Mechanisms Of CD44v2-10-mediated Tumour Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to investigate the mechanisms by which specificdomains in the CD44 variants actually cause tumour spread. Understanding of the various mechanisms involved in tumour spread, and targeting the functions of the domains has enormous potential as a therapeutic target.Read moreRead less
CD44v3 And V6 As Targets For Anti-metastasis Therapy
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to develop a number of specific methods of targeting CD44 in order to prevent the spread of cancer. We have and will develop additional agents directed to these key domains in CD44. Targeting these domains has great potential as metastasis therapy.Read moreRead less
Childhood Lymphatic Malformations: The Mechanism Of Rapamycin In Controlling Growth
Funder
National Health and Medical Research Council
Funding Amount
$456,579.00
Summary
Lymphatic malformations (also known as cystic hygromas or lymphangiomas) cause deformity and pain which can last lifelong. Current treatments help but do not fix all the symptoms. Rapamycin, a drug used for many years in children and adults with kidney transplants, may be useful for treating children with lymphatic malformations. We aim to understand how the drug works on the cells of lymphatic malformations in culture and in an animal model, to develop new and more effective treatments.
Until recently, cancer of the oesophagus was a very uncommon tumour in Australia and other western populations. However during the past three decades, there have been very large increases in the incidence of this disease. Indeed, rates of oesophageal cancer have risen faster than any other cancer in the United Statesand similar dramatic increases in incidence have been observed in Europe and Australia. With increasing population prevalence of the causes of cancer of the oesophagus in western soc ....Until recently, cancer of the oesophagus was a very uncommon tumour in Australia and other western populations. However during the past three decades, there have been very large increases in the incidence of this disease. Indeed, rates of oesophageal cancer have risen faster than any other cancer in the United Statesand similar dramatic increases in incidence have been observed in Europe and Australia. With increasing population prevalence of the causes of cancer of the oesophagus in western societies (namely acid reflux, obesity and poor diet), there are strong grounds for predicting that incidence will continue to rise, and that oesophageal cancer will constitute an increasingly large burden on society. Unfortunately, treatment options are limited, survival is often short, and there is no way of identifying which tumours will respond to therapy. This proposal will collect treatment and health outcomes data for a population-based cohort of patients with oesophageal cancer. The goal is to identify prognostic and predictive markers to aid patients and clinicians when making treatment decisions, as now exist for breast cancer. Such markers may also serve as novel targets for therapy. The proposed study builds upon the platform of the Australian Cancer Study [ACS], one of the world's largest studies of oesophageal cancer. This represents a unique opportunity to investigate a pressing clinical problem by building upon a study of acknowledged international importance.Read moreRead less
A Novel Tumour-targeting Nanoliposome Drug Delivery System For The Treatment Of Malignant Gliomas
Funder
National Health and Medical Research Council
Funding Amount
$445,097.00
Summary
Most patients with malignant brain tumours die within a year after diagnosis due to the difficulty in effectively delivering drugs to the tumour cells. We aim to develop a safe and novel drug delivery system to effectively deliver anticancer drugs and novel anticancer agents to brain tumour cells that remain in normal brain after surgery. The success of this project will bring us a step forward in our efforts to significantly improve the survival rate and quality of life of such patients.
Selective Therapies Targeting Tumour Vasculature Of Colorectal Liver Metastases
Funder
National Health and Medical Research Council
Funding Amount
$519,279.00
Summary
Cancer of the bowel is the second highest cause of cancer related deaths in Australia. Over 70% of these deaths are due to bowel cancer spread to the liver or liver metastases. Treatment options for the majority of patients with liver spread are limited. Although chemotherapies are a standard treatment option, they cause significant side-effects as they are small in size and thereby distributed to both cancer and normal tissue. Given the limitations of chemotherapy, our objective is to investiga ....Cancer of the bowel is the second highest cause of cancer related deaths in Australia. Over 70% of these deaths are due to bowel cancer spread to the liver or liver metastases. Treatment options for the majority of patients with liver spread are limited. Although chemotherapies are a standard treatment option, they cause significant side-effects as they are small in size and thereby distributed to both cancer and normal tissue. Given the limitations of chemotherapy, our objective is to investigate two new strategies which selectively destruct tumours with minimal effect to normal tissues. Cancer growth is dependent on an efficient blood supply. One strategy uses drug delivery systems (DDS) to selectively target cancers by exploiting the unique properties of tumour blood vessels. The second strategy uses vascular targeting agents (VTA's) which act on tumour vessels to reduce blood flow and starve the tumour of oxygen, leading to its destruction. We will be testing two agents: SMA-Pirarubicin, a DDS and an innovative VTA, Oxi4503, in an animal model of colorectal cancer liver metastases. Although these drugs are successful in destroying the majority of tumour cells, they have a patchy effect and do not completely destroy the cancerous growth. The varied effects of these agents may be due to variations in tissue hypoxia, tumour vessel structure or factors which trigger blood vessel formation and breakdown. These features will be investigated using techniques established within our laboratory. We will also investigate the combined effect of other novel agents and hyperbaric oxygen administration to improve the effectiveness of these drugs. A successful outcome will result in the development of an improved treatment method which targets tumours, producing maximum destruction with minimum side-effects. This has the potential to replace standard chemotherapies as the preferred treatment for patients with bowel cancer spread, with overall significant patient benefits.Read moreRead less