Abstract
Researchers are hopeful that their HER2 DNA vaccine may eventually be an answer for women who become resistant to the current anti-HER2 therapies
Breast cancer vaccine successfully eradicates HER2-positive tumors in mice
A new study by researchers at Wayne State University, MI, USA, has raised hopes that a breast cancer vaccine may have the potential to control HER2-positive tumors. Reported in the September 15 issue of Cancer Research, the vaccine was found to successfully eradicate HER2-positive tumors in mice, and was even found to be effective against cancers resistant to the current anti-HER2 therapy. In addition, no signs of toxicity were observed in the mice.
HER2 receptors are responsible for promoting normal cell growth, and are found in small amounts in normal breast cells. However, HER2-positive breast cells can contain many more receptors than is typical, promoting a particularly aggressive type of tumor that affects up to 30% of all breast cancer patients. Therapies exist to treat this form of the disease, including trastuzumab and lapatinib, which target the receptors; however, a significant proportion of patients develop resistance to these therapies, rendering them ineffective. The vaccine developed by Wei and colleagues contains genes that produce the HER2 receptor as well as a compound that stimulates the immune system, both housed in an inert bacterial plasmid.
In the study, electrical pulses were used to deliver the injected vaccine into the leg muscles of mice. Once there, the vaccine produced a huge quantity of HER2 receptors, which triggered a reaction by the animal' immune systems, priming them to fight cancer. The researchers also used an agent that temporarily suppressed the activity of regulatory T cells, allowing the immune system to respond much more strongly to the vaccine. They found that the cancer was subsequetly eliminated when HER2-positive tumors were implanted into the animals
“While HER2 receptors are not usually seen by the immune system when they are expressed at low level on the surface of normal cells, a sudden flood of receptors alerts the body to an invasion that needs to be eliminated,” lead researcher Wei-Zen Wei explains. “During that process, the immune system learns to attack cancer cells that display large numbers of these receptors.”
“The immune response against HER2-positive receptors we saw in this study is powerful. Both tumor cells that respond to current targeted therapies and those that are resistant to these treatments were eradicated. This may be an answer for women with these tumors who become resistant to the current therapies.”
Sarah Rawlings, of the charity Breakthrough Breast Cancer, UK, cautions that this is very early research that has only been carried out in mice, stating, “We don't actually know if it could be used in women. Much more research is needed to find out if it works, to either treat HER2-positive breast cancer or prevent the disease, and if there are any side effects.”
Amy Weise, a member of Wei's research team, makes a similar warning, concurring that research conducted in mice will not translate into success in humans. However, she notes, “It is hopeful.”
Wei states: “The greatest power of vaccination is protection against initial cancer development, and that is our ultimate goal with this treatment.”
Source: Whittington PJ, Piechocki MP, Heng HH et al.: DNA vaccination controls Her-2+ tumors that are refractory to targeted therapies. Cancer Res. 68 (18), 7502–7511 (2008).
The careHPV test demonstrates promise as a primary screening method for cervical cancer prevention in low-resource regions
A new rapid screening test for the human papillomavirus (HPV), created for use in developing countries, has been tested recently on a group of local women in the Shanxi province in eastern China and was demonstrated to be 90% accurate in detecting precancerous cervical disease.
The careHPV was designed by Attila Lorincz, a Professor of Molecular Epidemiology at Barts and The London School of Medicine and Dentistry, London, UK. It can be used to carry out screening in rural areas by personnel with minimal training. The test is able to detect 14 high-risk types of carcinogenic HPV and it can be performed in approximately 2.5 h.
“The clinical performance of my new HPV test in China appears promising, it is based on decades of research…”
Countries in the developed world have the necessary infrastructure to provide cytologic screening, which has led to a 50–80% decrease in mortality. However, to date it has been difficult to use cytologic screening in low-resource settings; there have been problems with taking smears and analyzing them correctly.
Research into the development of a rapid, simple and cheap HPV DNA screening test that could be used in rural and low-resource regions was carried out in collaboration with the Program for Appropriate Technologies in Health (PATH; Seattle WA, USA) and was funded by the Bill and Melinda Gates Foundation.
The test is modified from the Hybrid Capture test, the gold standard routine HPV DNA test, which was created by Lorincz for use in developed countries. It is a signal amplification assay that can be performed in a small bench-top work space.
There is no requirement for mains electricity or running water. The short assay time of approximately 2.5 h allows testing and clinical follow-up on the same day.
“The sensitivity of the test to detect precancerous cells was found to be 90%.”
Using the prototype careHPV test, 2388 women between the ages of 30 and 54 years, from the Shanxi province in China, were screened. The sensitivity of the test to detect precancerous cells was found to be 90%.
“The clinical performance of my new HPV test in China appears promising, it is based on decades of research and I hope it will be employed widely to save the lives of millions of women.
The new test needs to be studied in many countries to confirm its suitability for cervical cancer screening on the global stage,” commented Lorincz.
Source: Qiao YL, Sellors JW, Eder PS et al.: A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China. Lancet Oncol. (2008) (Epub ahead of print).
in brief…
van Dam RM, Li T, Spiegelman D, Franco OH, Hu FB: Br. Med. J. DOI: 10.1136/bmj.a1440 (2008) (Epub ahead of print).
A recent study evaluated the impact of combinations of lifestyle factors on mortality in middle-aged women. A total of 77,782 women aged 34–59 years were enrolled in the study. All women were free from cardiovascular disease and cancer in 1980. The researchers investigated the relative risk of mortality during 24 years of follow-up in relation to five lifestyle factors, including cigarette smoking, being overweight, participating in little moderate-to-vigorous exercise, no light to moderate alcohol intake and low diet quality score. During the study, 8882 deaths were documented, including 1790 from cardiovascular disease and 4527 from cancer. The relative risk for all five lifestyle risk factors compared with zero was 3.26 for cancer mortality, 8.17 for cardiovascular mortality and 4.31 for all-cause mortality. During follow-up, 28% of deaths could be attributed to smoking and 55% to the combination of smoking, being overweight and a low diet quality. Consideration of alcohol intake did not significantly alter this estimate. The researchers conclude that adherence to lifestyle guidelines is associated with a significantly lower mortality in middle-aged women and that those efforts to eradicate cigarette smoking and encourage regular physical activity and a healthy diet should be strengthened.
Chen Z, Maricic M, Aragaki AK et al.: Osteoporos. Int. (2008) (Epub ahead of print).
Researchers enrolled 146,959 postmenopausal women from the Women's Health Initiate prospective cohort. All the women had no history of cancer at baseline and were followed for up to 9 years and classified into the following groups: no cancer, incident breast cancer (BC) and incident other cancer (OC). The main outcomes measured were incident fractures before and after cancer diagnosis.
The results demonstrated that while the hip fracture risk prior to a cancer diagnosis was similar between the no cancer and cancer groups, hip fracture risk was significantly higher following BC diagnosis and the elevated risk was even more notable after OC diagnosis. In addition, risk of falls increased following diagnosis of BC or OC and incident clinical vertebral and total fractures were also significantly increased after OC diagnosis. The authors conclude that postmenopausal women have significantly elevated risks for falls and fractures following a cancer diagnosis. However, the causes for this remain to be elucidated.
Pazopanib demonstrates encouraging results in the treatment of advanced ovarian cancer
A Phase II trial investigating the use of pazopanib in the treatment of advanced ovarian cancer has revealed promising results. Results from the study were recently presented by Michael Friedlander from the Prince of Wales Hospital and Royal Hospital for Women, Sydney, Australia, at the 33rd Congress of the European Society for Medical Oncology (ESMO) in Stockholm.
Every year, approximately 125,000 deaths result from ovarian cancer making it the fifth leading cause of death from cancer in women. “The majority of patients with ovarian cancer will have advanced disease at the time of initial diagnosis,” Friedlander remarked. “Typically, these patients are managed with surgery followed by combination chemotherapy. Unfortunately, most patients will relapse, usually within 2 years following the initial therapy. There is, therefore, a real need to investigate novel agents such as pazopanib to ensure new therapeutic options for patients with ovarian cancer.”
Pazopanib is an oral angiogenesis inhibitor, meaning that it functions by inhibiting the formation of new blood vessels, an important process in the growth and spread of tumors. Pazopanib acts by targeting VEGF receptor (VEGFR), PDGF receptor (PDGFR) and c-kit, three proteins that play a role in angiogenesis.
“The majority of patients with ovarian cancer will have advanced disease at the time of initial diagnosis.”
In the international collaborative trial, pazopanib was administered to 36 patients with recurrent ovarian, fallopian tube or peritoneal carcinoma. The primary en point of the study was elevated CA-125 or small tumors on scans. Each patient was administered pazopanib 800 mg daily. Following treatment, patients were assessed for a decrease in blood levels of the protein CA-125, a cancer antigen that is elevated upon recurrence of the cancer. CA-125 can be detected approximately 3 months prior to the onset of symptoms or scan evidence of recurrence.
The results of the study demonstrated that 31% of the patients had a greater than 50% decrease in CA-125 levels. The drug was generally well tolerated, and any observed side effects were similar to those seen with other angiogenesis inhibitors.
“Many patients with ovarian cancer will have a recurrence of cancer following initial chemotherapy,” Friedlander commented.
“This study clearly demonstrates that pazopanib is an active, well-tolerated drug for women with recurrent ovarian cancer.”
It is expected that an international Phase III study investigating pazopanib for ovarian cancer will now proceed. The drug is also in development for the treatment of advanced or metastatic renal cell carcinoma as well as a variety of other tumor types.
Source: www.gsk.com/media/pressreleases/2008/2008_pressrelease_10105.htm
Resensitizing tumors to antihormonal therapy
Women suffering from hormone receptor-positive metastatic breast cancer are usually treated with antihormonal therapy, such as aromatase inhibitors. These aromatase inhibitors act by decreasing the levels of estrogen in the body. However, over time, the cancer can develop a resistance to endocrine therapy, leaving chemotherapy as the only option for treatment. “At first, the tumor's growth is halted because the aromatase inhibitor is depriving the cancer of the estrogen it needs to grow,” explained Claudine Isaacs, senior investigator of the study and clinical director of the breast cancer program at Georgetown University Medical Center's Lombardi Comprehensive Cancer Center, Washington, DC, USA. “Eventually, though, the cancer will figure out another way to thrive in the absence of the estrogen.”
It is believed that the resistance to aromatase inhibitors is caused by the activation of the ras–raf–MAPK pathway. This prompted Isaacs and colleagues to investigate the effects of sorafenib in overcoming this resistance. Sorafenib was chosen to be examined as it inhibits multiple kinases in the ras–raf–MAPK pathway. The researchers recruited 27 patients, all of whom were postmenopausal women who had receptor-positive metastatic breast cancer that had become unresponsive to aromatase inhibitors. Patients were administered sorafenib 400 mg twice daily plus a standard dose of anastrozole. Upon analysis, a clinical benefit of 26% was observed in patients taking both sorafenib and anastrozole.
It appears from these data that treatment with sorafenib can resensitize the tumor to anti hormonal therapy, thus allowing the aromatase inhibitors to combat the cancer once again. “Given what we know about the ineffectiveness of sorafenib alone in meta-static breast cancer, we believe the benefit that we're seeing may be attributable to the restoration of sensitivity to aromatase inhibitors,” Isaacs concludes. “To manage breast cancer long term, it's apparent that we may need to continually switch drugs to keep up with how a cancer evolves and evades each approach. In a sense, for each step back, we hope to take two steps forward.”
Source: Subramaniam DS, Wilkinson M, Liu M, et al.: Sorafenib in hormone-receptor positive (ER/PR+) metastatic breast cancer (MBC) resistant to aromatase inhibitors (AIs). Presented at: The Breast Cancer Symposium, American Society of Clinical Oncology. Washington, DC, USA, 5–7 September 2008.