tumors (recruiting: NCT01639911) Paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) in treating patients with solid malignancies that are metastatic or cannot be removed by surgery (recruiting: NCT01677559) Added to routine radiation therapy and Cetuximab in patients with head and neck cancer (recruiting: NCT01540682) Docetaxel as a treatment for advanced solid tumors (active: NCT01094288) Phase II In patients with unresectable stage III-IV melanoma (recruiting: NCT01316692), advanced nonhematological malignancies (active: NCT01045421; terminated: 2008-006981-27), relapsed or refractory non-Hodgkin’s lymphoma (completed: NCT00807495) [135], acute myeloid leukemia or myelodysplastic syndrome (completed: NCT00830518; ongoing: 2008-006977-34), with platinumrefractory or platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal carcinomas (completed: NCT00853307; 2008-006979-72 [136]; ongoing: 2009-011428-79), advanced or metastatic sarcoma (recruiting: NCT01653028), relapsed or refractory solid tumors or leukemia (active: NCT01154816), relapsed or refractory peripheral T-cell non-Hodgkin lymphoma (recruiting: NCT01466881), metastatic neuroendocrine prostate cancer (recruiting: NCT01799278) In combination with: Paclitaxel in patients with breast and ovarian cancers (active: NCT01091428) and with small cell lung cancer who have relapsed or did not respond to first line standard therapy (not yet open for recruitment: NCT02038647) Rituximab for relapsed or refractory B-cell non-Hodgkin lymphomas (recruiting: NCT01812005) Erlotinib hydrochloride in patients with advanced or metastatic non-small cell lung cancer (recruiting: NCT01471964) Abiraterone or Prednisone in prostate cancer (recruiting: NCT01848067) Bortezomib in treating patients with relapsed or refractory multiple myeloma (recruiting: NCT01034553) *From National Cancer Institute and EU Clinical Trials Register web pages: http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/ctr-search/search NA: Not available.


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Table 3. Aurora-A-kinase-specific inhibitors in clinical trials (continued). Inhibitor (source) Preclinical data

Specificity (IC50 in nM) Clinical trial information (status and identifier)*

Rituximab and Vincristine in patients with relapsed or refractory diffuse large B-cell lymphoma or transformed follicular lymphoma (active: NCT01397825; 2011-000609-32) Phase III In combination with Pralatrexate, Gemcitabine or Romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (recruiting: NCT01482962) *From National Cancer Institute and EU Clinical Trials Register web pages: http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/ctr-search/search NA: Not available.

and fatigue. Partial response was detected in 2 out of the 57 patients that were evaluated. Both of them were ovarian cancer cases. At least three different Phase II trials have been started (Table 3). One of them has shown a progression-free survival rate at 6 months of 22% with a median time to progression of 3.6 months [91]. This effect of ENMD-2076 in platinum-resistant ovarian cancers was not associated to any of the biomarkers analyzed in this study. However, some predictive biomarkers of sensitivity have been described in preclinical breast cancer models [92]. ENMD-2076 showed more robust activity against cell lines lacking estrogen receptor expression and those without increased HER2 expression. Within the triple-negative breast cancer subset, cell lines with a p53 mutation and increased p53 expression were more sensitive to the cytotoxic and pro-apoptotic effects of ENMD2076 exposure than those with decreased p53 expression. Finally, ENMD-2076 has also radiosensitizing properties in canine mast cell tumors in vitro [93], which highlights the potential of this inhibitor in combination with other cancer therapies. MK-5108 This agent, also known as VX-689, has been developed by Merck and Vertex. MK-5108 specifically inhibits AURKA with an IC50 of 0.064 nM. The first preclinical studies showed a potent antitumoral activity of MK-5108 alone or in combination with Docetaxel in cell lines from different tumor types [94]. Later, it was reported that MK-5108 was able to decrease the proliferation of epithelial ovarian cancer stem cells, the ones that are able to resist chemotherapy [95]. In uterine leiomyosarcomas, MK-5108 also inhibits proliferation and induces apoptosis both in vitro and in vivo, but it does not synergize with gemcitabine or docetaxel [96]. By contrast, a cooperative effect was detected in lymphoma cells treated with the histone deacetylase inhibitor vorinostat, neuroblastoma cells treated with the anti-GD2 ganglioside (GD2) 14G2a mouse mAb and lung cancer cell lines treated with cisplatin or docetaxel [97-99]. One Phase I trial has been completed for MK-5108 alone or in combination with docetaxel in patients with advanced solid tumors [100]. No dose-limiting toxicity was observed in the monotherapy arm; disease stabilization was seen in 32% of the patients treated 4.2

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with MK-5108 alone or in combination. Although partial response was observed in 12% of the patients in the combination arm, none was seen in the monotherapy arm. MLN8054 and MLN8237 (Alisertib) These two compounds from Millennium Pharmaceuticals are ATP-competitive and reversible inhibitors with a potent activity against AURKA (IC50 = 4 nM for MLN8054 and IC50 = 1 nM for MLN8237). MLN8054, which was patented in 2004, is a benzazepine-fused ring compound with potent antitumoral properties as it has been demonstrated in several preclinical studies. Specifically, MLN8054 inhibits the growth of colon, breast, lung, ovary, neuroblastoma and prostate cancer cell lines and that of colon cancer human xenografts [101-103]. Cellular defects induced by MLN-8054, spindle pole and chromosome congression/segregation abnormalities, were consisting with AURKA-specific inhibition [103,104]. Moreover, it has been shown that MLN-8054 can induce apoptosis in p53-negative cells in a p73-dependent manner [105]. Using this Aurora A inhibitor, it was suggested for the first time, both in vitro and in vivo, that the main cellular phenotype induced by Aurora A inhibition is senescence rather than apoptosis [106]. Two Phase I clinical trials initiated in advance malignancies and solid tumors showed somnolence and liver toxicity as the major dose-limiting toxicities for MLN-8054 (maximum once-daily administration dose was 30 mg/day) [107,108]. The formerly was a consequence of the structural and functional similarities that this agent has with benzodiazepines. Due to these adverse effects this oraladministrated drug could not be used in the doses that allowed a proper Aurora A inhibition. Therefore, MLN8054 development was abandoned. MLN8237, also named Alisertib, is by far the most frequently used AURKA inhibitor (Figure 4B). Patented in 2008, MLN8237 is another benzazepine-fused pyrimidine ring compound that inhibits Aurora A better than MLN8054 (IC50 = 1 nM) and has decreased tendency to cause somnolence. Several preclinical studies have shown, in vitro and in vivo, the antitumoral properties of MLN8237 in cancer cell lines from different tumor types including lymphomas [109,110], leukemias [111,112], multiple myeloma [113], breast, ovarian [114], bladder [115] and malignant peripheral nerve sheath [116] tumors. 4.3



Different works have demonstrated that MLN8237 induces the defects expected for a bona fide AURKA inhibitor [117] and inhibits cell proliferation mainly through the induction of senescence [118,119]. To note, is the fact that loss of p53 sensitizes cells to MLN-8237 treatment [120] and that Ki67 could be a good biomarker for the anti-proliferative effects of this AURKA inhibitor [121]. Several preclinical studies have shown that Alisertib cooperates with many compounds and cancer treatments (Table 3). Specifically, MLN8237 induces additive effects with: dexamethasone, doxorubicin or bortezomib in multiple myeloma cells [113]; tyrosine kinase inhibitor nilotinib or the DNA synthesis inhibitor cytarabine in myeloid leukemias [122,123]; the MT stabilizer docetaxel in mantle cell lymphomas and gastrointestinal adenocarcinomas [124,125]; radiation in atypical teratoid rhabdoid tumor cells [126]; the mTOR inhibitor rapamycin in uterine leiomyosarcoma [127]; the MT assembly inhibitor vincristine and the mAb against the protein CD20 rituximab in aggressive B-cell non-Hodgkin lymphoma [128]; the DNA crosslinker cisplatin in esophageal adenocarcinomas [129]; the histone deacetylase inhibitor vorinostat in pediatric neuroblastoma, medulloblastoma and leukemia cell lines [130] and the MT inhibitor paclitaxel in ovarian cancer cells [114]. Eight Phase I clinical trials have been completed for Alisertib in advanced solid tumors and lymphomas. In one of them (NCT00500903), the safety, pharmacokinetics, pharmacodynamics and the bioavailability of two oral formulations was evaluated [131]. Adverse effects included fatigue, nausea and neutropenia. Plasma exposures increased dose proportionally (5 -- 150 mg/day) and were similar for the two formulations (enteric-coated tablet and the original powder-in-capsule). The terminal half-life was 23 h. Partial response and stable disease was detected in 1 and 23% of the patients, respectively. In another Phase I trial (NCT00651664), patients with advanced solid tumors were selected and similar results were obtained [132]. Neutropenia and stomatitis were the most common dose-limiting toxicities. The maximum tolerated dose for the 7-day and 21-day schedules were 50 mg twice daily and 50 mg once daily, respectively. The mean terminal half-life was ~ 19 h. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and mitotic abnormalities in tumor specimens, which corroborates with the Aurora A inhibition by MLN8237. Stable disease was observed in ~ 10% of the patients, without notable cumulative toxicity. In a third Phase I trial (NCT011 54816), pharmacokinetic properties of MLN8237 were analyzed in 37 children with advanced/refractory tumors [133]. Myelosuppression, mood alteration and mucositis were the main dose-limiting effects. There was one partial response (3%) and six (18%) with prolonged stable disease among 33 evaluable subjects. Finally, a Phase I trial (NCT006 97346) testing MLN8237 in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia has been recently published [134]. The results were similar to the ones obtained in other Phase I trials for MLN 8237. Neutropenia (45%), thrombocytopenia (28%), anemia

(19%) and leukopenia (19%) were the main adverse effects found among the 58 enrolled patients. The maximum tolerated dose on the 7-day schedule was 50 mg twice daily and the terminal half-life was ~ 19 h. Six (13%) patients achieved partial responses and 13 (28%) stable disease. Up to 13 Phase II studies have been initiated in the US and in Europe to test Alisertib in a broad range of human tumors. The results from two of these studies have recently been published. In one of them (NCT00807495), 48 patients suffering from relapsed and refractory, aggressive B-cell and T-cell non-Hodgkin lymphomas were treated with Alisertib administered orally at 50 mg twice daily for 7 days in 21-day cycles [135]. The adverse events were similar to the ones detected in Phase I trials: low numbers of blood cells, stomatitis and fatigue. The overall response rate was 27%. The other, published Phase II study was conducted in the US and in Europe (NCT00853307; 2008-006979-72) in patients with platinum-resistant or platinum-refractory epithelial ovarian, fallopian tube or primary peritoneal carcinoma [136]. Responses (of 6.9 -- 11.1 months duration) and stable disease (mean duration of 2.86 months) were observed in 10 and 52% of the patients, respectively. This modest antitumor activity in patients with advanced ovarian cancers was observed together with the common Alisertib-associated adverse effects (neutropenia, leukopenia, stomatitis, thrombocytopenia and febrile neutropenia). At least 11 Phase I and 8 Phase II trials are recruiting or currently testing Alisertib in combination with other drugs or treatments (Table 3). Among the drugs/treatments, there are inhibitors for DNA synthesis, MT dynamics, angiogenesis, the immune system, proton pumps, antibiotics and different molecules such as EGFR, HDAC, CD20 and CYP17 (Table S3). As a consequence of the promising results obtained in Phase I and II studies with solid and non-solid tumors, confirmatory mono-therapy and combination studies have been initiated (Table 3). Furthermore, a Phase III trial (NCT0148 2962) is currently recruiting patients with refractory peripheral T-cell lymphoma to test Alisertib alone or in combination with pralatrexate, gemcitabine or romidepsin. 5.

Conclusions

AURKA has a two-sided importance in oncology. It is amplified and over-expressed in many human cancers and has been causally associated with tumor development and progression. On the other hand, its depletion or inhibition impairs cell proliferation of tumor cells, reason why it has been considered a therapeutic target for cancer treatment. Several Aurora kinase inhibitors have been developed during the last decade, and most pre-clinical studies showed the potent antiproliferative effect of these compounds. Approximately 20 Aurora kinase inhibitors have been or are going to be tested in almost one hundred clinical trials, and half of them use AURKA-specific inhibitors. Alisertib (MLN8237) is the most frequently tested Aurora A inhibitor (40 clinical trials


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completed, recruiting or active), and Phase I and Phase II trials have shown promising results in the treatment of different human cancers. The results obtained in monotherapies or combination trials with Aurora A kinase inhibitors during the next years will be critical to define the potential of this agent in anticancer therapy. 6.

Expert opinion

Given the essential role of Aurora A in mitosis, its inhibition could in principle impair the proliferation of any tumor. This makes Aurora A inhibitors potential universal drugs for the treatment of oncologic disorders. However, their inclusion in routine antitumor therapies is still far to be achieved, and a number of issues need to be addressed to improve the efficacy of AURKA inhibition for the treatment of cancer diseases. New and/or improved ways to inactivate AURKA Although very potent and specific Aurora A inhibitors have been developed, drug resistance has already been reported in tumor cells [137,138]. It will be therefore important to have compounds with different chemical structures or mechanisms of action. Although most Aurora inhibitors are ATP competitors, Tripolin A, which has a modest affinity for AURKA (IC50 = 1.5 µM) [139], shows a non-ATP competitive mode of action. Other strategies to prevent resistance are based on the mechanisms that allow cancer cells to resist the action of Aurora A inhibitors. That is the case of resistance to VX680 in breast cancer cells due to the induction of autophagy. Thus, repression of autophagy by depletion of either LC3 or ATG5 sensitizes cancer cells to VX-680-induced apoptosis [138]. Another example has been the identification of proteins that contribute resistance to other two Aurora inhibitors, CYC116 and ZM447439 [137]. Specifically, platelet-activating factor acetylhydrolase and GTP-binding nuclear protein Ran contribute to the development of resistance to ZM447439, whereas serine hydroxymethyltransferase, serpin B5 and calretinin help to overcome the effects of CYC116. Further studies in this area will provide clinicians with potent tools to monitor patients and avoid drug resistance to Aurora inhibitors. 6.1

Biomarkers Different markers have been used to predict or monitor the efficacy of Aurora inhibitors, including mitotic index, spindle bipolarity and chromosome alignment [104], nuclear volume [82] and percentage of aligned spindles [140]. The crosstalk between Aurora A and p53 [69] makes this protein a potential marker for a more potent effect of AURKA inhibitors. As Aurora A inhibits p53 [37], it can be postulated that a wild type, functional p53 pathway could be reactivated upon Aurora A inhibition and, therefore, sensitize cells to this treatment. In fact, depletion of Aurora A in Zebrafish causes p53-dependent cell death [141]. However, it has also been reported the opposite, the lack of p53-sensitizing cells to inhibition of Alisertib [120] and also that breast cancer cell 6.2

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lines with a p53 mutation are more sensitive to ENMD2076 [92]. Because AURKA inhibition leads to apoptosis in p53-deficient cancer cells in a p73-dependent manner [105], this last protein could also be studied to confirm its utility as a biomarker for AURKA inhibitors efficacy. High proliferative rates have also been associated with tumors that better respond to Aurora A inhibitors, since proliferation requires Aurora A activity. Aurora A and its regulator TPX2 are among the different markers that could be used to test proliferation status. Moreover, both TPX2 and Aurora A are co-overexpressed in many human tumors, which has made others to postulate the hypothesis that both Aurora A and TPX2 work as an oncogenic holoenzyme [72]. Interestingly, it has been shown that TPX2 can alter the binding mode with Aurora of the inhibitor VX-680 [142]. However, Aurora A amplification/overexpression has been analyzed, with negative correlation with clinical response, within a Phase II trial conducted in advanced lymphomas [135]. Other potential biomarkers for Aurora A inhibition activity are NEDD9, whose depletion in tumor cells increases sensitivity to Aurora A inhibitors [143]; p21, whose deficiency enhances the activity of BPRIK0609S1 [144]; and estrogen receptor and HER2, whose expression in breast cancer cells have been related with the antiproliferative activity of ENMD2076 [92]. All these proteins should be further analyzed to confirm their potential. Besides all these candidate-based approaches, genomic strategies such as deep sequencing, transcriptomics or the analysis of the methylome and metabolome must be used to identify new biomarkers. Combination therapies: looking for synergisms One of the most interesting uses of Aurora A inhibitors is their ability to potentiate the responses induced by other agents. Several Phase I and II trials have been initiated to test the effect of Aurora A inhibitors in combination with other drugs that already approved for cancer treatment (Table S3). Some of those trials have been completed offering promising results. We believe that further combinations could be explored. The newly discovered roles of Aurora A in DNA damage, senescence, aneuploidy and differentiation offer new possibilities [82,112,119]. Therefore, DNA repair inhibitors or agents that selectively kill aneuploid cells can be interesting candidates for combination therapies. Among them, ATR inhibitors, the energy stress-inducing agent AICAR, the protein-folding inhibitor 17-AAG and the autophagy inhibitor chloroquine have already shown antitumoral properties in preclinical studies [145,146]. In parallel, massive screenings must be considered for converting the senescence or differentiation phenotype induced by Aurora A inhibitors into cell death. Further research on the physiological relevance of Aurora A in different cell types may be required to provide a rationale for these new approaches in the future. In conclusion, the use of AURKA inhibitors have shown promising results during the last years. We anticipate that additional discoveries on the function of Aurora A kinase 6.3



will also significantly impact the field improving the clinical use of Aurora A kinase inhibitors.

Acknowledgments We want to apologize for all those works that have not been cited in this review due to space constrains.

Declaration of interest We want to thank David Partida for his technical assistance. This work was supported by grants from the Ministerio de Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Marcos Malumbres*1 PhD & Ignacio Perez de Castro†2 PhD †,* Authors for correspondence 1 Group Leader, Spanish National Cancer Research Centre (CNIO), Cell Division and Cancer Group, Melchor Fernańdez Almagro 3, E-28029 Madrid, Spain Tel: +34 91 224 6900; Fax: +34 91 732 8033; E-mail: [email protected] 2 Staff Scientist, Spanish National Cancer Research Centre (CNIO), Cell Division and Cancer Group, Melchor Fernańdez Almagro 3, E-28029 Madrid, Spain Tel: +34 91 224 6900; Fax: +34 91 732 8033; E-mail: [email protected]

Supplementary materials available online Tables S1, S2 and S3.


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Aurora-A Kinase as a Promising Therapeutic Target in Cancer.

Aurora Kinase Inhibitors: Current Status and Outlook.

A Cell Biologist's Field Guide to Aurora Kinase Inhibitors.

Signal Transduction Inhibitors as Promising Anticancer Agents.

A new challenging and promising era of tyrosine kinase inhibitors.

Monoamine oxidase inhibitors: promising therapeutic agents for Alzheimer's disease (Review).

β-Catenin Signaling Pathway Inhibitors: A Promising Cancer Therapy.

Design, synthesis and bioevaluation of N-trisubstituted pyrimidine derivatives as potent aurora A kinase inhibitors.

CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors.

Thr Kinase Pharmacophore Model.

Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors.

In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy.

New RAF kinase inhibitors in cancer therapy.

Aurora kinase inhibitor patents and agents in clinical testing: an update (2011 - 2013).

In vitro high throughput screening, what next? Lessons from the screening for aurora kinase inhibitors.

Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors.

Discovery of 7-aryl-substituted (1,5-naphthyridin-4-yl)ureas as aurora kinase inhibitors.

Elevated aurora kinase a protein expression in diabetic skin tissue.

Aurora isoform selectivity: design and synthesis of imidazo[4,5-b]pyridine derivatives as highly selective inhibitors of Aurora-A kinase in cells.

Aurora kinase inhibition: a new light in the sky?

Aurora kinase A in gastrointestinal cancers: time to target.

Selective disruption of aurora C kinase reveals distinct functions from aurora B kinase during meiosis in mouse oocytes.

Aurora kinase and RUNX: Reaching beyond transcription.