Development Of A Novel And Highly Selective CDK4/6 Inhibitor For Treating Cancer
Funder
National Health and Medical Research Council
Funding Amount
$1,171,199.00
Summary
We have identified and patented novel drug molecules targeting enzymes namely CDKs 4 and 6, that are important for survival of cancer cells. The drugs are highly selective and potent against CDK4/6, well absorbed orally, and have attracted much interest from a pharmaceutical company. Further detailed work is needed to characterize fully their anti-cancer effects and toxicity, thereby securing a major investment from our commercial partner for drug development for treating cancers.
Major progress has been made in the treatment of cancer by the development of inhibitors of oncogenes that drive cancer growth. This application will test whether this approach can be used for melanomas with activation of the CDK4 oncogene that becomes activated in over 50% of melanomas. We will indentify which patients melanomas respond best to this approach and understand why some melanomas but not other responds providing the scientific framework for clinical trials of CDK4 inhibitors.
The future of cancer therapy lies in the tailoring of treatment to the characteristic of individual tumour. We have previously identified a subset of breast tumours that are characterised by the presence of large excess of proteins called D-type cyclins. Similar overexpression of cyclin D1 has been shown to lead to the development of cancer in mammary gland in animal models. In normal cells, D-type cyclins are degraded rapidly, therefore the regulation of protein degradation, or proteolysis, is ....The future of cancer therapy lies in the tailoring of treatment to the characteristic of individual tumour. We have previously identified a subset of breast tumours that are characterised by the presence of large excess of proteins called D-type cyclins. Similar overexpression of cyclin D1 has been shown to lead to the development of cancer in mammary gland in animal models. In normal cells, D-type cyclins are degraded rapidly, therefore the regulation of protein degradation, or proteolysis, is crucial in preventing the accumulation of D-type cyclins. In the subset of breast cancers we have identified, D-type cyclin proteolysis is defective. We, and others, have obtained evidence for the involvement of the SKP2 gene in the proteolysis of D-type cyclins. SKP2 has also been shown to be required for the proteolysis of another important protein, called p27. In the clinic, accumulation of p27 in tumours is used as a good prognostic indicator. However, some exceptions have been found where the accumulation of p27 correlates with aggressive tumours. As D-type cyclins are able to counteract the effect of p27, we hypothesise that the aggressive behaviour of these tumours is due to the simultaneous accumulation of D-type cyclins and that this is due to a mutation in the SKP2 gene. The experiments described in this proposal are designed to test this hypothesis. As the choice of treatment is affected by the interpretation of p27 levels, the results obtained from this study may have a direct impact in the clinic.Read moreRead less
The West Nile Viral Protease, NS3: A Target For Antiviral Drug And Vaccine Design
Funder
National Health and Medical Research Council
Funding Amount
$230,500.00
Summary
The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Midd ....The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003) have been characterized by severe symptoms , severe neurological pathology, and fatalities. In the USA alone there were 4,156 infections and 284 deaths in 2002, 9122 infections and 223 deaths in 2003, and this mosquito borne virus has quickly spread since 1999 through all USA states and into Canada and Mexico (http:--www.cdc.gov-ncidod-dvbid-westnile-index.htm). No treatments or vaccines are available. This project focuses on an enzyme, known as the West Nile Virus NS3 protease, that is essential for replication of the virus. By studying the enzyme in the laboratory we can design small molecules that can block its function and these have real potential as leads for development of drug treatments for people infected by this virus. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections. Our studies will also be used to develop potential vaccines. The science involves experts on protease enzymes, drug design and development, virology including West Nile virology, and vaccine development. We expect to generate drug and vaccine candidates and new information for their development that is at the cutting edge of West Nile Virus research.Read moreRead less
The Role Of Proteinase Inhibitor 9 In Cytotoxic Lymphocyte Function
Funder
National Health and Medical Research Council
Funding Amount
$820,136.00
Summary
Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are a ....Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are aimed at understanding the role of the inhibitor in human immune and reproductive function. We will also design and evaluate synthetic compounds based on the natural inhibitor that will enable us to easily measure granzyme B levels and control its activity.Read moreRead less
Proteinase Inhibitor 6: A Multifunctional Intracellular Serpin
Funder
National Health and Medical Research Council
Funding Amount
$217,435.00
Summary
We have discovered and characterized an unusual protease inhibitor that is widely distributed in the body. We have shown that the inhibitor is present in immune cells that are responsible for fighting bacterial infection, and that its role is probably to protect these cells against a powerful endogenous protease produced to destroy ingested bacteria. The inhibitor probably has additonal roles because it is present in developing and adult brain, skin and other blood cells. In these tissues we hav ....We have discovered and characterized an unusual protease inhibitor that is widely distributed in the body. We have shown that the inhibitor is present in immune cells that are responsible for fighting bacterial infection, and that its role is probably to protect these cells against a powerful endogenous protease produced to destroy ingested bacteria. The inhibitor probably has additonal roles because it is present in developing and adult brain, skin and other blood cells. In these tissues we have evidence that inhibitor regulates other, unidentified, proteases. The purpose of this grant is to identify these proteases, and to elucidate the physiological significance of the inhibitor by studying mice that lack it.Read moreRead less
Progression Of Influenza Virus Within The Respiratory Tract
Funder
National Health and Medical Research Council
Funding Amount
$513,716.00
Summary
We are exploring how influenza virus moves down the respiratory tract after infecting the nose. We have identified a component of mouse saliva that can halt the progression from the nose to the trachea and lungs and will determine how it binds to the virus to stop infection. We will also examine how human and highly lethal avian viruses move from the upper respiratory tract to other organs in the mouse and also in the ferret, which is a much better model for mimicking what happens in man.