Publications by authors named "Elena Ardini"

18 Publications

  • Page 1 of 1

Entrectinib approval by EMA reinforces options for ROS1 and tumour agnostic targeted cancer therapies.

ESMO Open 2020 09;5(5):e000867

Oncology and Hemato-Oncology, Università degli Studi di Milano, Milano, Italy. Electronic address:

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http://dx.doi.org/10.1136/esmoopen-2020-000867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481078PMC
September 2020

Identification and characterization of a novel rearrangement in a colorectal cancer patient.

Oncotarget 2017 Aug 24;8(33):55353-55360. Epub 2017 Jul 24.

Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.

In colorectal cancer patients, chromosomal rearrangements involving gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors. Here we report the identification and functional characterization of a new fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients. We show that this novel fusion is oncogenic and sensitive to TRKA inhibitors. As suggested by other pieces of evidence, entrectinib - an orally available pan-TRK, ROS1 and ALK inhibitor - may have particular efficacy in patients with rearrangements. Therefore, screening for rearrangements involving genes may help identifying a subset of patients able to derive benefit from treatment with entrectinib or other targeted inhibitors.
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http://dx.doi.org/10.18632/oncotarget.19512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589663PMC
August 2017

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).

Cancer Discov 2017 04 9;7(4):400-409. Epub 2017 Feb 9.

Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring , or gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with -rearranged lung cancer. Gene fusions of , and (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583PMC
April 2017

Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

J Med Chem 2016 Apr 30;59(7):3392-408. Epub 2016 Mar 30.

Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00064DOI Listing
April 2016

Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications.

Mol Cancer Ther 2016 04 3;15(4):628-39. Epub 2016 Mar 3.

Nerviano Medical Sciences srl, Nerviano, Milan, Italy.

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available. Mol Cancer Ther; 15(4); 628-39. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0758DOI Listing
April 2016

Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer.

Br J Cancer 2015 Dec 3;113(12):1730-4. Epub 2015 Dec 3.

Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.

Background: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies.

Methods: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR.

Results: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20-29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response.

Conclusions: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.
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http://dx.doi.org/10.1038/bjc.2015.401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701996PMC
December 2015

Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer.

J Natl Cancer Inst 2016 Jan 12;108(1). Epub 2015 Nov 12.

Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy (ASB, AA, EV, LP, EB, GM, SV, AV, SS); Nerviano Medical Sciences S.r.l Nerviano, Milan, Italy (EA, RB, AS, LR, PB, AL, RA, AG, AI); Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy (SM, AB); University of Torino, Department of Oncology, Candiolo, Torino, Italy (AB); FIRC Institute of Molecular Oncology (IFOM), Milano, Italy (SM); Ignyta, Inc., San Diego, CA (DL, ZH, JL); Clioss S.r.l. Nerviano, Milan, Italy (MM, CD); Università degli Studi di Milano, Milan, Italy (SS).

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib.
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http://dx.doi.org/10.1093/jnci/djv306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712682PMC
January 2016

The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition.

Mol Oncol 2014 Dec 12;8(8):1495-507. Epub 2014 Jun 12.

Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.

The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the high-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3-NTRK1) resulting in expression of the oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition. We report the detailed characterization of the TPM3-NTRK1 genomic rearrangement in KM12 cells and through a cellular screening approach, the identification of NMS-P626, a novel highly potent and selective TRKA inhibitor. NMS-P626 suppressed TPM3-TRKA phosphorylation and downstream signaling in KM12 cells and showed remarkable antitumor activity in mice bearing KM12 tumors. Finally, using quantitative reverse transcriptase PCR and immunohistochemistry (IHC) we identified the TPM3-NTRK1 rearrangement in a CRC clinical sample, therefore suggesting that this chromosomal translocation is indeed a low frequency recurring event in CRC and that such patients might benefit from therapy with TRKA kinase inhibitors.
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http://dx.doi.org/10.1016/j.molonc.2014.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528583PMC
December 2014

Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.

Bioorg Med Chem 2013 Dec 2;21(23):7364-80. Epub 2013 Oct 2.

Oncology, Nerviano Medical Sciences, viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address:

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
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http://dx.doi.org/10.1016/j.bmc.2013.09.054DOI Listing
December 2013

RET inhibition: implications in cancer therapy.

Expert Opin Ther Targets 2013 Apr 6;17(4):403-19. Epub 2013 Mar 6.

UO Molecular Mechanisms, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via GA. Amadeo, 42-20133 Milano, Italy.

Introduction: The RET gene encodes a receptor tyrosine kinase essential for ontogenesis of the enteric nervous system and kidney. Following identification of RET, it was found that somatic rearrangements of this gene, conventionally designated as RET/PTC, are frequently present in papillary thyroid carcinoma. Subsequently, activating germ line point mutations of RET were identified as being responsible for the hereditary medullary thyroid carcinoma syndromes MEN2A, MEN2B and FMTC. RET rearrangements have recently been identified in a small fraction of lung adenocarcinomas.

Area Covered: The authors review the current field concerning the RET gene and protein, its involvement in cancer and the preclinical and clinical studies which highlight its role as a potentially important therapeutic target for several cancers.

Expert Opinion: Many multitargeted inhibitors which crossreact with RET have been developed and investigated in clinical trials targeting many cancer indications. In particular, VEGFR/PDGFR inhibitors, widely explored as antiangiogenics, have been intensively studied in thyroid carcinoma patients. Notwithstanding the efficacy observed with such agents, their common clinical activity in thyroid carcinoma is of short duration and includes frequent and severe side effects, limiting their therapeutic action. These findings are discussed and the need for improved, more specific RET-targeting drugs is highlighted.
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http://dx.doi.org/10.1517/14728222.2013.758715DOI Listing
April 2013

ALK Inhibitors, a Pharmaceutical Perspective.

Front Oncol 2012 22;2:17. Epub 2012 Feb 22.

Department of Cell Biology, Oncology, Nerviano Medical Sciences Milan, Italy.

In 2007, the ALK tyrosine kinase was described as a potential therapeutic target for a subset of non-small-cell lung cancer patients. Clinical proof of concept, culminating in the recent approval by the Food and Drug Administration of the Pfizer drug crizotinib followed in record time. The drug was approved together with a companion diagnostic for detection of patients eligible for therapy. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in a rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may additionally occur through ALK-independent mechanisms, which still need to be elucidated in detail. Here we discuss the factors that led to such a rapid approval of a targeted agent, and we describe the second-generation compounds currently in development.
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http://dx.doi.org/10.3389/fonc.2012.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356102PMC
August 2012

Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors.

Biochemistry 2010 Aug;49(32):6813-25

Nerviano Medical Sciences S.r.l., Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the development of several human cancers and, as a result, is a recognized target for the development of small-molecule inhibitors for the treatment of ALK-positive malignancies. Here, we present the crystal structures of the unphosphorylated human ALK kinase domain in complex with the ATP competitive ligands PHA-E429 and NVP-TAE684. Analysis of these structures provides valuable information concerning the specific characteristics of the ALK active site as well as giving indications about how to obtain selective ALK inhibitors. In addition, the ALK-KD-PHA-E429 structure led to the identification of a potential regulatory mechanism involving a link made between a short helical segment immediately following the DFG motif and an N-terminal two-stranded beta-sheet. Finally, mapping of the activating mutations associated with neuroblastoma onto our structures may explain the roles these residues have in the activation process.
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http://dx.doi.org/10.1021/bi1005514DOI Listing
August 2010

Through the "gatekeeper door": exploiting the active kinase conformation.

J Med Chem 2010 Apr;53(7):2681-94

Department of Chemical Core Technologies, Nerviano Medical Sciences, Oncology, Viale Pasteur 10, Nerviano 20014, Italy.

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http://dx.doi.org/10.1021/jm901443hDOI Listing
April 2010

Reliable high-throughput functional screening with 3-FABS.

Drug Discov Today 2004 Jul;9(14):595-602

Chemistry Department, Nerviano Medical Science, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

An NMR method called 3-FABS has extended the capabilities of NMR, enabling rapid, efficient and reliable high-throughput functional screening for the identification of inhibitors and for measuring their 50% mean inhibition concentration (IC(50)) with accuracy. The substrate is tagged with a CF(3) moiety and (19)F NMR spectroscopy is used for the detection of the substrate and product components. We provide comprehensive insight into 3-FABS, a discussion of its strength and weakness when compared with other HTS techniques and a presentation of some of its applications to the screening of different enzymes and to multiple screening.
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http://dx.doi.org/10.1016/S1359-6446(04)03161-7DOI Listing
July 2004

A general NMR method for rapid, efficient, and reliable biochemical screening.

J Am Chem Soc 2003 Nov;125(47):14620-5

Chemistry and Biology Departments, Pharmacia, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

High-throughput screening is usually the method of drug-lead discovery. It is now well accepted that, for a functional assay, quality is more important than quantity. The ligand-based or protein-based NMR screening methodologies for detecting compounds binding to the macromolecular target of interest are now well established. A novel and sensitive NMR method for rapid, efficient, and reliable biochemical screening is presented. The method named 3-FABS (three fluorine atoms for biochemical screening) requires the labeling of the substrate with a CF(3) moiety and utilizes (19)F NMR spectroscopy for the detection of the starting and enzymatically modified substrates. The method allows for high-quality screening of large compound or natural product extract collections and for measuring their IC(50) values. Applications of this technique to the screening of inhibitors of the Ser/Thr kinase AKT1 and the protease trypsin are presented. In addition, an interesting application of 3-FABS to functional genomics is also presented.
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http://dx.doi.org/10.1021/ja038128eDOI Listing
November 2003

p53-dependent downregulation of metastasis-associated laminin receptor.

Oncogene 2002 Oct;21(49):7478-87

Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy.

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild-type p53 (wt p53) ovarian carcinoma cell line and in a cisplatin-resistant subline with mutated p53. We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct. Cotransfection experiments showed that the promoter is downregulated by both wt and mutated p53. Deletion analysis of the first intron localized an enhancer activity in the first 5' 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53. Cotransfection, mutagenesis and gel-shift experiments identified a functional AP-2 cis-acting element in this intron region that is repressed by increased levels of both wt and mutated p53. Coimmunoprecipitation studies revealed AP-2 in physical association in vivo with both wt and mutated p53, indicating for the first time that interaction of p53 with AP-2 is involved in the repression mechanism and in the regulation of genes involved in cancer growth and progression.
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http://dx.doi.org/10.1038/sj.onc.1205957DOI Listing
October 2002

Identification of a novel function for 67-kDa laminin receptor: increase in laminin degradation rate and release of motility fragments.

Cancer Res 2002 Mar;62(5):1321-5

Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy.

The 67-kDa laminin receptor (67LR) is a high-affinity laminin-binding protein that is overexpressed on the tumor cell surface in a variety of cancers. We report here that the 67LR molecule also functions in the proteolytic cleavage of laminin-1, a relevant event in basement membrane degradation and tumor dissemination. In the presence of a synthetic peptide (peptide G) corresponding to the 67LR laminin binding site, the rate of laminin-1 degradation by the cysteine proteinase cathepsin B was significantly increased, and a new proteolytic fragment particularly active in in vitro cell migration assays was generated. The YIGSR peptide, corresponding to the 67LR binding site on laminin-1, blocked the peptide G-dependent proteolytic degradation. Our results shed light on the mechanism by which an adhesion receptor such as the 67LR plays a major role in tumor aggressiveness and metastasis.
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March 2002