Cardiovascular and Tumourivascular Laboratory

Research Overview

The Cardiovascular and Tumourivascular Laboratory is co-headed by Dr Peter Wookey and Professor David Hare.

The group focuses on the discovery of new targets, predominantly membrane proteins, in cancer and cardiovascular diseases. Cancer stem cells are an important target of our research. Each of the four projects begins with the development of novel antibodies which provide us with the tools for basic research and a pipeline for translational research. Of significance, antibodies have been raised against G protein-coupled receptors (GPCR) including extracellular epitopes, which have been notoriously problematic. The translational model involves collaborations with Pharma.

Novel antibodies against an epitope within the extracellular domain of the calcitonin receptor (CT Receptor) have been useful for imaging live cells undergoing stress and programmed cell death. A theoretical model for the function of CT Receptor in cell stress is being interrogated.

The brain tumour (glioblastoma) project involved the discovery of CT Receptor expressed by glioma stem cells (GSCs), the development of an anti-CT Receptor immunotoxin and the induction of cell death of GSCs. The pathway to the clinic has involved a collaboration with a group in Berlin, Germany, and an EU-based consortium for the Grand Cancer Challenges.

A novel anti-NPY1 receptor antibody is being validated for studies on breast and brain cancers.

Staff

• Professor David Hare
• Dr Peter Wookey
• Pragya Gupta - PhD Student

Collaborators

Dr Sebastian Furness (ARC Future Fellow), Drug Discovery Laboratories, Monash University, Royal Parade, Parkville. Studies with unique antibodies directed against an extracellular epitope of members of the family B GPCRs including CT Receptor and NPY1R.

Prof Hendrik Fuchs, Institute for Laboratory Medicine, Charité UniversitätMedizin, Berlin, Germany. Enhancer therapy to improve efficacy of a novel immunotoxin in the treatment of glioblastoma. The testing of anti- CT Receptor immunotoxin to restrict sc. tumour expansion in mouse subcutaneous xenograft models.

Grand Cancer Challenges, a consortium of groups in EU/UK/US: developing and testing immunotoxins in orthotopic, intracranial brain tumour mouse models

Funding

International PhD scholarships from the University of Melbourne, philanthropic funds, funds from the pharmaceutical industry and MEL-BER seed grant 2019. Other grant applications (ARC and NHMRC) and Grand Cancer Challenges are pending.

Research Outcomes

Dr Wookey Research Highlights:

1. Founder of Welcome Receptor Antibodies Pty Ltd to develop antibodies and related IP.
2. The development of anti-CTR antibodies (mAb2C4 & 9B4) that bind epitopes within the extracellular domain (2006).
3. Inventor on patent (2008), Diagnosis and treatment of diseased and damaged tissue. International PCT/AU2008/001435; WO 2009/039584, filed 28th September 2008. National phase PCT filed US (Application No 12/680520, granted October 2013) and Europe (Application No 08800070.8/Publication No 2203747: 7th July 2010, granted November 2016, Patent No 2203747).
4. The discovery of mAb2C4:fluorophore conjugate as a diagnostic marker for live cells undergoing programmed cell death [PCD] (2012) . A similar conjugate is being developed to image PCD in vivo.
5. The demonstration of a unique population of precursor pericytes that integrate into small blood vessels in the peri-infarct region following stroke and stabilize penumbral tissue (2012).
6. Inventor on patent (2014), Marker of cell death. Int PCT/AU2014/001081, filed 28th November 2014, published 04/06/2015, Public. No WO 2015/077826. National phase PCT in US (US20160274132A1, published 22/09/2016) & EU (2014865890 filed 22nd June 2016, published 05/10/2016 as EP3074771A1). Granted in US July 2019, pending in EU.
7. Founder of Apop Biosciences Pty Ltd (2016) to commercialise CalRexin conjugates.
8. The use of the antibody mAb2C4 conjugated with plant toxin to form an immunotoxin, which kills brain tumour initiating cells (BTICs derived from glioblastoma) with an EC₅₀ in the picomolar range (2017). This reagent is under development for the treatment of the brain tumour glioblastoma.
9. Inventor on provisional patent (2021), Anti-NPY-Y1 antibodies and uses thereof (2021901321).

Research Publications

1. Wookey PJ, Zulli A, Lo C, Hare DL, Schwarer AP, Darby IA, Leung A. Calcitonin receptor (CTR) expression in embryonic, foetal and adult tissues: developmental and pathophysiological implications. In: “The calcitonin gene-related peptide family; form, function and future perspectives”, Eds Debbie L Hay & Ian M Dickerson. Netherlands: Springer. 2010, pp199-233 [ISBN: 9789048129089].
2. Wookey PJ, McLean CA, Hwang P, Furness SGB, Nguyen S, Kourakis A, Hare DL, Rosenfeld JV. The expression of calcitonin receptor detected in malignant cells of the brain tumour glioblastoma multiforme and functional properties in the GBM cell line A172. Histopathol 60, 895-910, 2012.
3. Wookey PJ, Turner K, Furness J. Transient expression of the calcitonin receptor by enteric neurons in the embryonic and immediately post-natal period in the mouse. Cell Tissue Res, 347, 311-317, 2012.
4. Potes CS, Boyle CN, Wookey PJ, Riediger T, Lutz TA. Involvement of the extracellular-signal regulated kinase 1/2 signalling pathway in amylin’s eating inhibitory effect. Am J Physiol (Reg. Integr. Comp. Physiol.), 302, R340-R351, 2012.
5. Sharma V, Ling TW, Rewell S, Howells DW, Hare DL, Kourakis A, Wookey PJ. A novel population of α–smooth muscle actin –positive cells activated in a rat model of stroke: an analysis of the spatio-temporal distribution in response to ischaemia. J Cerebral Blood Flow Metab. 32(11), 2055-2065, 2012.
6. Bullock CM, Wookey PJ, Bennett A, Mobasheri A, Dickerson I, Kelly S. Increased peripheral calcitonin gene-related peptide receptor signalling drives mechanical sensitization of the joint in rat models of osteoarthritic pain. Arthritis & Rheumatology, 66(8), 2188-2200, 2014.
7. Gilabert-Oriol R, Weng A, Trautner A, Weise C, Schmid D, Bhargava C, Niesler N, Wookey PJ, Fuchs H, Thakur M. Combinatorial approach to increase efficacy of Cetuximab, Panitumumab and Trastuzumab by dianthin conjugation and co-application of SO1861. Biochem Pharmacol. 97 (3): 247-255, 2015.
8. Furness SGB, Hare DL, Kourakis A, Turnley AM, Wookey PJ. A novel ligand of calcitonin receptor reveals a potential new sensor that modulates programmed cell death. Cell Death Discovery 2016 Oct 10;2 16062.
9. Furness SGB, Liang Y-L, Nowell CJ, Halls ML, Wookey PJ, Dal Maso E, Inoue A, Christopoulos A, Wootten D, Sexton PM. Ligand-dependent modulation of G protein conformation alters drug efficacy. Cell 167:739-749, 2016.
10. Gilabert-Oriol R, Furness SGB, Stringer BW, Weng A, Fuchs H, Day BW, Kourakis A, Boyd AW, Hare DL, Thakur M, Johns TG, Wookey PJ. Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high grade glioma cell lines derived from glioblastoma. Cancer Immunol Immunother 66:1217-1228, 2017. Front cover feature.
11. Cappagli V, Potes CS, Ferreira LB, Tavares C, Eloy C, Elisei R, Sobrinho-Simoes M, Wookey PJ, Soares P. Calcitonin receptor expression in medullary thyroid carcinoma. PeerJ, doi:10.7717/peerj.3778, 2017.
12. Ostrovskaya A, Hick C, Hutchinson DS, Stringer BW, Wookey PJ, Wootten D, Sexton PM, Furness SGB. Expression and activity of the calcitonin receptor family in a sample of primary human high-grade gliomas. BMC Cancer, 2019, 19:157-168.
13. Gupta P, Furness SGB, Bittencourt L, Hare DL, Wookey PJ. Building the case for the calcitonin receptor as a viable target for the treatment of glioblastoma. Ther Adv Med Oncol, 12:1-15, 2020.
14. Wookey PJ, Gupta P, Bittencourt L, Cheung S, Furness SGB. Imaging calcitonin receptor activity (up-regulated during pre-apoptotic cell stress) in autophagy and apoptosis. Under review Cell Death Differentiation, April 2021.
15. Gupta P, Hare DL, Wookey PJ. Strategic development of an immunotoxin for the treatment of glioblastoma and other tumours expressing the calcitonin receptor. Special issue of the ADMET & DMPK New Therapeutic Modalities in Drug Discovery and Development: Insights & Opportunities. Eds Kansy M & Caron G. Under review, April 2021.