Konstantinos Kiakos, PhD

Konstantinos Kiakos, PhD

E-Mail: konstantinos.kiakos@univie.ac.at
Research Platform Translational Cancer Therapy Research

Project: “SENSinSTAT” – Resensitisation of chemotherapy resistant cancer cells through selective inhibition of the STAT3 signalling pathway

The transcription factor signal transducer and activator of transcription 3 (STAT3) is a member of the STAT protein family crucial for signal transduction from receptor and non-receptor tyrosine kinases in response to various cytokines and growth factors. Constitutive activation of STAT3 is prevalent in a variety of tumours and results in dysregulated transcription of a series of STAT3-target genes with known roles in promoting tumour proliferation, survival, angiogenesis, metastasis, invasion, and immunosuppression. Aberrant STAT3-activation has now been established as a key mediator for the emergence of resistance to both cytotoxic chemotherapy and molecular-targeted therapies through feedback activation. All the above render STAT3 a relevant, valid and highly sought-after target for the development of novel cancer therapies and within the scope of the INDICAR fellowship, a “druggable” target for restoring cellular sensitivity in chemotherapy resistant cancer cells. Although well-validated preclinically, the clinical application of STAT3 inhibitors as stand-alone agents or in combination therapies remains elusive.

As part of an ongoing drug development programme, novel, highly potent STAT3-specific inhibitors (piperidone analogues of Curcumin) as well as established small-molecule inhibitors will be tested in vitro, in combination with different drug regimens (DNA damaging drugs: monofunctional, bifunctional ICL-producing, pathway-targeted therapeutics) and drug interactions will be characterised in selected resistant cell lines.

Prompted by our initial observations of the synergistic interaction between our lead compound (as well as Curcumin and Stattic) and cisplatin, a comprehensive study of the effect of pathway inhibition in the modulation of processing/repair of drug-induced DNA damage will be undertaken, with a particular focus on DNA interstrand Crosslinks (ICLs) believed to be the critical cytotoxic adducts. Cellular studies as well as biochemical cell-free repair assays using substrates bearing site-directed ICLs will provide a mechanistic lead on the molecular origins of the observed chemosensitisation to – in this case - platinum drugs. The effects of the inhibition of STAT3 on other critical effectors/mediators related to STAT3 signaling and chemotherapeutic potency such as the generation of reactive oxygen species (ROS) or the modulation of expression of repair factors will also be investigated.

Ultimately it is envisaged that the synergistic interactions achieved in vitro, will be corroborated in relevant resistant models in vivo.

Deviating from STAT3 inhibition, but remaining well within the overarching aim of overcoming chemotherapy resistance, another strategy entails the concomitant occupancy of the two DNA grooves. Novel AT-sequence specific DNA minor groove alkylating drugs (Duocarmycin analogues) as well as rationally designed, non-covalent binding polyamides, will be studied in combination with platinum drugs (including novel oxaliplatin analogues).

At a time that it is evident that combination treatments of targeted agents with chemotherapy are necessary to overcome the activation of mechanisms of drug resistance, the proposed work aims to elucidate the molecular and cellular basis of the synergistic interaction of STAT3 inhibition with DNA-damaging chemotherapy and targeted agents and exploit it as a means to resensitise cancer cells. Understanding how these drug interactions work is essential for the formulation of rational drug combinations and the optimisation of future therapeutic strategies for the treatment of cancer patients.

Publications

  • Santoro V., Jia R., Thompson H., Nijhuis A., Jeffery R., Kiakos K., Silver AR., Hartley J.A and Hochhauser D. Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer. Journal of the National Cancer Institute (2015) 108(6).

  • Colmegna B, Uboldi S., Frapolli R., Licandro S., Panini N., Galmarini C., Badrì N., Spanswick V., Bingham J., Kiakos K., Erba E., Hartley J.A and D'Incalci M. Increased sensitivity to platinum drugs of cancer cells with acquired resistance to trabectedin. British Journal of Cancer (2015) 113(12):1687-93.

  • Kiakos K., Pett L., Satam V., Patil P., Hochhauser D., Lee M. and Hartley J.A. Nuclear Localisation and Gene Expression Modulation by a Fluorescent Sequence-Selective p-Anisyl-benzimidazolecarboxamido Imidazole-Pyrrole Polyamide. Chemistry and Biology (2015) 22(7):862-75.

  • Satam V, Babu B., Patil P., Brien K.A., Olson K., Savagian M., Lee M., Mepham A., Bingham J., Pett L., Wang S., Bruce C., Wilson D., Lee M., Hartley J.A. and Kiakos K. AzaHx, a Novel Fluorescent, DNA minor Groove and G/C recognition element: Synthesis and DNA binding Properties of a p-Anisyl-4-aza-benzimidazole-pyrrole-imidazole (azaHx-PI) Polyamide. Bioorganic and Medicinal Chemistry Letters  (2015) 25(17):3681-5.

  • Pett L., Hartley J.A. and Kiakos K. Therapeutic Agents based on DNA Sequence-selective Binding Compounds. Current Topics in Medicinal Chemistry (2015) 15(14):1292-322.

  • Boshle J., Kiakos K., Porter A.C.G., Wu J., Makris A., Hartley J.A. and Hochhauser D. Treatment with gefitinib and lapatinib induces drug resistance through downregulation of topoisomerase IIα expression. Molecular Cancer Therapeutics (2013) 12(12):2897-908.

  • Spanswick V.J., Lowe H.L., Newton C., Bingham J.P., Kiakos K., Craddock C., Ledermann J.A., Hocchauser D. and Hartley J.A. Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples. BMC Cancer (2012) 12(1):436.

  • Sengerova B., Allerston C.K., Abu M., Lee S.Y., Hartley J., Kiakos K., Schofield C.J., Hartley J.A., Gileadi O. and McHugh P.J. Characterisation of the human SNM1A and SNM1B/APOLLO DNA repair exonucleases. Journal of Biological Chemistry (2012) 287(31):26254-67.

  • Pors K., Loadman P.M., Shnyder S.D., Sutherland M., Sheldrake H.M., Guino M., Kiakos K., Hartley J.A, Searcey M. and Patterson L.H. Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity. Chemical Communications (2011) 47(44):12062-4.

  • Wang A.T., Sengerova B., Cattell E., Inagawa T., Hartley J., Kiakos K., Burgess-Brown N., Enzlin J.H., Schofield C.J., Gileadi O., Hartley J.A. and McHugh P.J. Human SNM1A and XPF-ERCC1 collaborate to initiate DNA interstrand cross-link repair. Genes and Development (2011) 25(17):1859-70.

  • Chavda S., Liu Y., Babu B., Davis R., Sielaff A., Ruprich J., Westrate L., Tronrud C., Ferguson A., Franks A., Tzou S., Adkins C., Rice T., Mackay H., Kluza J., Tahir S., Lin S., Kiakos K., Bruce C., Wilson W., Hartley J. and Lee M. Hx, a Novel Fluorescent, Minor Groove and Sequence Specific Recognition Element: Design, Synthesis, and DNA Binding Properties of p-Anisylbenzimidazole-imidazole/pyrrole-Containing Polyamides. Biochemistry (2011) 50(15):3127-36.

  • Kiakos K., Hartley J.M. and Hartley J.A. Measurement of DNA interstrand crosslinking in naked DNA using gel-based methods. Methods in Molecular Biology (2010) 613:283-302.

  • Kiakos K., Sato A., Asao T., McHugh P.J., Lee M., and Hartley, J.A. DNA sequence selective adenine alkylation, mechanism of adduct repair and in vivo antitumour activity of the novel achiral seco-amino- cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145. Molecular Cancer Therapeutics  (2007) 10:2708-18.

  • Sato A., McNulty L., Cox K., Kim S., Scott A., Daniell K., Summerville K., Price C., Hudson S., Kiakos K., Hartley J.A., Asao T. and Lee M. A novel class of in vivo active anticancer agents: achiral seco-amino- and seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) analogues of the duocarmycins and CC-1065. Journal of Medicinal Chemistry (2005) 48(11):3903-18.

  • Kiakos K., Howard  T.T.,  Lee  M.,  Hartley  J.A. and McHugh P.J. Saccharomyces cerevisiae RAD5 influences the excision repair of DNA minor groove adducts. Journal of Biological Chemistry (2002) 277(46):44576-81.