Development Of Anti-metastatic And Tumour Targeting Reagents By Design Of Inhibitors To Specific Eph/ephrin Cell-cell
Funder
National Health and Medical Research Council
Funding Amount
$200,000.00
Summary
Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (E ....Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (Ephs) and their membrane-bound ephrin ligands are crucial mediators of cell adhesion and motility and are notably overexpressed in metastatic tumours rather than primary (benign) lesions5. Our laboratories were the first to identify EphA3 7, and one of the first to isolate its ligand, ephrin-A5. EphA3 was isolated from acute lymphoblastoid leukemia and malignant melanoma patients, where increasing expression levels correlate with metastatic progression. Soluble, non-clustered forms of Ephs and ephrins are effective inhibitors of Eph activity 3 and provide opportunities to generate specific drugs for cancer therapy. We now propose a research and development program for the development of EphA3-specific drugs and their production for pre-clinical and clinical evaluation for placement onto a national and international market.Read moreRead less
Stage II In The Development Of Eph/ephrin Based Tumor Targeting Reagents: Optimisation Of Drug Efficacy And Delivery
Funder
National Health and Medical Research Council
Funding Amount
$204,125.00
Summary
In the final stage of cancer, including melanoma, tumor cells gain the ability to spread, a process called metastasis. Altered communication between cancer and normal cells is one of the causes of this invasive characteristic. We have started the development of novel agents that target and modulate proteins on the cell surface that control these properties and are found in metastatic tumors. We propose to refine the targeting and killing properties of these agents for early clinical testing.
Evaluation Of The Therapeutic Potential Of SFTI-FCQR, A Novel Kallikrein 4-specific Protease Inhibitor
Funder
National Health and Medical Research Council
Funding Amount
$167,303.00
Summary
Prostate and ovarian cancers are on the rise in Australia's ageing population. In previous work, we have studied prostate and ovarian cancer cells that we have engineered to make the protease KLK4. These cells show signs associated with aggressive tumours and in particular may have some of the changes found in cancer cells that spread from their site of origin (metastasize). In this project, we will look at a drug-like molecule that we have designed with the aim of blocking the activity of KLK4.
Targeted Alpha Therapy: Development Of A New Treatment For Metastatic Cancer
Funder
National Health and Medical Research Council
Funding Amount
$394,400.00
Summary
Breast cancer is the most commonly diagnosed, malignant cancer in women and prostate cancer is the most common non-life style related cancer in men. In spite of the most aggressive therapy, a significant percentage of men and women die of secondary disease (metastases) which usually spreads in the early stages. Currently, therapy is limited to chemotherapy and hormone therapy, both of which show clinical improvement but long term survival is uncertain. Targeted alpha therapy (TAT) is a new cance ....Breast cancer is the most commonly diagnosed, malignant cancer in women and prostate cancer is the most common non-life style related cancer in men. In spite of the most aggressive therapy, a significant percentage of men and women die of secondary disease (metastases) which usually spreads in the early stages. Currently, therapy is limited to chemotherapy and hormone therapy, both of which show clinical improvement but long term survival is uncertain. Targeted alpha therapy (TAT) is a new cancer treatment that we are developing in mouse models of human breast and prostate cancer. With TAT we are exploiting the fact that aggressive breast and prostate cancer cells, but not normal cells, express a particular tissue-barrier degrading protein system (uPA) which is specifically recognised by a natural inhibitor protein (PAI2). This protein inhibitor is labeled with a highly effective cell killing agent, a radioisotope that emits high energy alpha particles with a short range of only a few cell diameters . The alpha-labeled PAI2 selectively kills cancer cells at their most malignant stage by targeting the uPA system on these cells. Another benefit of TAT is that little radiation damage occurs to nearby or distant normal cells. Thus side-effects would be minimised. The outcome of our research to date has been to show the potential of our unique TAT approach as a possible new therapy for breast and prostate cancer. This therapy may well prove beneficial for other cancers. Further safety evaluations studies in mice will be followed by a dose tolerance clinical trial in humans. We expect to be able to show that our TAT will regress breast and prostate cancer tumours without complications in mice. The human trials will show the tolerance limits to TAT. If successful, TAT could provide the basis for a major change in prognosis and quality of life of breast and prostate cancer patients.Read moreRead less
The majority of deaths from cancer are due to metastasis, which is the formation of secondary tumours at sites remote from the primary tumour. Metastasis involves conversion of some tumour cells to an invasive, migratory form in a process that is controlled by small genetic regulators known as microRNAs. In this project we will conduct experiments aimed to provide a proof of principle demonstration in mice that microRNAs can be used to block the formation of metastases.
Production Of A Novel Humanised Anti Dendritic Cell Therapeutic Antibody For Graft Versus Host Disease
Funder
National Health and Medical Research Council
Funding Amount
$202,500.00
Summary
A transplant of bone marrow or other source of blood stem cells from a donor is often used to treat leukaemia patients whose disease has failed to respond to chemotherapy. The Mater Medical Research Institute has developed a world first dendritic cell depleting therapeutic antibody which may open a new strategy for the control of acute graft versus host disease, which is a very common and often fatal complication of bone marrow transplantation. The new antibody treatment is also likely to be use ....A transplant of bone marrow or other source of blood stem cells from a donor is often used to treat leukaemia patients whose disease has failed to respond to chemotherapy. The Mater Medical Research Institute has developed a world first dendritic cell depleting therapeutic antibody which may open a new strategy for the control of acute graft versus host disease, which is a very common and often fatal complication of bone marrow transplantation. The new antibody treatment is also likely to be useful for the prevention of rejection in solid organ transplantation. If successful, it will selectively control graft versus host disease, without compromising the essential anti-viral immunity and desired anti-leukemia activity of the graft.Read moreRead less
Phase 1 Clinical Trial Of Autologous Dendritic Cells To Induce Antigen-specific Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$165,125.00
Summary
We have previously generated modified dendritic cells in mice with the ability to suppress immune responses once they have started. This project will develop the dendritic cell vaccine as a platform technology for human clinical use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with rheumatoid arthritis taking drugs for their ....We have previously generated modified dendritic cells in mice with the ability to suppress immune responses once they have started. This project will develop the dendritic cell vaccine as a platform technology for human clinical use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with rheumatoid arthritis taking drugs for their diseaseRead moreRead less
Development Of Novel Anti-cancer And Immunosuppressive Drugs Derived From Pineapple Stems
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
We have discovered two molecules from pineapple stems that show anti-tumour activity in laboratory studies. One molecule, called ananain, blocks a cancer causing protein called Ras, which is defective in approximately 30% of all cancers. The other molecule, called canizain, stimulates the bodies own immune system to target and kill cancer cells. The proposed research seeks to provide proof of concept of the use of ananain and canizain as drug development targets. Once this early proof of princip ....We have discovered two molecules from pineapple stems that show anti-tumour activity in laboratory studies. One molecule, called ananain, blocks a cancer causing protein called Ras, which is defective in approximately 30% of all cancers. The other molecule, called canizain, stimulates the bodies own immune system to target and kill cancer cells. The proposed research seeks to provide proof of concept of the use of ananain and canizain as drug development targets. Once this early proof of principle phase has been completed, we believe that ananain and canizain would be extremely attractive targets for further investment by a major pharmaceutical company.Read moreRead less
Development Of Novel And Selective Anticancer Drugs Derived From Cysteine.
Funder
National Health and Medical Research Council
Funding Amount
$264,250.00
Summary
In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tum ....In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tumour drugs that possess unusually high selectivity in acting on cancer cells without killing normal human cells. Our current proof of concept will be turned into a drug development candidate that will improve our negotiating position with commercial partners.Read moreRead less
Development Of Modified IGF-binding Proteins As Novel Anti-cancer Chemotherapeutics
Funder
National Health and Medical Research Council
Funding Amount
$77,375.00
Summary
We propose to enhance the effectiveness of current anti-cancer treatments by co-administering a protein to sequester growth factors that promote the resistance of cancer cells to chemotherapy. We aim to achieve improved destruction of breast and colorectal cancers but with reduced adverse side effects. Our in vitro data show the effectiveness of this novel co-therapeutic which is a modified form of a natural carrier protein for these growth factors. This application seeks funding to enable proof ....We propose to enhance the effectiveness of current anti-cancer treatments by co-administering a protein to sequester growth factors that promote the resistance of cancer cells to chemotherapy. We aim to achieve improved destruction of breast and colorectal cancers but with reduced adverse side effects. Our in vitro data show the effectiveness of this novel co-therapeutic which is a modified form of a natural carrier protein for these growth factors. This application seeks funding to enable proof of concept in vivo in order to attract commercial funding for clinical trials.Read moreRead less