Gene therapy kills breast cancer stem cells, boosts chemotherapySeptember 13, 2011
HOUSTON -- Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.
In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.
"There are no effective methods to target BCICs, and they're urgently needed, especially for relapsed breast cancer patients," said senior author Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology. "This research suggests a potential therapeutic approach to breast cancer stem cells that will minimize recurrence and drug resistance."
Special delivery system targets cells
Gene therapy was deposited directly into breast cancer cells with an innovative delivery system called VISA, short for versatile expression vector, which was developed at MD Anderson. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue and a payload -- a Bik mutant gene called BikDD known to kill cancer cells. It's all packaged in a fatty ball called a liposome and delivered intravenously.
This system has been successfully applied in pancreatic, lung, liver and ovarian cancer preclinical models. MD Anderson clinical researchers are preparing a phase I clinical trial for pancreatic cancer.
Stem cells frequently stymie treatment
Breast cancer stem cells, often resistant to chemotherapy and radiotherapy, are a major obstacle for breast cancer treatment, Hung said. If any of these cells remain after treatment, a new tumor often forms. Although lapatinib, known commercially as Tykerb®, can stabilize the level of these cells, no drugs are available to reduce them.
The Bcl-2 family of proteins - especially the subtypes Bcl-2, Bcl-xL and Mcl-1 -- is essential for breast cancer tumor growth and treatment resistance. If too many of these three proteins are present, they can cause poor prognosis and resistance to chemotherapy drugs including lapatinib, as well as paclitaxel, doxorubicin and cisplatin.
This study shows that Bcl-2 proteins help breast cancer stem cells survive, causing resistance to treatment and likelihood of recurrence. However, using VISA to deliver BikDD can block the three key Bcl-2 proteins, eliminating the stem cells.
VISA-claudin4-BikDD cuts tumor burden
The researchers engineered a VISA that contained claudin4, a protein over-expressed in breast cancer, as a targeting agent to preferentially express BikDD in breast cancer cells. This process silenced the three Bcl-2 proteins and caused the cancer cells to self-destruct. Since the VISA focused the BikDD on cancer cells, normal cells were not affected.
Treating mice with the VISA-claudin4-BikDD therapy reduced tumor volume by 75 percent compared to control mice.
They also compared VISA-claudin4-BikDD therapy to BikDD packaged with a non-specific strong promoter from cytomegalovirus. Both versions reduced tumor burden and extended survival of mice, but tumor volume in mice treated with VISA-claudin4-BikDD was half that of the CMV-BikDD-treated mice. In a safety study using an unusually high dose, 60 percent of mice treated with CMV-BikDD survived after three days; all mice treated with VISA-Claudin4-BikDD survived for the duration of the 14-day safety profile study.
In cell line experiments, the CMV-BikDD also invaded and destroyed normal cells, while the VISA-Claudin4-BikDD did not.
Agent energizes lapatinib, other drugs
BikDD made HER2-positive breast cancer cells more sensitive to lapatinib when all three Bcl-2 proteins were inhibited but not when they were inhibited separately. HER2-positive breast cancer is a particularly aggressive type that makes too much human epidermal growth factor 2; it accounts for about 20 percent of breast cancers. BikDD also sensitized EGFR+ (epidermal growth factor positive) breast cancer cells to lapatinib and several other breast cancer cells lines to paclitaxel.
Moving discovery forward
Hung said this approach is promising for breast cancer treatment, especially recurrent disease.
"VISA-claudin4-BikDD gene therapy may provide an effective strategy to inhibit breast tumor growth," he said. "It demonstrates virtually no toxicity in normal cells and produces a profound killing effect in multiple breast cancer cell lines and synergy with other agents."
Hung said the next step is to move VISA-claudin4-BikDD into a Phase I clinical trial to test its effect on patients with breast cancer.
This work was supported by grants from the National Cancer Institute, including MD Anderson's Specialized Program in Research Excellence grant, the MD Anderson/China Medical University Hospital Sister Institution Fund, the Breast Cancer Research Foundation, National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Fund, MD Anderson's Center for Biological Pathways and NCI Cancer Center Support Grant, and the Taiwan Department of Health Cancer Center Research of Excellence Grant.
In addition to Hung, MD Anderson researchers include first author Jing-Yu Lang, Ph.D., first author, Jennifer Hsu, Ph.D., Chun-Ju Chang, Ph.D., Qingfei Wang, Ph.D., Xiaoming Xie, Ph.D., Yi Bao, Ph.D., Hirohito Yamaguchi, Ph.D. and Dihua Yu, M.D., Ph.D., Department of Molecular and Cellular Oncology; Funda Meric-Bernstam, M.D., Department of Surgical Oncology; Wendy Woodward, M.D., Ph.D., Department of Radiation Oncology; and Gabriel Hortobagyi, M.D., Department of Breast Medical Oncology.
Hung and Hsu hold joint appointments at China Medical University and Asia University, Taichung, Taiwan. Xie holds an appointment at Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
University of Texas M. D. Anderson Cancer Center
Related Breast Cancer Current Events and Breast Cancer News Articles
Keep on exercising, researchers advise older breast cancer survivors
To build and maintain muscle strength, it is best for older breast cancer survivors to follow an ongoing exercise program of resistance and impact training.
Biomarker linked to aggressive breast cancers, poor outcomes in African-Americans
Among African-American women with breast cancer, increased levels of the protein HSET were associated with worse breast cancer outcomes, according to results presented here at the Sixth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held Dec. 6-9.
Economic factors may affect getting guideline-recommended breast cancer treatment
Women with interruptions in health insurance coverage or with low income levels had a significantly increased likelihood of failing to receive breast cancer care that is in concordance with recommended treatment guidelines.
Novel method could help bring cancer biomarkers to clinic
An international team of scientists led by Fred Hutchinson Cancer Research Center cancer proteomics expert Amanda Paulovich, M.D., has demonstrated the feasibility of large-scale, standardized protein measurements, which are necessary for validation of disease biomarkers and drug targets.
Computer model suggests genetic breast cancer screening may benefit those at intermediate risk
Archimedes Inc., a healthcare modeling and analytics company, today announced results of a simulated clinical trial which found that the seven single-nucleotide polymorphisms (7SNP) genetic test for breast cancer was most cost effective when used to guide MRI screenings for patients found to have an intermediate lifetime risk of developing the disease.
3-D mammography increases cancer detection and reduces call-back rates, Penn study finds
Compared to traditional mammography, 3D mammography-known as digital breast tomosynthesis-found 22 percent more breast cancers and led to fewer call backs in a large screening study at the Hospital of the University of Pennsylvania (HUP).
Obesity, Smoking Increase Risk of Serious Complications after Immediate Breast Reconstruction with Implants
New research findings published in the December issue of the Journal of the American College of Surgeons confirm that factors such as smoking and obesity increase the odds of early implant loss in women who undergo mastectomy and immediate breast reconstruction with implants.
MR-guided ultrasound offers noninvasive treatment for breast cancer
A technique that uses focused ultrasound under magnetic resonance (MR) guidance to heat and destroy tumors may offer a safe and effective treatment for breast cancer, according to research being presented today at the annual meeting of the Radiological Society of North America (RSNA).
Secrets to 'extreme adaptation' found in Burmese python genome
The Burmese python's ability to ramp up its metabolism and enlarge its organs to swallow and digest prey whole can be traced to unusually rapid evolution and specialized adaptations of its genes and the way they work, an international team of biologists says in a new paper.
Researchers turn to machines to identify breast cancer type
Researchers from the University of Alberta and Alberta Health Services have created a computer algorithm that successfully predicts whether estrogen is sending signals to cancer cells to grow into tumours in the breast.
More Breast Cancer Current Events and Breast Cancer News Articles