Molecular Imaging As A Critical Tool In Discovery Of The Basis Of Tumour Heterogeneity And Developing Novel Therapies To Overcome Therapeutic Resistance
Funder
National Health and Medical Research Council
Funding Amount
$467,961.00
Summary
Determining treatment options for cancer currently relies on the size and extent of tumour deposits on imaging, combined with a biopsy. However, this approach fails to recognise the ability of tumours to evolve components that are, or become, resistant to treatment. My laboratory uses advanced molecular imaging, targeted biopsies, animal models and genetic analysis to detect and understand the basis of such resistance and thereby develop new, targeted treatments to improve patient outcomes.
Identifying The Pathological Mechanism Of Polyalanine Expansion Mutations In The X-linked Hypopituitarism Gene SOX3
Funder
National Health and Medical Research Council
Funding Amount
$402,846.00
Summary
Mental retardation (MR) is a debilitating disorder which affects 1-3% of the population. In many cases, MR results from changes (mutations) in genes which regulate the development of the brain before birth. We are studying families with an inherited form of MR termed X-linked Hypopituitarism (XH) in which only boys are affected. In addition to intellectual disability, boys with XH also have poor pituitary function resulting in short stature and slow metabolism. In severe cases, where the pituita ....Mental retardation (MR) is a debilitating disorder which affects 1-3% of the population. In many cases, MR results from changes (mutations) in genes which regulate the development of the brain before birth. We are studying families with an inherited form of MR termed X-linked Hypopituitarism (XH) in which only boys are affected. In addition to intellectual disability, boys with XH also have poor pituitary function resulting in short stature and slow metabolism. In severe cases, where the pituitary has failed to form completely, these babies are extremely ill and in some instances do not survive. We have previously shown that XH is due to an unusual change in the SOX3 gene in which the number of consecutive alanine residues is increased above a critical threshold (polyalanine expansion mutations). Similar mutations have recently been identified in several other genes that also cause severe birth defects. However, little is currently known about how polyalanine expansion mutations cause these disorders. The overall aim of this proposal is generate a mouse model for this disorder. Analysis of these mice will help us to answer many unresolved questions about this disorder including: How does the mutant protein cause this disorder? Which parts of the brain and pituitary are affected and how is their function altered? How does the mutant protein affect other genes and proteins in the cell? Ultimately, we hope that this mouse model will help us to develop new and improved therapies for XH and other disorders that are caused by alanine expansion mutations.Read moreRead less
HEREDITARY ENDOCRINE CANCER: A MODEL BASED ON PHAEOCHROMOCYTOMA- PARAGANGLIOMA SYNDROMES
Funder
National Health and Medical Research Council
Funding Amount
$875,894.00
Summary
Phaeochromocytomas and paragangliomas are tumours remarkable for their very high heritability. They have a high burden of disease themselves, and their associated hereditary syndromes include risks for other malignancies. Our study will rationalize the pathological approach to diagnosing these hereditary syndromes, find new therapeutic targets for metastatic disease, and provide a template for other cancers with high heritable component.
The Role Of The Cytokine Receptor Gp130 In Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Prostate cancer is a leading cause of cancer deaths in men in the Western world. Neuroendocrine cells may play an important role in the development of these cancers, but their biology is essentially uncharacterized. Activation of the cell-bound protein gp130 results in neuroendocrine differentiation, growth and chemotherapeutic drug resistance of prostate cancer cells. We will use gp130-dependent differentiation to understand how neuroendocrine cells influence normal and cancerous prostate cells ....Prostate cancer is a leading cause of cancer deaths in men in the Western world. Neuroendocrine cells may play an important role in the development of these cancers, but their biology is essentially uncharacterized. Activation of the cell-bound protein gp130 results in neuroendocrine differentiation, growth and chemotherapeutic drug resistance of prostate cancer cells. We will use gp130-dependent differentiation to understand how neuroendocrine cells influence normal and cancerous prostate cells, and to identify neuroendocrine-cell specific genes that may be of diagnostic or therapeutic benefit in prostate cancer. Gp130 can be activated by a group of hormones called the interleukin-6 type cytokines in the presence of certain cell-bound proteins (receptors). If these receptors are inappropriately expressed in the prostate, inappropriate activation of gp130 could occur resulting in prostate cancer cell growth or neuroendocrine differentiation. If we can determine that these receptors are expressed in prostate cancer, but not in non-cancerous prostate, this would have diagnostic or therapeutic benefit.Read moreRead less
Novel Interactions Between GnRH Receptor And E2F4 Transcription Factor.
Funder
National Health and Medical Research Council
Funding Amount
$462,750.00
Summary
The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reducti ....The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reduction of gonadotropin secretion and consequent decline in steroid production. As the majority of tumours treated with GnRH analogues are hormone-dependent, this starves the tumour of the steroid support required for growth. However, the concept of a direct anti-tumour effect of GnRH, independent of the pituitary-gonadal axis, is supported by the in vitro inhibition of both cell growth and DNA synthesis in a number of tumour cell lines. Despite the wide use of GnRH analogues, the molecular basis of the growth inhibitory effects resulting from the activation of this receptor is not fully understood. Unravelling the protein interactions underlying receptor-mediated signalling events will provide valuable information towards understanding of receptor function in vivo. We have identified a novel interaction involving the GnRHR and E2F4, a transcription factor involved in suppression of the transcription of genes involved in cell cycle progression. In addition, over 80% of E2F4 knockout mice are sterile. Owing to the role of the GnRHR in the reproductive pathway we are interested in determining whether the GnRHR-E2F4 interaction has an influence on the development of the hypothalamic-pituitary-gonadal axis, hence affecting reproductive capacity. The interaction identified and studied in this proposal has implications for the treatment of reproductive tumours, such as those of the breast and prostate, and understanding the development of the hypothalamic-pituitary-gonadal axis.Read moreRead less
NABNEC: A Randomised Phase II Study Of Nab-paclitaxel In Combination With Carboplatin As First Line Treatment Of Gastrointestinal Neuroendocrine Carcinomas
Funder
National Health and Medical Research Council
Funding Amount
$1,393,083.00
Summary
Patients with advanced neuroendocrine carcinomas (NEC) have one of the poorest cancer outcomes. So far, no randomised trials have been done to confirm NEC treatment. Current NEC chemotherapy is etoposide & carboplatin (EC), based on lung cancer trials. The NABNEC study will use a new drug, nab-paclitaxel, with carboplatin or EC, collect PET scan, tumour & blood samples result to help understand how treatment works and to ultimately improve NEC patients’ health and progress future research.