Navigation Links
Gene therapy kills breast cancer stem cells, boosts chemotherapy

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.


Contact: Scott Merville
University of Texas M. D. Anderson Cancer Center

Related biology news :

1. Game-changing project combines anxiety therapy and video games
2. Targeting a cure: Research looks at developing a bulls-eye therapy to combat lung cancer
3. Popular herbal supplements may adversely affect chemotherapy treatment
4. Genetically engineered spider silk for gene therapy
5. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy
6. Mice point to a therapy for Charcot-Marie-Tooth disease
7. Engineering excitable cells for studies of bioelectricity and cell therapy
8. Gene therapy delivered once to blood vessel wall protects against atherosclerosis in rabbit studies
9. Plenary speakers address challenges in the delivery of sustained antiretroviral therapy in developing countries, call for social scientists to take their place at the HIV/AIDS policy-making table, and stress the need for a long-term response to AIDS
10. Trastuzumab and chemotherapy improved survival in HER2-postive breast and brain cancer patients
11. Study uses new stem cell therapy in patients up to 19 days after stroke
Post Your Comments:
(Date:11/16/2015)... , Nov 16, 2015  Synaptics Inc. (NASDAQ: ... interface solutions, today announced expansion of its TDDI ... touch controller and display driver integration (TDDI) ... smartphones. These new TDDI products add to the ... resolution), TD4302 (WQHD resolution), and TD4322 (FHD resolution) ...
(Date:11/11/2015)... , Nov. 11, 2015   MedNet Solutions , ... spectrum of clinical research, is pleased to announce that it ... Clinical Trials (PCT) event, to be held November 17-19 ... able to view live demonstrations of iMedNet ... learn how iMedNet has been able to deliver ...
(Date:11/9/2015)... SAN JOSE, Calif. , Nov. 9, 2015 /PRNewswire/ ... of human interface solutions, today announced broader entry into ... of vehicle-specific solutions that match the pace of consumer ... drivers, and biometric sensors are ideal for the automotive ... the vehicle. Europe , ...
Breaking Biology News(10 mins):
(Date:11/26/2015)... November 26, 2015 --> ... specializing in imaging technologies, announced today that it has received ... of the Horizon 2020 European Union Framework Programme for Research ... clinical trial in breast cancer. , --> ... --> --> The study aims ...
(Date:11/25/2015)...  PharmAthene, Inc. (NYSE MKT: PIP) announced  today that ... plan (Rights Plan) in an effort to preserve the ... Section 382 of the Internal Revenue Code (Code). ... of its NOLs could be substantially limited if the ... 382 of the Code. In general, an ownership change ...
(Date:11/25/2015)... Studies reveal the differences in ... pave the way for more effective treatment for one of ...   --> --> Gum ... in cats, yet relatively little was understood about the bacteria ... been conducted by researchers from the WALTHAM Centre for Pet ...
(Date:11/25/2015)...  Neurocrine Biosciences, Inc. (Nasdaq: NBIX ) announced ... of Neurocrine Biosciences, will be presenting at the 27th ... York . .   ... minutes prior to the presentation to download or install ... be available on the website approximately one hour after ...
Breaking Biology Technology: