RANKL, A Key Factor In Breast Cancer Metastasis.

When doctors discover high concentrations of regulatory T cells in the tumors of breast cancer patients, the prognosis is often grim, though why exactly has long been unclear.
Now new research at the University of California, San Diego School of Medicine suggests these regulatory T cells, whose job is to help mediate the body’s immune response, produce a protein that appears to hasten and intensify the spread of breast cancer to distant organs and, in doing so, dramatically increase the risk of death.
The findings are reported in the Feb. 16 advance online edition of the journal Nature.
The researchers found that mice with breast cancer were more likely to develop metastatic lung cancer due to elevated levels of RANKL, an inflammatory protein normally involved in bone remodeling. Regulatory T cells were found to be the primary source of RANKL in these tumors. However, the same increase in metastasis was seen when synthetic RANKL was injected directly into tumors, suggesting that RANKL was the key to the ability of regulatory T cells to promote the spread of breast cancer. The scientists also determined that interfering with the ability of RANKL to interact with cancer cells seemed to block tumor progression, and may represent a potential target for drug therapy.

“What is exciting about this study is that now that we understand an increase in RANKL translates to an increase in metastasis, we can get to work on figuring out ways to stop or slow the production of RANKL in breast cancer patients,” said Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UCSD's Laboratory of Gene Regulation and Signal Transduction and Moores Cancer Center.

RANKL is a well-known factor in a variety of degenerative bone diseases, including rheumatoid arthritis and bone metastasis. In June 2010, the Food and Drug Administration approved the first RANKL-inhibiting drug for use in postmenopausal women at risk for osteoporosis.

“When we were able to control the RANKL production in the mice, we were able to slow or stop the spread of the cancer,” Karin said. “The next logical step is to turn to drugs that block RANKL production to see how they might affect the spread of breast cancer.”

Other breast cancer studies have linked RANKL to early stages in the development of synthetic progestin-driven breast tumors. According to the Women’s Health Initiative and the Million Women Study, hormone replacement therapy and contraceptives with progestin significantly increase the risk of developing breast cancer. The findings from these studies and the new UCSD research suggest that drugs that block RANKL may be effective in preventing both the early stages of breast cancer and the advanced progression of the disease.
Collaborators on the study are first authors Wei Tan and Weizhou Zhang, Amy Strasner and Sergei Grivennikov, UCSD Laboratory of Gene Regulation and Signal Transduction; Jin Q. Cheng, Department of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, Fla.; and Robert M. Hoffman, AntiCancer Inc, San Diego.
The research was supported by the National Institutes of Health, Susan G. Komen Breast Cancer Foundation and Crohn’s and Colitis Foundation of America.
The journal Nature.

Breast Cancer Clinical Trials And Quality Of Life (QOL) A Quality And Value Assesment

Even though the incorporation of Quality of Life (QOL) in clinical studies of cancer treatment trials began more than 30 years ago, it was reported that only 60 such trials included QOL in the study, before the year 2000. But it is changing, a research team led by Julie Lemieux, MD, from the Université Laval in Québec City, Quebec, Canada.found that during the period of 2001-2009, this number jumped to 190. The report is an extension to the study carried out by the same group previously. Dr. Patricia Ganz, the editor of the editorial accompanying the report says that these researchers are extending our understanding of how QOL and treatment trials interact;

how measurement of QOL outcomes adds value to randomized clinical trials in breast cancer. During the past decade, an impressive number of trials were published (n = 190) that added to those previously reported on (n = 66), reflecting the increasing interest in the inclusion of QOL and patient-reported outcomes in clinical trials, as well as the high volume of treatment and behavioral intervention research focused on patients with breast cancer

The authors also found limitations to these studies even thought he incorporation of QOL is increasing in the Cancer treatment clinical trials. The inconsistencies lies in the quality statical methods, description of statistical power and/or sample size calculation for the QOL outcomes, documentation of missing data, and reporting of the clinical significance of the QOL findings.

The authors provide the following recommendations based on their updated review findings:

1) QOL should be included as a secondary endpoint in adjuvant therapy trials only when the treatment expectation is equivalence or noninferiority, for example, when treatment decisions will be based on differences in patient outcomes between study arms or when the trial focuses on a vulnerable population (eg, elderly women) or is testing substantially different modalities (eg, endocrine vs chemotherapy) or a new treatment for which descriptive information is needed; 

2) QOL assessments should be included in metastatic breast cancer treatment trials only when a minimal survival difference is expected or the treatments have substantial differences in toxicity or descriptive information about a new treatment is needed; 

3) QOL-specific sample size calculations should be performed and QOL should be measured only in the subset of the study population that was defined by these calculations; 

4) when QOL is not the primary trial endpoint, the results should ideally appear in a companion article published at the same time as the medical outcomes article, so that a complete appraisal of the risks and benefits of the intervention can be evaluated (

1. Lemieux J, 
2. Goodwin PJ, 
3. Bordeleau LJ, 
4. Lauzier S, 
5. Theberge V

. Quality-of-life measurement in randomized clinical trials in breast cancer: an updated systematic review (2001-2009). J Natl Cancer Inst. 2010;103(3):xxx-xxx.).

Full Text of the article at the JNCI, The Journal Of The National Cancer Institute

New Class Of Drug Might Improve Herceptin (trastuzumab) Capability In Treating Aggressive Form Of Breast Cancer

The Breakthrough Breast Cancer-funded team at the University of Oxford showed that combining Herceptin with pan-HER inhibitors kills cancer cells much more effectively than Herceptin on its own. The drug combination does this by knocking out the activity of HER2 and, crucially, its related proteins, too. These results were then confirmed in mouse models.
Dr Anthony Kong, the Breakthrough Breast Cancer clinician scientist who led the study, said: “It was incredible to see how much more potent Herceptin becomes when combined with a new type of drug. We think this could have a big impact in improving survival rates for patients with HER2 positive breast cancer. “We are hoping to set up a clinical trial in the near future to test this treatment combination in patients.”

Source

pan-HER

SAN DIEGO, Dec. 20, 2010 /PRNewswire/ -- Ambit Biosciences (Ambit), today announced that it has initiated separate Phase I trials for two products AC430, a selective Janus Kinase 2 (JAK2) inhibitor, and AC480, a pan-HER inhibitor.

The Phase I trial for AC430 is a two part, placebo-controlled, single ascending, and multiple ascending dose trial in healthy volunteers.  AC430 will be administered orally once-daily and doses escalated until a maximum tolerated or maximum feasible dose is established.  In addition to evaluating the safety, tolerability, and pharmacokinetics of AC430, the study will also assess cytokine signal transduction.  

The Phase I trial for AC480 is a multi-center, dose escalation study with AC480 administered by intravenous infusion on days one and two of a 21 day cycle, either alone or in combination with docetaxel.  The trial will assess safety, pharmacokinetics and anti-tumor activity of AC480 in patients with advanced solid tumors.

"The initiations of these studies are important milestones," said Alan Lewis, President and CEO Ambit Biosciences. "AC430 has demonstrated convincing efficacy in pre-clinical models of autoimmune and inflammatory diseases, and AC480 IV was developed to assess whether pulsatile doses of a pan-HER inhibitor administered in combination with a taxane such as docetaxal would produce synergistic anti-tumor activity."

About AC430

AC430 was specifically developed to be a best-in-class JAK2 inhibitor.  In preclinical studies, AC430 has exhibited potency against JAK2 in cell-based models that is at least equivalent, and in most cases superior to, competing JAK2 inhibitors, and also has excellent oral pharmacokinetic properties.  In preclinical oncology and autoimmune models, AC430 is well tolerated and has significant efficacy at oral doses as low as 10 mg/kg/day.  JAK2 has been implicated as a target for therapy in both oncology and autoimmune disease.

About AC480

AC480 is a small molecule kinase inhibitor that selectively inhibits the HER family of receptors, HER1, HER2, HER3 and HER4.  Excessive HER signaling has been associated with the development of a wide variety of types of solid tumors, including those found in lung, breast, head and neck and brain cancers.  Currently marketed HER inhibitors inhibit only one or two of the HER family members and a pan-HER inhibitor that inhibits all of the HER receptors may be effective in more cancer types.  Published data with oral HER inhibitors administered in combination with taxanes, such as docetaxel, demonstrate activity in clinical studies and these clinical data are supported by preclinical data demonstrating that combining HER inhibitors with taxanes produces synergistic anti-tumor activity.  An intravenous formulation of a pan-HER inhibitor such AC480 enables high pulsatile doses to be administered in combination with taxanes.

About Ambit Biosciences

Ambit Biosciences Corporation is a biotechnology company engaged in discovering, developing and commercializing targeted small molecule therapeutics for the treatment of cancer.

Ambit contacts:

Alan Fuhrman, Chief Financial Officer, Ambit Biosciences (858) 334-2133, afuhrman@ambitbio.com

Christopher Morl, Chief Operating Officer, Ambit Biosciences (858) 334-2134, cmorl@ambitbio.com

Triple-Negative Breast Cancer A Review On Current Concepts.

Tripple Negative Breast Cancer appeared on PubMed, (A medical document archive) somewhere in 2006 and since then it has grown to be about 600 articles. This also shows the interest by oncologists, pathologists, and geneticists, and certainly by the approximately 12 to 17% of women with breast cancer who have triple-negative breast cancer. Triple breast cancer is generally diagnosed based upon the presence, or lack of, three "receptors" known to fuel most breast cancers: estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2). The most successful treatments for breast cancer target these receptors.
A triple negative breast cancer diagnosis means that the offending tumor is estrogen receptor-negative, progesterone receptor-negative and HER2-negative, thus giving rise to the name established as "triple negative breast cancer."
There is a Foundation, TNBF (Tripple Negative Breast Cancer Foundation) which  is devoted to finding targeted treatment for triple negative breast cancer. You too can help them as well as download PDF of the Guide to Understanding Triple Negative Breast Cancer,
A team of experts, including Dr. Foulkes at the Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, have written an article on current concepts on Tripple Negative Breast Cancer with concluded with the following conclusion.
The article is available at NEJM, New England Journal of Medicine and from McGill University.

Histologic and Immunohistochemical
Features of Triple-Negative and Core Basallike
Breast Cancers.

Taken in their entirety, triple-negative and basal like breast cancers show aggressive clinical behavior, but a subgroup of these cancers is markedly sensitive to chemotherapy and is associated with a good prognosis when treated with conventional chemotherapy regimens. Furthermore, some triple-negative and basal-like cancers may harbor a dysfunctional BRCA1 pathway and thus may be sensitive to agents such as platinum salts and inhibitors of the PARP enzyme that selectively target cells deficient in homologous recombination DNA repair. It seems very likely that neither triple-negative nor basal-like breast cancers are single entities but rather are a collection of different diseases. Hence, studies that address the molecular underpinning of this heterogeneity and attempt to identify the drivers of therapeutically relevant subgroups of triple-negative and basal-like breast cancers are warranted.
A diagnosis of triple-negative disease has currently important implications for the choice of systemic therapies. Given the lack of an internationally accepted definition of basal-like breast cancer, it is not surprising that this diagnosis has no clinical implications — especially since a substantive portion of these cancers may be ER-positive or may over express HER2. It could be argued that instead of identifying descriptive and prognostic molecular subgroups (e.g., basal-like and claudin-low) within the triple-negative group, it would be more clinically relevant to identify those patients whose triple-negative tumors are sensitive to specific chemotherapy agents (or combinations thereof) and targeted therapies. The expressions “triple-negative” and “basal-like” are essentially operational rather than diagnostic. In time, they will probably be replaced by other, more specific terminology.

OncoSemantic, A Portal, Database And A Social Hub Fro Oncology Information.

We are in the process of preparing the OncoSemantic, a site focusing on oncology (cancer) information, chemotherapy protocols, oncology research, cancer treatment regimens and even individual drugs. The site is mainly meant for Healthcare providers in the field of Oncology but we are confident, that everyone will find, valuable information.
Bringing together all the data together via semantic technologies will aid all users since thay do not need to traverse, hundreds of sites, just to get information on, just say, breast cancer.