Curtis, A

Gueorguieva, M

Hoskins, C

Kong Thoo Lin, P

Lees, M

Malekigorji, Maryam

Queen's University Belfast Research Portal

Thermally triggered theranostics for pancreatic cancerMalekigorji, M., Kong Thoo Lin, . P., Lees, M., Gueorguieva, . M., Curtis, A., & Hoskins, C. (2016). Thermallytriggered theranostics for pancreatic cancer: Volume 61, Supplement 1. S129. Poster session presented at 24thBiennial Congress of the European Association for Cancer Research, Manchester, United Kingdom.Document Version:Publisher's PDF, also known as Version of recordQueen's University Belfast - Research Portal:Link to publication record in Queen's University Belfast Research PortalPublisher rightsCopyright 2016 The Author.General rightsCopyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or othercopyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associatedwith these rights.Take down policyThe Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made toensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in theResearch Portal that you believe breaches copyright or violates any law, please contact openaccess@qub.ac.uk.Download date:09. Sep. 2018EACR24 Poster Sessions / European Journal of Cancer 61, Suppl. 1 (2016) S9–S218 S129Conclusion: Our study shows that miR-625-3p induces oxaliplatin resistanceby abrogating MAP2K6-p38 regulated apoptosis and cell cycle controlnetworks, and corroborates the predictive power of miR-625-3p. This hassigniﬁcant clinical potential as the expression level of miR-625-3p, possiblycombined with the expression level of MAP2K6, has the potential to serveas a predictive biomarker. Since ~20% of metastatic CRC patients have highmiR-625-3p expression, the number of patients potentially beneﬁting from theuse of miR-625-3p/MAP2K6 is substantial.No conﬂict of interest.585 Gli1/DNA interaction is a druggable target for Hedgehog-dependenttumorsP. Infante1, M. Mori1, R. Alfonsi2, C. Ingallina1, B. Botta3, L. Di Marcotullio2.1Istituto Italiano di Tecnologia, CNLS@Sapienza, Rome, Italy, 2SapienzaUniversity, Molecular Medicine, Rome, Italy, 3Sapienza University, Chimica eTecnologie del Farmaco, Rome, ItalyBackground: Hedgehog (Hh) pathway is essential for tissue developmentand stemness, and when deregulated leads to tumorigenesis. Although manyHedgehog-driven human cancers involve upstream pathway activation (i.e.either loss-of-function of the receptor Ptch1 or gain-of-function mutations ofthe transmembrane transducer Smo), Smo-independent hyperactivation ofthe downstream Gli transcription factor is responsible for the development ofseveral tumors and resistance to therapy. This raises the need to identify novelGli1 inhibitors, a challenging issue mostly due to the lack of information on thestructural requirements of Gli1/DNA interaction.Material and Methods: Molecular characterization of Gli1/DNA binding wasperformed by a mix of computational and experimental structure-based invitro studies. Molecular dynamics simulations were carried out to identify theresidues in Gli1 zinc-ﬁnger involved in DNA binding. The data obtained werethen used to set up the docking-based virtual screening of a natural productslibrary available in house, with the aim to discover pharmacological agents ableto interfere with Gli1/DNA interaction. The molecules identiﬁed as potentialGli1 inhibitors were investigated for their functional activity through a Gli-dependent luciferase reporter screening assay. The most active was tested forits effectiveness to counteract Hh-dependent tumor growth by medulloblastomaand basal cell carcinoma allograft model from Ptch+/− mice and ortothopicmedulloblastoma xenograft.Results:We identiﬁed a small molecule, Glabrescione B (GlaB), an isoﬂavonenaturally found in the seeds of Derris glabrescens (Leguminosae), able toimpair Gli1/DNA binding as revealed by Chip and EMSA assays. In agreementwith these molecular results, GlaB revealed great antitumor efﬁcacy. Indeed,we observed that GlaB strongly inhibited the growth of Hedgehog-dependenttumor cells in vitro and in vivo as well as the self-renewal ability andclonogenicity of tumor-derived stem cells.Conclusions: Our study highlighted the relevance of structural details ofGli1/DNA interaction as a promising tool to discover small molecules ableto inhibit Hh pathway by directly targeting Gli1. Here we identiﬁed GlaB asa potent and speciﬁc Gli1 inhibitor able to interfere with Gli1/DNA binding,resulting in the inhibition of Hh-dependent tumor cells and cancer stem cellsgrowth, thus becoming a proﬁtable pre-clinical candidate.No conﬂict of interest.586 The unique binding mode of NTRC 0066-0, a novel inhibitor ofthe spindle assembly checkpoint kinase TTK (Mps1), leads tolong target residence time and potent anti-tumor activityG. Zaman1, J. Uitdehaag1, J. De Man2, N. Willemsen-Seegers1,J.G. Sterrenburg2, J. De Wit1, J. De Roos1, M. Prinsen1, R. Buijsman2.1Netherlands Translational Research Center B.V., Biology, Oss, Netherlands,2Netherlands Translational Research Center B.V., Chemistry, Oss,NetherlandsIntroduction: An abnormal number of chromosomes, or ‘aneuploidy’, is acommon feature of solid human tumors and a predictor of poor prognosisin breast, lung, brain and colorectal cancer. Aneuploidy is caused bymalfunctioning of the Spindle Assembly Checkpoint (SAC), a surveillancemechanism that ensures the ﬁdelity of chromosome segregation. The proteinkinase TTK (commonly referred to as Mps1) is a component of the SAC.Inhibition of TTK gene expression by RNA interference and inhibition ofTTK kinase activity by small molecule kinase inhibitors causes chromosomemissegregation and cancer cell death.Material and Method: A novel class of compounds was identiﬁed thatpotently inhibits TTK enzyme activity and cancer cell line proliferation [1]. Itsbinding mode and that of reference inhibitors was characterized by proteincrystallography. Binding kinetics and target residence time were determinedby surface plasmon resonance. Anti-proliferative activity was measured on abroad panel of cancer cell lines [2,3].Results and Discussion: The clinical candidate, NTRC 0066-0, inhibits TTKwith subnanomolar potency (IC50) in a kinase enzyme assay and is morethan 200 times selective over 276 kinases examined, including mitotic and cellcycle dependent kinases (CDKs). X-ray structures of the TTK kinase domain incomplex with NTRC 0066-0 and analogs indicate that this class of compoundsinduces a large conformational shift in the glycine-rich loop, invoking aninactive kinase conformation. In surface plasmon resonance experiments,NTRC 0066-0 exhibited slow dissociation kinetics, resulting in a long targetresidence time. Parallel surface plasmon resonance experiments conﬁrmedthe exquisite selectivity of NTRC 0066-0 for TTK over Aurora and Polo-likekinases. NTRC 0066-0 inhibited the proliferation of a wide variety of humancancer cell lines in the same potency range as marketed cytotoxic agents. Thecrystal structure, binding kinetics and cellular potency of NTRC 0066-0 werecompared to that of other TTK inhibitors such as Mps1-IN-2, AZD-3146, Mps-BAY2b, Bay 1161909 as well as analogs from the NTRC 0066-0 series. Thissuggests that the unique binding mode of NTRC 0066-0 results in long targetresidence time which contributes to its strong anti-tumor activity. In subsequentmouse xenograft models of human cancer cell lines, NTRC 0066-0 inhibitedtumor growth as a single agent after oral administration at 20mg per kg.Conclusions: NTRC 0066-0 is a novel TTK inhibitor with outstanding in vitroproperties and potent anti-tumor activity in mouse xenograft models. Our datasuggest that long target residence time corresponds with potent cellular activityfor TTK inhibitors.Reference(s)[1] Maia et al. (2015) Annals of Oncology 26, 2180–2192.[2] Uitdehaag et al. (2014) PLOS ONE 9(3) e92146.[3] Uitdehaag et al. (2015) PLOS ONE 10(5) e0125021.Conﬂict of interest: Ownership: I am a shareholder of NetherlandsTranslational Research Center B.V. (NTRC). Board of Directors: I ama managing director of Netherlands Translational Research Center B.V.(NTRC). Other Substantive Relationships: I am a co-founder of NetherlandsTranslational Research Center B.V. (NTRC).587 Thermally triggered theranostics for pancreatic cancerM. Malekigorji1, P. Kong Thoo Lin2, M. Lees3, M. Gueorguieva4, A. Curtis5,C. Hoskins5. 1Keele University, Institute of Science and Technology, Keele,United Kingdom, 2Robert Gordon University, School of Pharmacy and LifeSciences, Aberdeen, United Kingdom, 3University of Warwick, PhysicsDepartment, Warwick, United Kingdom, 4University of Dundee, Institutefor Medical Sciences and Technology, Dundee, United Kingdom, 5KeeleUniversity, School of Pharmacy, Keele, United KingdomBackground: Pancreatic cancer is the 4th most aggressive cancer in thewestern world with less than 34% of patients surviving past 5 years. Lackof speciﬁc symptoms results in delayed diagnosis. Theranostics are newplatforms, which offer simultaneous diagnosis and therapy resulting in adecrease in treatment time. Here treatments are conjugated onto diagnosticsby stimuli responsive binding allowing for controlled drug release resulting ina rapid and localised clinical effect. Hybrid nanoparticles are composed ofan iron oxide core surrounded by a rigid gold shell. These particles undergomanipulation due to inherent magnetism of the core whilst laser irradiation oftheir gold shell results in localised heating due to surface plasmon resonance.Hence, they can be utlilised as diagnostics using MRI and laser irradiation canbe used as a trigger for drug release.Methods: Proof of concept studies have been carried out using a novelbisnaphthalamido (BNIP) based drug series. BNIPs are a series of novelcompounds, which have exhibited exciting potential as chemotherapy agents.HNPs were fabricated and characterised using PCS, TEM, MRI, SQUID andzeta potential measurement. Drug conjugation and release was quantiﬁedusing reverse phase HPLC. Cellular response and cytotoxicity assays werecarried out using trypan blue exclusion, MTT assay and atomic forcemicroscopy.Results and Discussion: In our studies, we designed hybrid nanoparticles(50 nm) capable of drug loading onto their surface (3:1:0.25, Drug:Fe:Au).By exploiting the gold surface-to-drug interaction of a range of novelBisnaphtalamido based agents a system with heat triggered drug release wasproduced. In vitro studies of these formulations showed the novel formulationspossess a 10-fold lower IC50 value when compared with the free drug afteronly 24 h. These cytotoxicity studies combined with cellular uptake studiesshowed the formulations to be signiﬁcantly more effective compared withgemcitabine. In vivo trials have commenced to further elucidate their viabilityfor use as theranostics.Conclusion: These data highlight the potential of HNPs as dual imagingagents and contrast agents for pancreatic cancer therapy.No conﬂict of interest.

Thermally triggered theranostics for pancreatic cancer:Volume 61, Supplement 1

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Thermally triggered theranostics for pancreatic cancer:Volume 61, Supplement 1

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