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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
Novel Vaccine Formulation For Immunotherapy Of Adenocarcinomas
Funder
National Health and Medical Research Council
Funding Amount
$178,400.00
Summary
We have designed a vaccine based on a unique delivery system. Mice immunised with vaccine were protected from a tumour challenge. We will now design a vacine with a cancer associated protein so that people once immunised can make killer cells. Since humans have different genetic makeup we will produce a vacine which is more effective and will benefit everyone. This vaccine will be more effective than a current vacine in that has yielded promising results in humans.
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.
Production Of Chimeric Monoclonal Antibodies To Pim1, A Novel Therapeutic Target For Cancer Treatment
Funder
National Health and Medical Research Council
Funding Amount
$188,850.00
Summary
Almost one in six men will develop prostate cancer during his lifetime. Every year, around 10,000 Australian men are diagnosed and more than 2,500 die of the disease, making prostate cancer the second largest cause of male cancer deaths after lung cancer. The research progress made on prostate cancer over the past 10 years has been encouraging. However the five-year survival rate remains low. There is a vital need to develop new methods to treat this disease. An exciting principle has emerged re ....Almost one in six men will develop prostate cancer during his lifetime. Every year, around 10,000 Australian men are diagnosed and more than 2,500 die of the disease, making prostate cancer the second largest cause of male cancer deaths after lung cancer. The research progress made on prostate cancer over the past 10 years has been encouraging. However the five-year survival rate remains low. There is a vital need to develop new methods to treat this disease. An exciting principle has emerged recently with the use of monoclonal antibodies (Mabs) such as Herceptin (a humanised anti-HER2 Mab), which is now being widely used to treat breast cancer. We produced 2 Mabs to Pim1, which significantly inhibited prostate cancer cell growth in mouse prostate cancer model. Pim1 is a novel oncoprotein, a biomarker for the treatment of prostate cancer as it overexpresses in more than 90% of prostate cancer, but not or less expressed in normal prostate, demonstrated by genearrays and immunohistochemical staining. Pim1 plays an important role in cell survival, proliferation and metastasis. Pim1 is a novel target, and the anti-Pim1 Mabs may be of value for the cancer therapy in humans. However, the murine Mab can not be repeatedly used in human because human would produce anti-mouse antibody response, and the murine Mab would be rapidly removed from circulation, which will greatly limit the therapeutic potential of the Mabs. Fortunately, the problem can be overcome by the use of hybrid chimeric antibodies. In this study, we are going to use chimeric technology to humanise the anti-Pim1 Mab and test them in vitro and in mouse model for the preclinical studies. We have had patent to protect our finding, and we are confident to produce mouse-human chimeric Mab for the future clinical trial as we have proper knowledge, techniques. We are also optimic for the future clinical trial as we have the experiences on commercialisation.Read moreRead less
A Novel Non-invasive Diagnostic Imaging Technique Of Metastatic Cancer Using Plasminogen Activator Inhibitor Type 2.
Funder
National Health and Medical Research Council
Funding Amount
$187,750.00
Summary
This project aims to develop a non-invasive tumour diagnostic imaging agent based on a non-toxic protein (PAI2) that we know specifically identifies a critical marker of malignancy. PAI2 will be labelled with commonly used imaging radioisotopes. This novel imaging technique has important potential clinical uses including, determination of the most appropriate treatment for individual patients, assessing the success of such treatments, and a novel non-invasive prognostic indicator of malignancy.
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.
Modulating Immune Responses By Targeting Dendritic Cells Using Dendritic Cell Specific Markers.
Funder
National Health and Medical Research Council
Funding Amount
$197,750.00
Summary
The ability to modulate immune responses would have major health benefits. Dendritic cells (DC) are key regulators of the immune system. Different types of DC possess different cell surface molecules and have differing regulatory functions. We have identified four novel DC surface molecules that can be used to target different types of DC. We aim to use antibodies against these molecules to either enhance the effectiveness of vaccines or to suppress autoimmune diseases.
Development Of A Simple Chemical Test For Detecting DNA-interacting Compounds For Medical And
Funder
National Health and Medical Research Council
Funding Amount
$315,450.00
Summary
The project exploits a simple chemical reaction to detect and measure the interaction of compounds with DNA. The test will be useful in the early screening of drug candidates for genotoxicity, identifying new anticancer drugs and also find application in the environmental, cosmetic and food industries. Work will focus on establishing peak conditions for the test, determining the scope of application, testing a panel of control compounds and performing a blind study to provide proof of concept.