Addressing the importance of CXC-chemokines in modulating bone colonisation and microenvironment-mediated resistance of PTEN-deficient prostate cancer to enzalutamide.
Background: Patients with advanced castrate-resistant prostate cancer (CRPC) invariably have extensive metastasis to the bone. Use of androgen deprivation therapy (ADT) e.g. abiraterone-acetate or enzalutamide only extends the median overall survival of CRPC patients by less than 6 months (1). Loss of the tumour suppressor gene PTEN and activation of the phosphatidyl-inositol-3 kinase (PI3K) pathway is prevalent in CRPC (2). PTEN-deficient CRPC patients have poorer prognosis and abiraterone has reduced clinical activity in this cohort of patients, characterized by a shorter time-to-progression and lower response rates (3). We have observed that PTEN-loss results in a selective and marked elevation in the expression and secretion of the CXC- chemokines CXCL8 (Interleukin-8) and CXCL1 in human tumour cell lines and transgenic mouse models (4) and cancer biopsies (unpublished). While the elevation in autocrine CXCL8 signalling sustains the survival and proliferation of PTEN-deficient tumour cells (4), reducing their sensitivity to AR-targeted therapeutics (5), the paracrine effects of CXC-chemokines impact on myeloid-derived innate immune cells (6,7), vascular endothelial cells and stromal fibroblasts within the tumour microenvironment (8). The influence of this chemokine signalling upon response to ADT within the microenvironment of the bone has not been studied to date.
Aims and Hypothesis:
Hypothesis: Tumour-derived CXC-chemokine signalling modulates colonisation, tumour outgrowth and drug resistance of PTEN-deficient metastatic CRPC within the bone
Aim 1. Exploit a human bone scaffold model to demonstrate the functional importance of CXC-chemokines in regulating osteoclast/osteoblast function in response to PTEN-deficient CRPC.
Aim 2: Evaluate how CXC-chemokine signalling affects the response of PTEN-deficient prostate cancer cells to ADT using the human bone scaffold model in vivo.
Research Plan: We will utilise the engineered bone microenvironment developed by co-applicant Bock (9) to study the colonisation of two isogenic PTEN-expressing and PTEN-deficient prostate cancer lines of LNCaP and PC3 lineage in vivo. Tumour engraftment rates, lesion growth and effects on bone morphology, including osteoblast/osteoclast differentiation will be analysed by μCT imaging and IHC analysis. The importance of tumour-derived chemokine signalling on these parameters will be evaluated by administration of a CXCR1/CXCR2-targeting pepducin, a CXCR2 antagonist AZD5069 (which we are using in a clinical trial in CRPC) and a neutralizing antibody to CXCL8. Furthermore, we will use a multi-colour FACS analysis protocol to characterise myeloid lineage within these engrafted tumours. Finally, we will determine how administration of enzalutamide (MDV3100) or abiraterone-acetate affects the morphological and molecular composition of the tumour/bone lesion and how concurrent inhibition of CXC-chemokine signalling modulates the therapeutic response to ADT. Excised tumours will be subjected to extensive characterisation of osteoclast/osteoblast biomarkers by C-ISH/IHC and where tissue levels make it possible, by the use of CyTOF/single cell genomic profiling (external collaboration Alex Swarbrick, Garvan Institute).
Clinical and Commercial Significance: The applicant is co-investigator of an Investigator-Initiated Clinical Trial of AZD5069 (AstraZeneca) in combination with Enzalutamide in CRPC. This will add further mechanistic understanding to explain any clinical benefits observed in enrolled patients. Moreover, the research will derive new IP to potentially develop new commercial opportunity and/or progress licencing of current patents held by the primary applicant .
Australian and International applicants are eligible to apply. Selected candidates will be required to apply to competitive scholarships through the Faculty of Health, QUT and will be assisted with their applications. PhD scholarships are approx. $(AUD) 27 596pa for 3.5 years full time study. PhD applicants must have completed or be expected to complete a first class hons or a Masters degree (>25% research).
Demonstrated research excellence, such as academic awards, presentations and peer-reviewed publications are desirable, but not essential.
International students must meet entry requirements for QUT https://www.qut.edu.au/research/study-with-us/how-to-apply#Step_1_Entry_requirements.
For more information about scholarships and postgraduate study at QUT https://www.qut.edu.au/research/study-with-us.