The Role Of Intracellular Uptake And Retention Of Abl Kinase Inhibitors In Modifying Clinical Response In CML
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Imatinib is one of the first targeted anticancer drugs to be clinically developed. It is designed to inhibit the kinase activity of BCR-ABL, a mutant protein found in some cases of leukaemia, particularly chronic myeloid leukaemia. Blocking the kinase activity of BCR-ABL has proven to be highly effective therapy for most patients, achieving prolonged remissions and significantly improving survival. However resistance to imatinib is a problem, including failure to respond to imatinib, loss of res ....Imatinib is one of the first targeted anticancer drugs to be clinically developed. It is designed to inhibit the kinase activity of BCR-ABL, a mutant protein found in some cases of leukaemia, particularly chronic myeloid leukaemia. Blocking the kinase activity of BCR-ABL has proven to be highly effective therapy for most patients, achieving prolonged remissions and significantly improving survival. However resistance to imatinib is a problem, including failure to respond to imatinib, loss of response, and long term persistence of low levels of leukaemia. New ABL kinase inhibitors (AKIs) have been developed that are more potent than imatinib, but they also appear to be prone to resistance. One potentially important cause of resistance to AKIs is the ability of some leukaemic cells to modify their cellular pathways to reduce the effective concentration of the drug by either reducing its movement into the cell (influx) or increasing its movement out (efflux). We will investigate the mechanisms used by resistant leukaemic cells to reduce intracellular drug levels of these AKIs and test ways of countering these effects by blocking the proteins responsible for drug efflux or promoting drug influx. These studies will use our stored collections of leukaemic cells from responsive and resistant patients to determine the importance of specific influx and efflux pumps. It will help to identify patients where this form of resistance is limiting response. This may allow us to develop more effective AKIs that are less prone to these forms of drug resistance. We will also test whether other anti-cancer drugs have an impact on AKI drug transport because this could reduce the effectiveness of combination treatment. The effects on drug transport of concomitant administration of commonly used drugs together with AKIs will also be studied because this can reduce the effectiveness of AKis or in some cases improve their effectiveness by increasing their uptake and retention.Read moreRead less
Melanoma Genetics: Clinical Translation Of The Germline-somatic Continuum
Funder
National Health and Medical Research Council
Funding Amount
$2,231,372.00
Summary
While new targeted and immune therapies can improve prognosis from metastatic melanoma, long-term survival for most patients remains elusive due to drug resistance or failure of the immune system to kill the tumour. There thus remains a significant need to improve early detection, monitoring of relapse, and treatment strategies, to increase survival and provide cures. My research vision addresses these three pillars of cancer research using innovative and cutting edge genetic approaches.
Translation Of Genomic Findings To Improve Outcomes In Patients With Myeloid Blood Cancers
Funder
National Health and Medical Research Council
Funding Amount
$1,913,403.00
Summary
Changes within the DNA of blood cancer cells are responsible for causing cancer, but also control the progression through various stages of blood cancers and regulate the response of patients to treatment. It is fundamentally important to not only understand these genetic changes at the molecular level, but also to use these findings to rationally design clinical treatments that target these genetic changes to improve outcomes for patients with blood cancers.
Therapeutic Induction Of Tertiary Lymph Nodes In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$995,010.00
Summary
Immunotherapy has been an important recent advance in cancer treatment by using the body's own immune cells to fight cancer. Although there have been unprecedented dramatic results, not all patients benefit, and most benefits are temporary. The cellular environment in which cancers are embedded is crucial for controlling treatment success. We aim to apply novel 'precision' therapies to this environment to expose the cancer and enable attack by immune cells for improved immunotherapy.
There is a need to improve early detection, monitoring of relapse, and treatments for melanoma, to increase long-term survival. My research vision is to use innovative and cutting edge approaches to conduct a range of complementary studies under three broad but inter-related themes: Theme 1 – Genetic predisposition to melanoma in the general population; Theme 2 – Genetic predisposition to melanoma in high-density families; Theme 3 – Somatic aberrations underlying melanoma development.
Developing Smart Nanomedicine To Enable Advanced Diagnosis And Stimuli-responsive Treatment For Atherosclerosis And Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$523,342.00
Summary
The early detection and accurate characterization of life-threatening diseases such as cardiovascular diseases are critical to the design of treatment. A therapeutic approach that provides an efficient treatment with minimal side-effects is highly desired by both patients and healthcare systems. This project aims to develop smart nanomedicine with incorporated diagnostic sensor and external stimuli-responsive treatment mechanisms for cardiovascular diseases.
The Use Of Real-World Evidence To Support Regulatory And Reimbursement Decisions
Funder
National Health and Medical Research Council
Funding Amount
$91,538.00
Summary
Traditionally, medicines are studied extensively in clinical trials before they are widely available. More recently, some medicines have been allowed to enter the market without complete data on their benefits and risks. This means that these issues can only be studied once a medicine is on the market and used in routine clinical practice; this is referred to as real-world evidence. This research evaluates if this evidence is sufficient to prove that a medicine is safe and that it works
Therapeutic Targeting Of MYCN Oncoprotein Stability In Neuroblastoma
Funder
National Health and Medical Research Council
Funding Amount
$590,206.00
Summary
A high level of MYCN protein is a major indicator of aggressive neuroblastoma (NB) but unfortunately there have been many barriers to the design of targeted therapies. We have identified a protein called PA2G4 which is a cofactor for MYCN in promoting cancer cell growth. We have developed a compound which inhibits PA2G4 and MYCN protein levels and reduces tumour growth. We will examine how PA2G4 cause aggressive tumour characteristics and test new methods to block PA2G4.
Identifying Resistance Mechanisms Of Targeted BRAF Inhibitors In Metastatic Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$379,015.00
Summary
Late-stage melanoma is an aggressive skin cancer for which traditional treatment strategies such as chemotherapy are ineffective. Recently, a new class of targeted drugs (BRAF inhibitors) has become the standard of care for a subset of melanoma patients; however, long term treatment success is complicated by drug resistance. This study will identify the causes of resistance with the purpose to improve targeted drug strategies and increase survival rates for late-stage melanoma patients.