Over-expression Of Human Cytochrome P450 2J2 Activates Phase II Biotransformation Genes That Influence Anti-cancer Drug Efficacy
Funder
National Health and Medical Research Council
Funding Amount
$489,155.00
Summary
Increased expression of some enzymes in human tumours contributes to anticancer drug resistance. In many tumours the fatty acid epoxygenase cytochrome P450 2J2 (CYP2J2) is over-expressed. We have found that CYP2J2 activates the expression of phase II enzymes that eliminate anticancer drugs; this is mediated by fatty acid epoxides. In this project we will define the underlying mechanisms of these effects, which may lead to novel strategies to overcome anticancer drug resistance.
Pharmacological Development Of Synthetic Analogues Of Cytochrome P450-mediated Omega-3 Fatty Acid Epoxides As Novel Anti-metastatic Agents
Funder
National Health and Medical Research Council
Funding Amount
$865,174.00
Summary
Dietary ?-3 and ?-6 fatty acids respectively decrease and increase the risk of cancer spread, or metastasis. We have found that ?-3 fatty acid epoxide metabolites inhibit the growth and migration of tumour cells. We have prepared derivatives of these ?-3 epoxides that retain anti-cancer properties in cells. In this project we will develop analogues of these ?-3 epoxides that are suitable for in vivo testing in animal models of breast cancer metastasis as a new class of potential anti-metastatic ....Dietary ?-3 and ?-6 fatty acids respectively decrease and increase the risk of cancer spread, or metastasis. We have found that ?-3 fatty acid epoxide metabolites inhibit the growth and migration of tumour cells. We have prepared derivatives of these ?-3 epoxides that retain anti-cancer properties in cells. In this project we will develop analogues of these ?-3 epoxides that are suitable for in vivo testing in animal models of breast cancer metastasis as a new class of potential anti-metastatic drugs.Read moreRead less
The Molecular Basis Of Cytochrome P450 Ligand Binding: Towards Predicting Enzyme Substrate Selectivity And Drug-drug Interaction Potential
Funder
National Health and Medical Research Council
Funding Amount
$558,447.00
Summary
Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism (i.e. chemical breakdown) of drugs, a process that is essential for their detoxification and elimination from the body. This project will combine advanced computational and experimental approaches to elucidate the molecular basis for the binding of drugs to CYP enzymes, which is crucial for the design of drugs with favourable metabolic properties and decreased propensity for harmful interactions with co-administered drugs.
Development Of Novel Anti-cancer Agents Based On Cytochrome P450-mediated Epoxides Of Omega-3 Fatty Acids
Funder
National Health and Medical Research Council
Funding Amount
$949,433.00
Summary
There are few effective treatments for advanced breast cancer. Dietary ?-3 and ?-6 fatty acids respectively decrease and increase the risk of cancer spread. We have found that ?-3 fatty acid epoxide metabolites inhibit the growth of tumour cells and have prepared analogues that are highly active in vivo in animal models of breast cancer. This project will improve and optimise these agents that hold promise as a new class of anti-cancer drugs with the potential to treat advanced disease.
Pharmacological Development Of A Stable Cytochrome P450-mediated Omega-3 Fatty Acid Epoxide Analogue As A Novel Anti-metastatic Agent
Funder
National Health and Medical Research Council
Funding Amount
$599,847.00
Summary
Dietary ?-3 fatty acids decrease the risk of cancer metastasis. We have found that a certain ?-3 fatty acid metabolite inhibits tumour cell migration but is too unstable to be a useful drug. We have now prepared a stable version of this metabolite for in vivo use as a potential anti-metastatic drug. In this project we will define the mechanism of action of this novel agent and evaluate how it may be best used in patient treatments by testing in a range of in vivo animal models of metastasis.
Is CYP11A1 Critical For The Vitamin D Photoprotective System In Skin?
Funder
National Health and Medical Research Council
Funding Amount
$517,567.00
Summary
Sunlight produces DNA damage. When inadequately repaired, this damage produces skin cancer. The vitamin D system in skin helps protect against this skin damage, but the vitamin D compounds involved and how they work is unclear. Recent data shows new vitamin D compounds with photoprotective activity and that vitamin D compounds increased expression of DNA repair proteins. These studies may enable pharmacological enhancement of protection from sunlight.
Predicting Drug-drug Interactions Due To Tyrosine Kinase Inhibitors: Inhibition Of Drug Metabolising Enzymes And Transporters
Funder
National Health and Medical Research Council
Funding Amount
$535,495.00
Summary
Tyrosine kinase inhibitors (TKIs) are a new class of anticancer agents. Cancer patients typically receive multiple drugs, for the treatment of cancer and other diseases, increasing the probability of interactions between coadministered drugs. Despite the widespread use of TKIs, their potential to cause drug interactions is poorly understood. Using novel in vitro approaches, this project will identify drug interactions precipitated by TKIs thereby improving drug efficacy and patient safety.
A Multi-site Study Of Tamoxifen Dose Escalation Study In Breast Cancer Patients With CYP2D6 Polymorphisms (TADE Study)
Funder
National Health and Medical Research Council
Funding Amount
$340,768.00
Summary
Tamoxifen is a selective anti-oestrogenic medication commonly used to treat breast cancer. Recent evidence suggests that tamoxifen may not be adequately activated in the body of some people because of their genetic make-up, and that this may reduce its effectiveness. In this study of 120 women, we will determine whether increasing tamoxifen dosage is a useful strategy in people with low activation levels. This could provide practical guidance for patients and clinicians managing breast cancer.
Control Of Bone Remodelling By Osteoclastic Metabolism Of Vitamin D
Funder
National Health and Medical Research Council
Funding Amount
$694,635.00
Summary
Vitamin D is essential for bone health. This study will build on our extensive body of preliminary data to investigate the extent to which bone-resorbing osteoclasts are controlled by circulating levels of the pro-hormone 25-hydroxyvitamin D. Our work will identify new approaches to the treatment of osteoporosis, by targetting the osteoclast as a vitamin D-responsive cell type.