Exploring A New Way To Overcoming Endocrine Resistance In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$441,764.00
Summary
Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to res ....Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to resistance to the drug leading to the disease relapse. Therefore, it is imperative to better understand the mechanisms responsible for the resistance and to explore new strategies that overcome this clinical problem in order to prolong the overall survival of patients with breast cancer. Our recent work have shown that a recently-identified enzyme, termed sphingosine kinase, plays an important role in promoting breast cancer cell growth. We also found that cells that have a high level of the enzyme had bad outcomes in response to anti-estrogen drug, tamoxifen. Thus this project seeks to identify the role of this enzyme in contributing towards drug resistance, and test if inhibition of this enzyme could improve and-or restore the drug response in breast cancer. It will ultimately pave a new way to overcoming the drug resistance for improving the treatment and prevention of breast cancer.Read moreRead less
Wnt-5a Signalling - A Novel Therapy For Triple Negative And Tamoxifen Resistant Breast Cancer Patients
Funder
National Health and Medical Research Council
Funding Amount
$330,534.00
Summary
Breast cancer is the most common cancer in women. Commonly used drugs target the estrogen receptor (ER). However, one third of breast cancer patients lack ER, and do not respond to treatment. Cancers that lack ER also lack a gene called Wnt5a, which is linked to better prognosis. We have shown that fixing Wnt5a can restore ER allowing cells to respond to Tamoxifen. We would now test this in animals, in the hope of developing a new drug for breast cancer patients currently with limited options.
Follow-up Phase Of A Randomised Trial Of Tamoxifen Or Placebo For Breast Cancer Prevention In High Risk Women.
Funder
National Health and Medical Research Council
Funding Amount
$459,900.00
Summary
Each year over 10,000 new cases of breast cancer are diagnosed in Australia and over 2500 women die. Tamoxifen, a non-toxic tablet used to control the growth of breast cancer, has safely been taken by over a million women long term . This project measures tamoxifen's role in preventing breast cancer in high risk women compared to placebo, in a randomised double blind clinical trial. The trial has the potential to benefit many millions of women worldwide. The study is called IBIS1 (International ....Each year over 10,000 new cases of breast cancer are diagnosed in Australia and over 2500 women die. Tamoxifen, a non-toxic tablet used to control the growth of breast cancer, has safely been taken by over a million women long term . This project measures tamoxifen's role in preventing breast cancer in high risk women compared to placebo, in a randomised double blind clinical trial. The trial has the potential to benefit many millions of women worldwide. The study is called IBIS1 (International Breast cancer Intervention Study) , and is conducted in Australia by the Australian New Zealand Breast Cancer Trials Group (ANZ BCTG), and internationally by the Imperial Cancer Research Fund (ICRF) in London. On the trial women have regular, annual mammography, 6 monthly clinical checks and take a tablet each day called TAMPLAC, which is either tamoxifen or placebo. The accrual phase has been funded by the NHMRC and by November 2000 the target number of women on the trial was reached ahead of schedule - over 7000 internationally including over 2500 from Australia. Follow-up is being completed with planned data analysis within the next three years. Funding for this phase in Australia is now being sought. The ANZ BCTG and over 2500 women at increased risk of breast cancer have demonstrated a remarkable commitment to complete accrual. It is now vitally important that the essential follow-up with careful monitoring is completed to facilitate anaysis of the data at the earliest opportunity. The only other large randomised trial testing tamoxifen (NSABP P-1) ceased and unblinded in 1998, with an average follow-up of less than 4 years. This trial has had to re-commence follow-up to determine longer term tamoxifen effects. The IBIS 1 study is now the only large, blinded trial remaining in the world, and it's follow-up is of very high international importance. The completion of follow-up and the publication of results will have substantial impact worldwide.Read moreRead less
Follow-up Of A Randomised Trial Of Tamoxifen Or Placebo For Breast Cancer Prevention In High Risk Women.
Funder
National Health and Medical Research Council
Funding Amount
$893,483.00
Summary
Each year over 10,000 new cases of breast cancer are diagnosed in Australia and over 2500 women die. Tamoxifen, a non-toxic tablet used to control the growth of breast cancer, has safely been taken by more then a million women long term . This project measures tamoxifen's role in preventing breast cancer in high risk women compared to placebo, in a randomised double blind clinical trial. The trial has the potential to benefit many millions of women worldwide. The study, IBIS I (International Bre ....Each year over 10,000 new cases of breast cancer are diagnosed in Australia and over 2500 women die. Tamoxifen, a non-toxic tablet used to control the growth of breast cancer, has safely been taken by more then a million women long term . This project measures tamoxifen's role in preventing breast cancer in high risk women compared to placebo, in a randomised double blind clinical trial. The trial has the potential to benefit many millions of women worldwide. The study, IBIS I (International Breast Cancer Intervention Study), is conducted in Australia by the Australian New Zealand Breast Cancer Trials Group (ANZ BCTG), and internationally by Cancer Research UK (CRUK). On the trial women have regular, annual mammography, 6 monthly clinical checks and take a tablet each day called TAMPLAC, which is either tamoxifen or placebo. The accrual phase has been funded by the NHMRC and the target number of women on the trial was reached ahead of schedule - 7154 internationally including 2674 from Australia. By April 2006 all women will have completed the treatment phase. Funding is now being sought, in Australia, for continued follow-up and investigations of additional risk factors (breast density and types of tumors which occur-have occurred on IBIS I). The ANZ BCTG and all the women involved in IBIS I have demonstrated remarkable commitment. It is now vitally important that the essential follow-up is completed to facilitate analysis of the data, including the post-treatment phase, as well as related risk factors and types of tumors which develop. The only other large randomised trial testing tamoxifen (NSABP P-1) ceased and was unblinded in 1998, with an average follow-up of less than 4 years, the trial had to re-commence follow-up to determine longer term tamoxifen effects. The IBIS 1 study remains the only large, blinded trial in the world, and completion of it's follow-up and analysis is of very high international importance.Read moreRead less
Anti-Estrogens - A Potential Treatment For Bipolar Affective Disorder In Women?
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness is a serious mental illness with high morbidity and mortality. The cause of the illness is still unclear and the underlying neurochemical changes are different for the manic phase compared with the depressive phase. The current treatments for BPAD are limited in scope and not biochemically well understood. There are gender differences in the presentation and outcomes for BPAD which adds to the complexity of the illness. We are proposi ....Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness is a serious mental illness with high morbidity and mortality. The cause of the illness is still unclear and the underlying neurochemical changes are different for the manic phase compared with the depressive phase. The current treatments for BPAD are limited in scope and not biochemically well understood. There are gender differences in the presentation and outcomes for BPAD which adds to the complexity of the illness. We are proposing a study to develop a new type of treatment for the manic phase of BPAD and are exploring the use of anti-estrogens in women with mania. The background to our proposed study comes from a few case reports suggesting that anti-estrogen agents such as progesterone and tamoxifen may be useful adjuncts to treatment. We conducted a small pilot study comparing the addition of oral tamoxifen with oral progesterone and placebo in 10 women with mania and found that the women who received tamoxifen made significantly better improvements in their manic symptoms over a 28-day trial. The research study we are now proposing is a larger, three-arm, double blind, placebo controlled, 28-day adjunctive study in women with mania to expand and clarify our pilot study findings. Patients in our proposed study would receive either 40mg per day tamoxifen or 20mg per day progesterone or placebo in addition to standardised lithium medication. We will measure enzyme activity (protein kinase C) and estrogen-progesterone levels to understand more about the mechanisms of action by these new hormone treatments. BPAD is a crippling disorder and if we are successful, then tamoxifen treatment may be an important new treatment. This proposed study will also shed new light on some of the neurochemical mechanisms underlying BPAD as well as opening up the new area of hormone treatments for serious mental illness.Read moreRead less
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less