Posts Tagged ‘obesity’

Study identifies gene network behind untreatable leukemia, possible treatment target

Scientists from the Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children’s Hospital Medical Center report their results in a study posted online Sept. 4 by Cell Reports.

The specific forms of AML and MDS in the current study involve deletions on the arm of a specific chromosome in blood cells (del(5q). In patients with less aggressive forms of del(5q) MDS, the percentage of bone marrow blasts in their blood (the earliest, most immature cells of the myeloid cell line) is less than 5 percent. This means treatment prognosis for those patients typically is good, according to the study’s lead investigator, Daniel Starczynowski PhD, a researcher in the division of Experimental Hematology and Cancer Biology, part of the CBDI at Cincinnati Children’s.

“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” Starczynowski said. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”

The researchers conducted their study in human AML/MDS cells and mouse models of del(5q) AML/MDS. They found that reduced expression of a certain gene in blood cells (miR-146a) led to activation of a molecular signaling network involving several components of NF-kB, one of which involved a protein called p62 — a critical regulator of cell metabolism, cellular remodeling and certain cancers.

Deletion of the miR-146a gene led to overexpression of p62, which caused sustained activation of what researchers identified as an NF-kB signaling network. This fueled the survival and aggressive growth of leukemic cells in cells and in mouse models.

Earlier attempts in previous studies to directly inhibit NF-kB (a key molecular facilitator to the leukemic process) have not proven successful, according to investigators on the current paper. So the authors performed follow-up laboratory tests to look for possible vulnerabilities to NF-kB and a potential workaround by targeting instead p62 within the NF-kB signaling network.

The researcher next tested inhibiting/knocking down p62 as an experimental treatment strategy in mouse models of leukemia and in human cells. The authors reported that targeting p62 prevented expansion of leukemic cells in mouse models and reduced the number of leukemia cell colonies by 80 percent in human AML/MDS cells.

Starczynowski stressed that significant additional research is needed to further verify the findings and learn more about the molecular processes involved. He also cautioned that laboratory results in mouse models do not necessarily translate to humans, and it isn’t known at this time how the findings might be directly applicable to clinical treatment.

source : http://www.sciencedaily.com/releases/2014/09/140904131603.htm

Blood test for ‘nicked’ protein predicts prostate cancer treatment response

The study evaluated two groups of 31 men with prostate cancer that had spread and whose blood levels of prostate-specific antigen (PSA) were still rising despite low testosterone levels. Investigators gave each man either enzalutamide (Xtandi) or abiraterone (Zytiga) and tracked whether their PSA levels continued to rise, an indication that the drugs were not working. In the enzalutamide group, none of 12 patients whose blood samples tested positive for AR-V7 responded to the drug, compared with 10 responders among 19 men who had no AR-V7 detected. In the abiraterone group, none of six AR-V7-positive patients responded, compared with 17 responders among 25 patients lacking AR-V7.

Enzalutamide and abiraterone have been very successful in lengthening the lives of about 80 percent of patients with metastatic prostate cancer, says Emmanuel Antonarakis, M.D., assistant professor of oncology at Johns Hopkins, but the drugs do not work in the remaining 20 percent of patients.

“Until now, we haven’t been able to predict which patients will not respond to these therapies. If our results are confirmed by other researchers, a blood test could use AR-V7 as a biomarker to predict enzalutamide and abiraterone resistance, and let us direct patients who test positive for AR-V7 toward other types of therapy sooner, saving time and money while avoiding futile therapy,” says Antonarakis.

Prostate cancer thrives on male sex hormones (or “androgens”), including testosterone. Enzalutamide and abiraterone target proteins called androgen receptors and block the receptors’ ability to activate prostate cancer cells. AR-V7 is a shortened form of the androgen receptor that lacks a binding spot targeted by enzalutamide and abiraterone. With no binding spot for the two drugs, AR-V7 is free to manipulate prostate cancer cells’ genetic material, which makes the cancer cells grow and spread.

Antonarakis and his colleague Jun Luo, Ph.D., who first identified AR-V7 in 2008, also tracked patients’ progression-free survival (the length of time a patient lives with the disease but does not get worse) and overall survival. They found that, in men receiving enzalutamide, progression-free survival was 2.1 months in AR-V7-positive patients and 6.1 months in AR-V7-negative patients, while overall survival was 5.5 months in AR-V7-positive men and up to 9 months in AR-V7-negative men. Similarly, in men receiving abiraterone, progression-free survival was 2.3 months in AR-V7-positive patients and up to 6 months in AR-V7-negative patients, while overall survival was 10.6 months in AR-V7-positive men and up to 12 months in AR-V7-negative men. The investigators caution that most of the study patients had advanced disease and received multiple prior therapies, so their outcomes may not be generalizable to all men with prostate cancer.

“Patients whose blood samples contained AR-V7 got no benefit from either enzalutamide or abiraterone,” says Antonarakis. He adds that the shortened AR-V7 protein could appear in patients’ blood samples at the very start of therapy or acquired later, after therapy has begun. He says, “This test could be used before starting enzalutamide or abiraterone therapy, and if the test shows the presence of AR-V7, patients may opt for a different therapy. It could also be used to monitor patients receiving enzalutamide or abiraterone for AR-V7, providing an indication these drugs may not work for much longer.”

source : http://www.sciencedaily.com/releases/2014/09/140903203752.htm

Disparities persist in early-stage breast cancer treatment

The study, to be presented at the 2014 Breast Cancer Symposium, finds that those barriers that still exist are socio-economic, rather than medically-influenced. Meeghan Lautner, M.D., formerly a fellow at MD Anderson, now at The University of Texas San Antonio, will present the findings.

BCT for early stage breast cancer includes breast conserving surgery, followed by six weeks of radiation. It has been the accepted standard of care for early stage breast cancer since 1990 when randomized, prospective clinical trials confirmed its efficacy — leading to the National Institute of Health issuing a consensus statement. Yet, a number of patients still opt for a mastectomy. In hopes of ultimately democratizing care, it was important to look at surgical choices made by women and their association with disparities, explains Isabelle Bedrosian, M.D., associate professor, Surgical Oncology at MD Anderson.

“What’s particularly novel and most meaningful about our study is that we looked at how the landscape has changed over time,” says Bedrosian, the study’s senior author. “We hope this will help us understand where we are and are not making progress, as well as identify the barriers we need to overcome to create equity in the delivery of care for our patients.”

For the retrospective, population-based study, the MD Anderson team used the National Cancer Database, a nation-wide outcomes registry of the American College of Surgeons, the American Cancer Society and the Commission on Cancer that captures approximately 70 percent of newly-diagnosed cases of cancer in the country. They identified 727,927 women with early-stage breast cancer, all of whom were diagnosed between 1998 and 2011 and had undergone either BCT or a mastectomy.

Overall, the researchers found that BCT rates increased from 54 percent in 1998 to 59 percent in 2006, and stabilized since then. Adjusting for demographic and clinical characteristics, BCT use was more common in women: age 52-61 compared to younger or older patients; with a higher education level and median income; with private insurance, compared to those uninsured; and who were treated at an academic medical center versus a community medical center.

Geographically, BCT rates were higher in the Northeast than in the South, and in those women who lived within 17 miles of a treatment facility compared to those who lived further away.

An important question to then ask, says Bedrosian, was to compare barriers for women receiving BCT in 1998 to 2011 — and understand how have those barriers changed. The researchers found that, overall, usage of BCT has dramatically increased across all demographic and clinical characteristics, however, significant disparities related to insurance, income and distance to a treatment facility still exist.

Bedrosian is gratified to see that in the areas where physicians and the medical field can make a direct impact — such as geographic distribution and practice type — disparities have equalized over time. However, she notes that factors outside the influence of the medical field, such as insurance type, income and education, still remain. Of great interest is the insurance disparity, says Bedrosian.

“Now with healthcare exchanges providing new insurance coverage options, will we rectify the disparity and overall increase BCT use? We will have wait to see,” she says.

Bedrosian hopes that health policy makers will take note of the findings and barriers related to women receiving BCT and make appropriate changes to democratize care.

source : http://www.sciencedaily.com/releases/2014/09/140904103338.htm