Abstract
A team of researchers at the Cleveland Clinic (OH, USA), led by immunologist Vincent Tuohy, has developed a prophylactic vaccine that has prevented the growth of tumors in mice prone to develop breast tumors, according to an article published online in Nature Medicine on 30 May 2010.
“Tuohy and his team, therefore, sought to find a target antigen that would attack tumor cells without inducing autoimmunity.”
Researchers have been trying to develop vaccines against various cancers for years but have generally focussed on aberrantly expressed antigens taken from the patient's tumor, meaning that the tumor has already grown to a detectable level before the vaccine is administered. Vaccines are most effective when given prophylactically; however, since tumor antigens are variations on normal ‘self’ proteins, vaccines given prophylactically could lead to profound autoimmune complications.
Tuohy and his team, therefore, sought to find a target antigen that would attack tumor cells without inducing autoimmunity. They chose α-lactalbumin because it is a breast-specific differentiation protein expressed in the majority of breast cancers but not in normal, non-lactating breast tissue. This makes it a suitable vaccination target in women over the age of 40 years, when they are less likely to become pregnant and increasingly likely to develop breast cancer.
Mice that were genetically predisposed to develop breast cancer by the age of 10 months were injected with either a vaccine containing the α-lactalbumin antigen and an immune-boosting adjuvant or a placebo at age 2 months. After 10 months, none of the six mice that received the vaccine showed any sign of breast cancer, whereas all six of the mice that received the dummy injection had large tumors. In a separate experiment, the authors demonstrated that, as well as preventing autochthonous tumor formation in transgenic mouse models of breast cancers, the vaccine also provided therapy against transplanted 4T1 tumors in BALB/c mice.
“We believe that this vaccine will someday be used to prevent breast cancer in adult women… If it works in humans the way it works in mice, this will be monumental. We could eliminate breast cancer.”
Tuohy stated that human trials of the vaccine could begin to enrol patients as early as next year and, if successful, the vaccine could save thousands of lives.
“We believe that this vaccine will someday be used to prevent breast cancer in adult women in the same way that vaccines have prevented many childhood diseases.” He enthused, “If it works in humans the way it works in mice, this will be monumental. We could eliminate breast cancer.”
Source: Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-Wit D, Tuohy VK: EMA approves Prolia® (denosumab) for the treatment of postmenopausal osteoporosis. Nat. Med. DOI:10.1038/nm.2161 (2010) (Epub ahead of print).
Study links oral and nonoral hormonal contraceptives with higher risk of female sexual dysfunction
A study of female German medical students found that women taking hormonal contraception, either in oral or nonoral forms, were found to be at highest risk of female sexual dysfunction (FSD), and, interestingly, women taking nonhormonal contraceptives were at a lower risk for FSD compared with women not using any contraceptive.
“FSD is a very common disorder, with an estimated prevalence of about two in five women having at least one sexual dysfunction, and the most common complaint appearing to be low desire,” comments study author Lisa-Maria Wallwiener from the University of Heidelberg (Germany). Fellow researchers Christian and Markus Wallwiener from the University of Tuebingen (Germany) add that, “The causes of FSD are multifunctional and in recent years the possible role of hormonal contraception has been discussed … Women tend to be aware that sexual dysfunction is often influenced by various factors such as stress and relationships, but our study has shown it might also be influenced by exogenous hormone application.”
Approximately 2.5% of the overall female medical student population in Germany (1086 women) participated in the study, and completed questionnaires designed to identify sexual function problems and lifestyle factors relevant to reproductive health. Of the participants, 87.4% had used contraceptives in the last 6 months, and 97.3% had been sexually active within the last 4 weeks. To study the effect of contraception on sexual function, women using multiple forms of contraception and the 0.7% that had not been sexually active were excluded, leaving 1046 participants. Of these women, 32.4% were considered at risk for FSD: 5.8% at high risk for hypoactive sexual desire disorder, 1% for arousal disorder, 1.2% for decreased lubrication, 8.7% for orgasm disorder, 2.6% for satisfaction problems and 1.1% for pain.
The participants were then divided into four subgroups depending on their class of contraception; oral hormonal contraception (OC), nonoral hormonal contraception (NOHC), nonhormonal contraception (NHC) and no contraception (NC). The group at lowest risk for FSD was NHC, followed by NC and OC, with women on NOHC at highest risk. For desire and arousal, both OC and NOHC groups were the highest risk groups.
“This type of study cannot demonstrate causality but rather association.”
“In future research it would be interesting to see if there is a difference between the dosage of estrogen and the various synthetic progestins used in hormonal contraceptives in terms of an impact on female sexual function,” suggested coauthor Harald Seeger, University of Tuebingen. “We would also urge some caution in interpretation of our present results and would like to highlight that this type of study cannot demonstrate causality but rather association and there might exist a multitude of factors that have an impact on female sexual function.”
Sources: Wallwiener CW, Wallwiener LM, Seeger H, Mück AO, Bitzer J, Wallwiener M: Prevalence of sexual dysfunction and impact of contraception in female german medical students. J. Sex. Med. DOI: 10.1111/j.1743-6109.2010.01742.x. (2010) (Epub ahead of print); Science Daily: www.sciencedaily.com
In brief…
An autoimmune-mediated strategy for prophylactic breast cancer vaccination
Amgen Inc.'s Prolia® (denosumab) has been granted marketing authorization by the EMA for the treatment of postmenopausal osteoporosis in women at increased risk of fractures. It has also been approved for the treatment of bone loss due to hormone ablation in prostate cancer patients at increased risk of fractures and is the first approval of the drug across the World. In addition to the 27 EU member states, denosumab has also been approved in Iceland, Lichtenstein and Norway.
The marketing authorization was based on six Phase III trials and results from the two pivotal studies demonstrated that denosumab reduced the incidence of fractures when administered as a 60 mg subcutaneous injection every 6 months. The Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) trial involved 7808 women with postmenopausal osteoporosis and demonstrated a 68% decrease in the relative risk of suffering a new vertebral fracture, a 40% decrease in the relative risk of suffering a hip fracture and a 20% decrease in the relative risk of suffering a nonvertebral fracture at 36 months, compared with placebo. Bone mineral density was also seen to increase at all skeletal sites tested in all six Phase III studies.
Socrates E Papapoulos, Leiden University Medical Center (The Netherlands), comments, “Osteoporosis is a serious, chronic disease that can significantly impact the lives of millions of affected women. Despite widely available treatments, new options are still needed to help protect against fractures. By targeting RANK Ligand, Prolia offers an innovative new approach that helps reduce fracture risk.”
“…results from the two pivotal studies demonstrated that denosumab reduced the incidence of fractures.”
Approximately 30% of all postmenopausal women in Europe suffer from osteoporosis and, of those, more than 40% will suffer osteoporotic fractures. The marketing authorization of denosumab is a significant breakthrough in the treatment of this silent epidemic.
Source: http://www.ext.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1432232
Novel biomarkers predict resistance to endocrine therapy in breast cancer
Researchers at University College Dublin, Ireland, have identified two new biomarkers that indicate resistance to endocrine therapy in breast cancer patients. These biomarkers could lead to the development of prognostic tests that could also help in the decision regarding which therapies will be most effective for a particular tumor.
“…researchers at University College Dublin have discovered a novel pathway of resistance to endocrine therapy.”
Endocrine therapy, a treatment that involves removal or replacement of hormones, is one of the most effective treatments for breast cancer. However, 40–50% of patients with estrogen receptor-positive breast cancers still relapse following this treatment. Estrogen receptor and HER2 analysis has increased clinicians’ ability to predict who will benefit from endocrine therapy. Nevertheless, resistance to endocrine therapy is still poorly understood.
Now, researchers at University College Dublin have discovered a novel pathway of resistance to endocrine therapy. In this study, they used a proteomics-based approach to identify proteins that are associated with the endocrine-resistant phenotype. In particular, two proteins that interact in the same pathway were identified: HOXC11, a transcription factor of the homeobox family of proteins; and SRC-1, the steroid receptor coactivator protein. These two proteins cooperate to regulate expression of the calciumbinding protein S100beta in resistant breast cancer cells.
Nuclear HOXC11 and S100beta were found to predict poor disease-free survival in breast cancer patients and these proteins could be detected in the blood. The UK based charity Breast Cancer Campaign is funding further work on this project with the aim of developing new blood tests to predict which patients will benefit from which therapies.
“Nuclear HOXC11 and S100beta were found to predict poor disease-free survival in breast cancer patients.”
Leonie Young, the lead researcher on the project, hopes that “this research will provide vital information about drug resistance to ensure that people with breast cancer are getting treatments that will benefit them.”
Source: Royal College of Surgeons in Ireland: www.rcsi.ie