Abstract
Researchers have identified that the targeted silencing of a specific gene could allow more effective treatment and measurable reductions in tumor size.
A new protein has been identified by researchers that could be involved in the development of drug-resistance in breast cancer. The lemur tyrosine kinase-3 (LMTK3) receptor has been implicated in estrogen response to breast cancer. The scientists, based at University College London, UK, hope that the protein could serve as a target for new treatments.
Therapies that target the estrogen receptor (ER)a have allowed great advances in the treatment of breast cancer in recent years. Speaking to Women's Health, Georgios Giamas, one of the authors of the research, explains how they identified the protein: “We performed a whole human kinome siRNA screening and examined what happens to the activity of the ERa after individually inhibiting each of the approximately 700 known kinases. We discovered approximately 15–20 novel kinases that haven't been implicated before in the regulation of ERa. One of them was LMTK3. Interestingly, after checking amongst these kinases, which, if any, have undergone evolutionary changes between humans and chimpanzees, we observed that only LMTK3 has undergone Darwinian positive selection, making this molecule interesting and challenging to focus on”.
Using an orthotopic mouse model for breast cancer, the team successfully demonstrated that the silencing of LMTK3 prevented proliferation of ERa+, but not ERa− cells. This activity indicated the role of LMTK3 in ERa activity and the silencing of the LMTK3 protein demonstrated reduced tumor volume.
In human cancer, an abundance of LMTK3 was associated with disease-free survival, and predicted a positive response to endocrine therapy. The results also indicated the targeting of LMTK3 could play an important role in the treatment of drug resistant cancer. Giamas explains, “Based on the results we have from cell lines, it appears that LMTK3 inhibition also ‘resensitizes’ cells to endocrine treatment (tamoxifen). Therefore, another potential future therapy could include the combination of LMTK3 and tamoxifen for breast cancer patients, because as we know >50% of patients after a few years of tamoxifen treatment become resistant; therefore understanding the mechasnisms of developing resistance is crucial. Based on our results so far, LMTK3 appears to play a role in this as well”.
IHC for low and strong LMTK3 expression in breast cancer tissues. Image courtesy of Georgios Giamas, Imperial College London, UK.
The findings indicate LMTK3 is a promising new therapeutic agent, and gives new insights into the natural history of breast cancer natural history in humans. Looking to the future, Giamas comments, “the ultimate goal now is to try and design a specific inhibitor against this kinase in order to stop its expression in breast cancer models. Our preliminary data, from cell lines and the animal xenograft models are very encouraging as it is more than obvious that tumor volume is reduced upon LMTK3 inhibition”.
Source: Giamas G, Filipovic A, Jacob J et al. Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. Nat. Med. 17(6), 715–719 (2011).
Variation in the gene that regulates cholesterol may be linked to infertility in women
Recent research suggests that variations in the cholesterol-regulating scavenger receptor class B type 1 gene may cause in infertility in women.
Researchers at Johns Hopkins University School of Medicine (Baltimore, MD, USA) have identified a link between the scavenger receptor class B type 1 gene (SCARB1) involved in cholesterol regulation in the bloodstream and infertility in women. It appears that this gene is also capable of influencing progesterone production, possibly leading to a substantial number of infertility cases.
The team of researchers, led by Annabelle Rodriguez, analyzed granulosa cells and follicular fluid from 274 women who were undergoing IVF treatment as they were unable to conceive naturally, between November 2007 and March 2010. Out of these women, 207 had their eggs collected, fertilized in a test tube and implanted back into their womb. The team developed a blood test to differentiate between five SCARB1 SNPs. Nine of the women tested had a mutated SCARB1. Rodriguez and colleagues then determined whether there was a fetal heartbeat or a gestational sac 42 days post-embryonic transfer. Of the nine women with the mutated SCARB1, none were pregnant. Rodriguez believes the genetic variation seen here could be present in 8–13% of the population. In addition, women with the altered SCARB1 gene conveyed low levels of progesterone, a hormone that is essential in maintaining pregnancy, even though they had progesterone supplementation during their IVF treatment.
“It appears that this gene is also capable of influencing progesterone production, possibly leading to a substantial number of infertility cases.”
The research originally stemmed from Rodriguez's work on genetically engineered mice that no longer had the receptor for high-density lipoproteins (HDLs). Therefore, these mice had abnormally high blood HDL levels and were found to be at increased risk of heart disease. In addition, the females were also infertile. Researchers at the Massachusetts Institute of Technology (MA, USA) found that the fertility of the mice could be restored using a cholesterol medication known as probucol, which acts through decreasing levels of circulating cholesterol. The drug was developed many years ago, yet is no longer approved for use in the US because of fears that it dangerously lowers HDL, although use in Japan is seen for some conditions.
Rodriguez is optimistic “that this drug or one like it could also restore fertility in women”. When asked to comment for Women's Health on her future work, Rodriguez said “My laboratory is now exploring this possible treatment for SCARB1 deficient women, and we need to first obtain permission from the US FDA for such use”.
Sources: Johns Hopkins Medicine: www.hopkinsmedicine.org/news/media/releases/gene_variation_linked_to_infertility_in_women_study_finds; Yates M, Kolmakova A, Zhao Y, Rodriguez A: Clinical impact of scavenger receptor class B type I gene polymorphisms on human female fertility. Hum. Reprod. 26(7), 1910–1916 (2011).
About the Bulletin Board
The Bulletin Board highlights some of the most important events and research in the field of women's health. If you have newsworthy information, please contact:
Rebecca Owen, Managing Commissioning Editor, Women's Health, Future Medicine Ltd, Unitec House, London, N3 1QB, UK,
Breast cancer may be linked to the obesity gene
New research suggests that a variant of the fat mass obesity-associated gene, seen in 18% of individuals, may increase the risk of developing breast cancer.
Researchers at Northwestern University (Chicago, IL, USA) have discovered a link between the fat mass and obesity-associated gene (FTO) and increased occurrence of breast cancer. Individuals were 30% more likely to develop breast cancer if they had a variant of the FTO gene. Lead researcher, Virginia Kaklamani, believes “This is a fascinating early finding, which fits with the known connections between obesity and breast cancer”.
Whilst all of the population carries the FTO gene, only 18% have the variant of the gene that is linked to breast cancer. Genetic testing is not currently available for the FTO variant but Kaklamani believes it may be in the future, similar to testing for BRCA mutations. “10 years ago we didn't know about the BRCA gene mutation, which has been linked to breast and ovarian cancer. Today, we offer genetic testing and a specialized clinic for those at risk in order to minimize their risk and detect any indication of cancer early”, stated Kaklamani “This knowledge helps us better identify who is at an increased risk so that one day, we can counter that risk through preventative measures and advanced screening”.
Whilst research to identify why the association between the FTO gene and breast cancer exists is in progress, Kaklamani commented to Women's Health that “results from these kind of studies can pave the path to individualized medicine”, whereby the option for monitoring and prevention of illness is available, as well as future treatment options.
Sources: Northwestern Memorial Hospital Press release: www.nmh.org/cs/Satellite?c=eHA_Content_C&cid=1244688575859&pagename=nm%2FCentral_Template; Kaklamani V, Yi N, Sadim M et al. The role of the fat mass and obesity associated gene (FTO) in breast cancer risk. BMC Med. Genet. 12, 52 (2011).
VivaGel® demonstrates positive results in Phase II study
Promising results from a Phase II study investigating the efficacy of VivaGel® for the treatment of bacterial vaginosis (BV) have recently been reported.
Bacterial vaginosis is one of the most common causes of infection in the female reproductive system. It is caused when the normal flora (Lactobacillus) of the vagina is out-populated by abnormally growing bacteria. In the USA, approximately a third of the adult female population is estimated to be affected with BV. Symptoms include vaginal irritation, discharge and odor. BV has also been reported to increase the risk of acquiring some sexually transmitted infections, including HIV.
The study conducted was a double-blind, randomized, placebo-controlled, dose-ranging Phase II study, which enrolled 132 women. Participants were randomized to receive VivaGel at either 0.5, 1 or 3% SPL7013, or placebo oncedaily for 7 days. The results demonstrated that 74% of patients achieved Clinical Cure of BV 2–5 days following completion of therapy, compared with 22% in the placebo group. Furthermore, 2–3 weeks after treatment, 46% of patients were reported to have achieved clinical cure of BV in comparison to 12% in the placebo group. It should also be noted that clinical cure 2–3 weeks following completion of therapy is currently the US FDA's preferred end point for assessing cure of BV. Both results demonstrated high statistical significance.
The main symptoms of BV, unpleasant vaginal discharge and odor, were reported to be cured in 89 and 78% of patients treated with VivaGel, respectively.
The incidence of adverse events, including genitourinary adverse events, was similar across all placebo gel and VivaGel groups.
In conclusion, the study met the primary end point demonstrating efficacy for the treatment of BV. Owing to these encouraging results, Starpharma are currently planning to commence Phase III trials in late 2011 or early 2012.
Source: www.starpharma.com/news/67
In brief…
A Swedish study has revealed that increased intake of dietary calcium to compensate for lost calcium does not significantly reduce the risk of fractures or osteoporosis in later life. The study consisting of 61,433 women, born between 1914 and 1948, was carried out over 19 years. The primary outcome measures were hip fractures and incident fractures of any type. Diet assessment was performed by repeated food questionnaires. During follow-up, 14,738 women expereinced a first fracture of any type, and 3871 a hip fracture; of these women, 1012 were determined as being osteoporotic. Those women with the highest amount of dietary calcium did not experience a reduced risk of fracture or osteoporosis, but were found to have a higher rate of hip fracture.
In this work, the authors assessed markers of ovarian reserve and age as long-term predictors of ovarian function after chemotherapy. The study was conducted among premenopausal women at the time of diagnosis of early breast cancer. The main outcome measures assessed were ovarian function at 5-year follow-up in relation to pretreatment hormonal and ultrasound markers of ovarian reserve. The authors observed, whilst studying serum markers, (including estradiol, inhibin B, FSH and anti-Müllerian hormone [AMH]) from 42 women receiving neoadjuvant chemotherapy, that continuing menses 4–5 years after diagnosis reflected ovarian activity. Pretreatment serum AMH, FSH, antral follicle count and age predicted late ovarian activity; however, only AMH was found to be predictive in a multivariate logistic regression. The authors concluded that the measurement of AMH at cancer diagnosis predicts long-term ovarian function after chemotherapy and may allow better prediction of chemotherapy-related risk to future fertility if adopted in clinical practice.