Evaluation Of A Novel Antiosteolytic Agent: Potential In Breast-to-bone Metastasis And Mechanism Of Action
Funder
National Health and Medical Research Council
Funding Amount
$352,583.00
Summary
In breast cancer the spread of cancer (metastasis) to bone occurs frequently and causes significant problems including pain, fracture, immobility and paralysis. We have recently discovered that a drug, widely used in Japan and Korea for skin disorders, inhibits breast cancer growth in bone using animal model systems of this disease. This is a very exciting and novel finding. We will further investigate the potential of this drug and identify precisely how it works at the molecular level.
Integrin Beta3 As A Therapeutic Target For Breast Cancer Metastasis To Bone
Funder
National Health and Medical Research Council
Funding Amount
$431,675.00
Summary
There are limited effective treatments for advanced breast cancer. The project investigates the role of a protein called integrin beta3 in the spread of breast tumours to bone, the most common site of secondary tumour formation (metastasis) in breast cancer patients. We will determine if the presence of integrin beta3 in breast tumours identifies patients at risk of developing bone metastases and test novel drugs against integrin beta3 in mice.
Contribution Of Tumour And Stroma Derived Cysteine Cathepsins To Breast Cancer Metastasis To Bone
Funder
National Health and Medical Research Council
Funding Amount
$447,094.00
Summary
Breast cancer is a serious clinical problem once the disease spreads to distant tissues such as lung and bone. We have identified a group of genes called the cysteine cathepsin proteases that have increased activity in breast cancers that spread to bone and we have shown this in a mouse model and also in human cancer. We will investigate the contribution of these genes to invasion and test whether inhibiting specific cathepsins can prevent spread of breast cancer to bone in our mouse model .
There are a number of important medical conditions that are characterised by a loss of bone. These include osteoporosis, cancer-induced bone loss, and the bone loss that causes loosening of orthopaedic prostheses. Bone loss is understood to be due to an excess of bone resorption by osteoclasts in relation to bone formation. Understanding of the regulation of osteoclast formation and activity has increased greatly in the last few years, but important questions remain. In particular, more informat ....There are a number of important medical conditions that are characterised by a loss of bone. These include osteoporosis, cancer-induced bone loss, and the bone loss that causes loosening of orthopaedic prostheses. Bone loss is understood to be due to an excess of bone resorption by osteoclasts in relation to bone formation. Understanding of the regulation of osteoclast formation and activity has increased greatly in the last few years, but important questions remain. In particular, more information is needed about the process of human osteoclast formation. We have devised a novel cell culture model of human osteoclast formation, in which osteoclast precursor cells mature into osteoclasts under the influence of human osteoblast cells. The importance of this model is that it allows us, for the first time, to investigate the role, and the potential relevance in human disease, of agents that positively and negatively affect osteoclasts. We intend also to use this model to study the way in which cancer cells in bone cause bone loss, as well as the involvement of cells of the immune system in osteoclast formation, in normal bone and in inflammatory conditions.Read moreRead less
Targeting The Vicious Cycle Of Cancer-induced Bone Disease With TRAIL And Bisphosphonates
Funder
National Health and Medical Research Council
Funding Amount
$443,696.00
Summary
The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly ....The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly targeting cancer cells within bone, and with no evidence of toxic side effects to normal tissues. Death receptor targeting by TRAIL, and bisphosphonates induce cancer cell apoptosis through different but overlapping signaling pathways. Therefore, combination of the two approaches may facilitate killing of tumour cells that resist death induction through either one of the pathways. Combination therapy may also reduce the probability of acquired resistance to either therapy. We propose that a combinatorial approach, using bisphosphonates to selectively target osteoclasts and TRAIL to selectively target cancer cells, would be an ideal therapeutic and safe approach to delay, slow or completely eliminate growth of cancer within bone.Read moreRead less
The Molecular And Cellular Mechanisms Responsible For The Skeletal Complications Associated With Multiple Myeloma.
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Multiple myeloma is an incurable disease of the antibody-producing B cell. Patients with MM, nearly always present with bone pain and unexplained bone fractures. These fractures are caused by the cancerous MM B cells, which are found in large numbers in discrete pockets throughout the bone marrow, close to the inner bone surface. The way that the cancerous B cells cause the local bone lesions is thought to be through the heightened activation of recruitment of osteoclasts. Osteoclasts are cells ....Multiple myeloma is an incurable disease of the antibody-producing B cell. Patients with MM, nearly always present with bone pain and unexplained bone fractures. These fractures are caused by the cancerous MM B cells, which are found in large numbers in discrete pockets throughout the bone marrow, close to the inner bone surface. The way that the cancerous B cells cause the local bone lesions is thought to be through the heightened activation of recruitment of osteoclasts. Osteoclasts are cells which normally, in a controlled manner, resorb bone as part of the ongoing process of new bone formation. We propose that myeloma cells, which exhibit characteristics of osteoclasts, home to sites in the bone marrow and initiate this bone breakdown and furthermore secrete factors required for osteoclast maturation and activity. We believe that these molecules include the recently defined molecule, termed osteoclast differentiation factor, which is normally produced by bone-producing cells known as osteoblasts. Moreover, we feel that myeloma B cells alter the function of osteoblast cells, which results in a decrease in bone formation. Finally, we propose that this disease and its associated bone defects originate from changes in the expression of a number of genes. The results from theses studies should provide a greater understanding of the way in which this B cell cancer originates and how it causes bone defects. This will lead to the development of better treatments to improve the survival of patients with MM, and will lead to therapies to prevent the associated bone complications.Read moreRead less
The Role Of CXCL12 (SDF-1)/CXCR4 In Pathological Angiogenesis And Osteolytic Bone Disease In Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$665,896.00
Summary
Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine mol ....Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine molecule called CXCL12 which acts as a calling card for plasma cells to leave the lymph node and migrate to the BM. Once within the BM, the cells rapidly grow in response to BM-derived growth factors. This rapid growth causes a depletion in oxygen availability within the tumour and it becomes hypoxic. In response to this hypoxia, the tumour expresses a gene called hypoxia-inducible factor-1 (HIF-1) which regulates the expression of many proteins, including the chemokine CXCL12. Our studies show that the abnormal expression of CXCL12 by the plasma cells acts to promote blood vessel formation within the tumour, which in turn leads to greater tumour growth. In addition, our studies suggest that abnormal CXCL12 expression also promotes the recruitment and activation of large numbers of osteoclast (OC) precursors form the peripheral blood. OC are cells which normally remove unwanted or damaged bone. This proposal will study the interplay between HIF and CXCL12 in the establishment and development of MM and the associated bone destruction.Read moreRead less
Nutrition And Rehabilitation In Advanced Cancer Patients
Funder
National Health and Medical Research Council
Funding Amount
$225,991.00
Summary
This preliminary project aims to evaluate associations between cancer cachexia, psychosocial factors and cytokine levels in blood. The final decline of most patients with advanced cancer is associated with the cancer cachexia syndrome, triggered in part by cytokine release. Measuring cytokines may enable identification of patients about to enter this final stage. Further, factors like mood and social support appear to alter cytokine levels. The associations established by this study may point to ....This preliminary project aims to evaluate associations between cancer cachexia, psychosocial factors and cytokine levels in blood. The final decline of most patients with advanced cancer is associated with the cancer cachexia syndrome, triggered in part by cytokine release. Measuring cytokines may enable identification of patients about to enter this final stage. Further, factors like mood and social support appear to alter cytokine levels. The associations established by this study may point to treatment options that can delay the terminal phase while improving quality of life.Read moreRead less
Molecular And Cellular Mechanisms Of Skeletal Disease Mediated By Plasma Cell Dyscrasias
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in add ....Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in addition to other skeletal tumors, and our strong background in both OC and osteoblast biology. MM is a hematological malignancy characterised by plasma cell dyscrasia, which typically causes progressive and severe destruction of the skeleton, with accompanying bone pain, fracture and finally, hypercalcaemia of malignancy. Two related diseases, MGUS and POEMS, have been chosen for study because of their key similarities and differences with MM, and are likely to shed new light on the activities of MM in the bone. MGUS does not cause identifiable bone defects, whereas POEMS can give rise to both osteolytic and osteosclerotic lesions. Comparison of these conditions will uniquely enable us to examine why these seemingly related neoplasms are able to mediate disparate skeletal disease states. Primarily, and since there are few curative therapies for MM at present, our proposed studies are designed to identify targets for therapy that will treat the most serious manifestation of this disease, namely its destruction of bone tissue.Read moreRead less
Is Hypoxia Inducible Factor 2 The Trigger Of The Angiogenic Switch And A Driver Of Disease Progression In Myeloma?
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Multiple myeloma (MM) is a fatal cancer of plasma cells (PC). PC migrate to the bone marrow, which compared with other organs is low in oxygen (hypoxic). In response to this hypoxia, the cancer cells turn on the expression of genes called hypoxia-inducible factors (HIF). HIFs activate the expression of genes that encourage blood vessel formation, which in turn stimulates greater tumour growth and disease progression. This proposal will investigate the role of HIFs in the progression of MM.