The DRMCRL has expertise in molecular, translational and clinical research and runs several internationally recognised programs aimed at ultimately improving the clinical management of patients with prostate and breast cancer.
Research at the DRMCRL focuses on understanding how androgenic hormones (such as testosterone) and the androgen receptor (AR) play a role in the growth of prostate cancer and breast cancer, which are leading causes of cancer-related death for Australian men and women, respectively. The research program in the DRMCRL aims to understand at the molecular and cellular level how breast and prostate cancers grow and escape from hormonal control. This research is essential to develop new strategies for the treatment of both of these cancers that are more specific and more effective. Growth of both cancers is initially controlled by sex hormones (estrogens and androgens in women and men respectively).Current treatments work either by inhibiting the production of estrogens and androgens or by blocking their action in the cancer cells. Unfortunately, not all patients continue to respond to these hormonal treatments, and therefore alternative therapies are urgently required.
A major research focus at the DRMCRL is the development of novel androgen receptor (AR)-targeted therapies for both breast and prostate cancer. In prostate cancer, this involves the generation of drugs to inhibit aberrant forms of the AR that are unresponsive to conventional androgen deprivation therapies. In the case of breast cancer, our research has led to new strategies to activate the AR and inhibit the growth of tumours that are driven by the estrogen receptor. Professor Tilley’s laboratory has also pioneered the development of unique preclinical models of human breast and prostate cancers, especially ex vivo culture of human solid tumours, to facilitate translation of the breast and prostate cancer research into the clinic.
- Prostate Cancer
Head, Dr Luke Selth
Contact: +61 8 8222 3618 or firstname.lastname@example.org
Prostate cancer will affect approximately 1:7 Australian men and results in >3,000 deaths per year in Australia alone. The growth of prostate cancer (PCa) is exquisitely dependent on male sex hormones, androgens, and the transcription factor that mediates androgen function, the androgen receptor (AR). Thus, the primary treatment option for men with metastatic prostate cancer is androgen deprivation therapy, which inhibits AR activity. While most men initially respond to this therapy, their cancer inevitably returns in an incurable and lethal form termed castration resistant prostate cancer (CRPC).
To improve outcomes for men with this disease, the Prostate Cancer Research Group at DRMCRL has the following overarching goals:
1) To characterise the mechanisms by which tumours become resistant to AR-targeted therapies;
2) To better understand how tumours metastasise from the prostate;
3) To use these novel mechanistic insights into therapy resistance and metastasis to develop new drugs that could save lives.
Our research programs use a unique assortment of model systems (patient-derived xenografts, patient-derived tumour material cultured in the lab, and cell lines) and contemporary ‘omic’ techniques to provide unprecedented insight into the mechanisms of therapy resistance and metastasis. We also collaborate with an outstanding assortment of international and national collaborators to facilitate our research.
The Prostate Cancer Research Group is focussed on impacting patient outcomes: to this end, we collaborate with leading clinical researchers locally and worldwide (e.g. UT Southwestern, USA; British Columbia Cancer Agency, Canada; University of Washington, USA).
The Prostate Cancer Research Group is funded in part by a major international and interdisciplinary grant from the US Department of Defence, the first of its kind awarded to an Australian group. The Group recently received a 4 year NHMRC Project Grant commencing in January 2017.
More information on two key ongoing projects is provided below:
Dual targeting of the androgen receptor for effective and durable control of lethal prostate cancer (current funding from NHMRC and the US Department of Defense)
All approved AR-directed therapies target the binding of androgens to the AR. However, this strategy alone cannot provide durable disease control and we propose that drug development efforts must shift to a non-ligand-centric focus.
In this project, we aim to develop a new drug that targets a part of the AR unrelated to its androgen binding function. We propose that such a drug would be used in combination with current therapies to increase anti-tumour efficacy as well as to delay or prevent treatment resistance. This project has high potential to improve survival outcomes for men with prostate cancer.
MicroRNA as regulators and biomarkers of prostate cancer metastasis (current funding from NHRMC)
MicroRNAs are small, non-coding RNAs that act to fine-tune gene expression in the cell and play key roles in all normal physiological processes. Given the critical function of miRNAs, it is not surprising that aberrant expression of these molecules is a common feature of many cancers, including prostate cancer.
In this project, we aim to identify miRNAs associated with prostate cancer metastasis. Such miRNAs could have clinical utility as: i) prognostic biomarkers, which are urgently required to guide treatment decision-making; ii) therapeutic targets, to suppress prostate cancer metastasis.
Das R, Gregory PA, Fernandes RC, Denis I, Wang Q, Townley SL, Zhao S, Hanson AR, Pickering MA, Armstrong HK, Lokman NA, Ebrahimie E, Davicioni E, Jenkins RB, Karnes RJ, Ross AE, Den RB, Klein E, Chi KN, Ramshaw HS, Williams ED, Zoubeidi A, Goodall GJ, Feng FY, Butler LM, Tilley WD, Selth LA. MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2. Cancer Res. Accepted Nov 2016.
Selth LA, Das R, Townley SL, Coutinho I, Hanson AR, Centenera MM, Stylianou N, Sweeney K, Soekmadji C, Jovanovic L, Nelson CC, Zoubeidi A, Butler LM, Goodall GJ, Hollier BG, Gregory PA and Tilley WD. A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer. Oncogene. 2016. (In Press June 2016)
Asim M, Massie CE, Orafidiya F, Pértega-Gomes N, Warren AY, Esmaeili M, Selth LA, Zecchini HI, Luko K, Qureshi A, Baridi A, Menon S, Madhu B, Escriu C, Lyons S, Vowler S, Zecchini VR, Shaw G, Hessenkemper W, Russell R, Mohammed H, Stefanos N, Lynch AG, Grigorenko E, D’Santos C, Taylor C, Lamb A, Sriranjan R, Yang J, Stark R, Dehm SM, Rennie PS, Carroll JS, Griffiths JR, Tavaré S, Mills IG, McEwan IJ, Baniahmad A, Tilley WD and Neal DE. Choline kinase alpha is an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target. J Natl Cancer Inst. 2015 Dec 11;108(5). pii: djv371. Print 2016 May.
Raj GV, Selth LA, Day TK and Tilley WD. Evolution of androgen deprivation therapy. Cancer Forum. Vol 39; Issue No 3. November 2015.
Chan SC, Selth LA, Li Y, Nyquist MD, Miao L, Bradner JE, Raj GV, Tilley WD, and Dehm SM. Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Research. Apr 23. 2015. [Epub ahead of print]
Das R, Gregory PA, Hollier BG, Tilley WD, Selth LA. Epithelial plasticity in prostate cancer: principles and clinical perspectives. Trends Mol Med. Nov;20(11):643-51. 2014.
Robinson JJL, Hickey TE, Warren AY, Vowler SL, Carroll T, Lamb AD, Papoutsoglou N, Neal DE, Tilley WD, Carroll JS. Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype. Oncogene. Dec 11;33(50):5666-74. 2014.
Selth LA, Townley SL, Bert AG, Stricker PD, Sutherland PD, Horvath LG, Goodall GJ, Butler LM, Tilley WD. Circulating microRNAs predict biochemical recurrence in prostate cancer patients. Br J Cancer. 6;109(3):641-50. 2013.
Ravindranathan P, Lee T-K, Yang L, Centenera MM, Butler LM, Tilley WD, Hsieh J-T, Ahn J-M, Raj GV. Peptidomimetic targeting of critical androgen receptor-coregulator interactions in prostate cancer. Nat Commun. 4:1923, 2013.
Centenera MM, Gillis JL, Hanson A, Jindal S, Taylor RA, Risbridger G, Sutherland PD, Scher HI, Raj GV, Knudsen KE, Yeadon T, Tilley WD, Butler LM. Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. Clinical Cancer Research. 18:3562-3570, 2012.
Thompson VC, Day TK, Selth LA, Han G, Bianco-Miotto T, Thomas M, Buchanan G, Scher HI, Greenberg NM, APCBio, Butler LM, Tilley WD. A gene signature identified using a mouse model of androgen receptor-dependent prostate cancer predicts biochemical relapse in human disease. Int J Cancer, 131:662-672, 2012.
Selth LA, Townley S, Gillis JL, Ochnik A, Murti K, Macfarlane RJ, Chi KM, Tilley WD, Butler LM. Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease. Int J Cancer, 131:652-61, 2012.
Risbridger G, Davis ID, Birrell SN, Tilley WD. Breast and prostate cancer: more similar than different. Nat Rev Cancer10 (3):205-12, 2010.
- Breast Cancer
Head, Dr Theresa Hickey
Contact: +61 8 8222 3225 or email@example.com
At least 70% of breast cancers are driven by the sex hormone estrogen, which acts via the estrogen receptor alpha (ERα). Therapies that target ERα have effectively increased survival of women diagnosed with ERα+ disease but resistance to current therapeutics invariably develops. Therefore, alternative strategies to treat women with ERα+ breast cancer, particularly those resistant to ERα targeting drugs, are a clinical imperative.
The Breast Cancer Research Group has been exploring crosstalk between the estrogen receptor (ER) and AR, or more recently, with the progesterone receptor (PR), to explain heterogeneity of response to target therapies with view to forging new possibilities for therapeutic targeting that will improve disease outcomes. As all three receptors have historically been targeted in the treatment of breast cancer, a wide range of old and new generation drugs are available, offering a unique opportunity for drug repurposing and a faster track to clinical translation compared to new drugs that have never been tested in people.
These new strategies not only have promise for controlling tumour growth, but may also improve the patient’s quality of life by circumventing deleterious side-effects of current therapies. In addition, this group is working on a new drug that may be useful in the treatment of women with tumours not driven by the estrogen hormone receptor, a very aggressive form of breast cancer.
Our program is well funded by grants from the National Health and Medical Research Council (NHMRC), Cancer Australia and the National Breast Cancer Foundation, and was successfully awarded 4 year $1 million NHMRC Project Grant commencing in January 2017.
Key projects ongoing in the Breast Cancer Research Group include:
Selective activation of androgen receptor to treat estrogen receptor positive breast cancer. (Current funding by the NHMRC)Androgens, acting via the androgen receptor (AR), a protein related to the estrogen receptor (ER), are natural inhibitors of estrogen-stimulated breast cancer growth. Although androgens are commonly considered to be male hormones, females produce androgens throughout their life. AR typically is present in the same cells as ER, resulting in estrogen and androgen hormones exerting opposing forces on the growth of ER-positive breast cancers, with estrogen having growth promoting and androgens protective effects.
The goals of this project are to 1) investigate how stimulation of the androgen receptor (AR) by a synthetic androgen which has been shown to be well tolerated by women, inhibits the growth of estrogen-sensitive breast tumours, and 2) develop and evaluate proteins identified as being potential biomarkers of response to androgenic therapies.
The clinical significance of sex hormone crosstalk in estrogen receptor positive breast cancer. (Current funding by the NHMRC)
Breast cancer is mainly a disease in which the sex hormone estrogen stimulates uncontrolled growth. We have recently discovered that other sex hormones, including progesterone and androgen, can redirect the actions of estrogen in breast cancers to halt growth or make a tumour disappear. This study will examine the complex interaction between all three sex hormones to develop new, more effective strategies for treating breast cancer.
For the first time, we will investigate the three-way interplay between ERα, PR and AR in contemporary models of breast cancer including patient derived xenografts and ex-vivo cultured primary tumour tissues. The ultimate goal is to determine clinical scenarios in which PR, AR or both could be optimally therapeutically targeted to treat ERα+ breast cancer, particularly disease resistant to current ERα targeting drugs.
Carroll JS, Hickey TE, Tarulli GA, Williams M and Tilley WD. Deciphering the divergent roles of progestogens in breast cancer. Nature Reviews Cancer. In Press Nov 2016.
Singhal H, Greene ME, Tarulli G, Zarnke AL, Bourgo RJ, Laine M, Chang Y-F, Ma S, Dembo AG, Raj GV, Hickey TE, Tilley WD and Greene GL. Genomic Agonism and Phenotypic Antagonism between Estrogen and Progesterone Receptors in Breast Cancer. Science Advances. (Accepted 31 May 2016)
Castro MAA, de Santiago I, Campbell TM, Vaughn C, Hickey TE, Ross E, Tilley WD, Markowetz F, Ponder BAJ, Meyer KB. Regulators of genetic risk of breast cancer identified by integrative network analysis. Nat Genet. 2016 Jan;48(1):12-21. Epub 2015 Nov 30
Hickey TE, Irvine CM, Dvinge H, Tarulli GA, Hanson AR, Ryan NK, Pickering MA, Birrell SN, Hu DG, Mackenzie PI, Russell R, Caldas C, Raj GV, Dehm SM, Plymate SR, Bradley RK, Tilley WD*, Selth LA*. (*Co-corresponding authors). Expression of androgen receptor splice variants in clinical breast cancers. Oncotarget. 2015. Nov 7.
Mohammed H, Russell A, Stark R, Rueda OM, Tarulli GA, Hickey TE, Saadi A, Menon S, Hadfield J, Pugh M, Raj GV, Brown GD, D'Santos C, Robinson JLL, Perou CM, Serandour AAA, Stingl J, Caldas C, Tilley WD* and Carroll JS*. (Co-corresponding authors). Progesterone receptor modulates estrogen receptor-α action in breast cancer. Nature. In Press July 8 2015.
Hilton HN, Doan TB, Graham JD, Oakes SR, Silvestri A, Santucci N, Kantimm S, Huschtscha LI, Ormandy CJ, Funder JW, Simpson ER, Kuczek ES, Leedman PJ, Tilley WD, Fuller PJ, Muscat GE, Clarke CL. Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease. Oncotarget. Sep 30;5(18):8651-64. 2014
Tarulli GA, Butler LM, Tilley WD, Hickey TE. Bringing androgens up a NOTCH in breast cancer. Endocr Relat Cancer. Aug;21(4):T183-202. 2014.
Doan TB, Eriksson NA, Graham D, Funder JW, Simpson ER, Kuczek ES, Clyne C, Leedman PJ, Tilley WD, Fuller PJ, Muscat GE, Clarke CL. Breast cancer prognosis predicted by nuclear receptor-coregulator networks. Mol Oncol. Jul;8(5):998-1013. 2014.
Moore NL, Buchanan G, Harris J, Selth LA, Bianco-Miotto T, Hanson AR, Birrell S, Butler LM, Hickey T, Tilley WD. An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity. Endocr Relat Cancer. 19(4):599-613, 2012.
Robinson JL, Macarthur S, Ross-Innes CS, Tilley WD, Neal DE, Mills IG, Carroll JS.Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 30:3019-27, 2011.