The Characterisation Of The Genetic Basis Of Paget's Disease Of Bone
Funder
National Health and Medical Research Council
Funding Amount
$266,402.00
Summary
Paget's disease is a bone disease in which the normal process of bone being formed and then broken down doesn't take place in the usual way. This results in bones that are enlarged, misshapen, dense and fragile. Paget's disease usually affects people of middle age or older. Although some cases are asymptomatic, Paget's disease is a major cause of bone pain and deformity. In Australia, 3-5% of people aged 40 years and over have Paget's disease. Paget's disease usually affects one of the long bone ....Paget's disease is a bone disease in which the normal process of bone being formed and then broken down doesn't take place in the usual way. This results in bones that are enlarged, misshapen, dense and fragile. Paget's disease usually affects people of middle age or older. Although some cases are asymptomatic, Paget's disease is a major cause of bone pain and deformity. In Australia, 3-5% of people aged 40 years and over have Paget's disease. Paget's disease usually affects one of the long bones in the leg, the pelvic bone, the skull or the spine. One of the most serious complications of Paget's disease is the devlopment of bone cancer. A genetic predisposition is an important factor in the development of Paget's disease. At least a quarter of patients with Paget's disease have at least one close relative with the same condition. Although it is more than 100 years since Sir James Paget first described Paget's disease, the underlying cause remains unknown. We have identified a large family with over 200 members in which there are 35 subjects affected by Paget's disease. The pattern of inheritance in this family is consistent with an autosomal dominant disorder. We have identified a discrete genetic region that is linked with the inheritance of Paget's disease in this family, indicating that a suscpetibility gene for Paget's disease lies in this region. The research program outlined in this application will refine this localisation and will define and characterise this susceptibility gene for Paget's disease. This research program is of great clinical relevance as the identification of the causative gene will open up new approaches for the treatment and prevention of this disease.Read moreRead less
Paget's Disease Of Bone Associated Sequestosome 1/p62 Mutations In Autophagy-mediated Processes And Bone Resorption
Funder
National Health and Medical Research Council
Funding Amount
$474,892.00
Summary
Paget’s disease of bone (PDB) is a common, chronic bone disorder characterized by focal lesions of increased bone degradation initiated by giant overactive osteoclasts. Subsequent bone formation is irregular, resulting in bones that are structurally weak. Genetic mutations are a common cause of PDB in Caucasians. Understanding the genetic mutations and their regulation on bone cells may lead to the discovery of a new drug target for the treatment of PDB.
A/Prof Thomas' Senior Research Fellowship will provide support for the continued development of a broad-based, national and international research program focused on the biology and clinical aspects of connective tissue tumours. A/Prof Thomas' career goals are to continue work in basic, translational and clinical research into these tumours which include osteosarcoma, liposarcoma, giant cell tumour of bone and the inherited risk of development of these neoplasms.
Pre-clinical Evaluation Of The LSD1 Inhibitor HCI-2509: Defining The Biomarkers Of Sensitivity And The Mechanisms Of Resistance
Funder
National Health and Medical Research Council
Funding Amount
$340,068.00
Summary
Despite aggressive multi-modal treatment strategies, limited progress in the treatment of Ewing sarcoma (paediatric bone malignancy), has been achieved over the past 30 years. As such, the advent of novel and targeted therapeutics with favourable efficacy/toxicity profiles are eagerly awaited. This proposal will investigate the therapeutic utility of LSD1 inhibition as a treatment for Ewing sarcoma and the underlying mechanisms of sensitivity/resistance to this unique agent.
A Phase II Study Of Continuous, Low-dose LBH 589 (Panobinostat) In Patients With Refractory Solid Tumors, Including CNS Tumors
Funder
National Health and Medical Research Council
Funding Amount
$811,512.00
Summary
Research done recently across three separate Australian laboratories has shown great promise with a new anti-cancer drug LBH589 used for cancers in children and young adults. We wish to start a clinical trial of LBH589 in children and young adult patients with cancer.
An International Whole Genome Study To Definitively Map Heritable Risk In Sarcomas
Funder
National Health and Medical Research Council
Funding Amount
$836,550.00
Summary
We want to understand why some people get sarcomas, and others do not. This is likely due to genetic causes, because these cancers affect the young. We now have the tools to address this question, and have created the largest and best characterised study of sarcoma families in the world upon which to apply these tools. This project will create an enduring foundation for research into the genetic basis of sarcomas for the next 20 years.
I am interested in using new technologies to understand how and why cancers develop. I am focused on sarcomas, cancers that particularly affect the young, but rare and neglected cancers more generally. I want to use the knowledge we can gain from basic research to develop new models of clinical care, that will reduce the morbidity and mortality from these deadly diseases.
Identification Of Novel Familial Patterns And Genotypes Associated With Inherited Risk In Adult-onset Sarcoma: The International Sarcoma Kindred Study
Funder
National Health and Medical Research Council
Funding Amount
$552,855.00
Summary
Inherited genetic risk is important in cancers that affect the young. The International Sarcoma Kindred Study (ISKS) is the world's first prospective study aiming to better understand how sarcomas can be inherited in families, and the genes that cause sarcomas. The ISKS is a multinational study led from Australia, with partners in the US, Europe and India, and aims to recruit over 3000 families affected by sarcoma.
V-ATPases Subunit D2 Is Critical For Acdification And Bone Resorption.
Funder
National Health and Medical Research Council
Funding Amount
$531,264.00
Summary
Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, aci ....Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, acidification and bone resorption. Understanding the molecular and cellular mechanisms by which V-ATPases regulate osteoclast function and bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone disordersRead moreRead less