Targeted Gene Therapy Takes Down Breast Cancer Stem Cells

An intravenously delivered genetic bomb primed to go off only in breast cancer cells kills tenacious breast cancer-initiating cells, MD Anderson researchers report in this week's edition of Cancer Cell.

In cell line and mouse studies, expression of a mutant version of Bik, a gene known to promote cell suicide, reduced these treatment-resistant breast cancer stem cells by blocking three proteins that prevent cellular self-destruction.

"There are no effective methods to target breast cancer-initiating cells, 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."

The BikDD therapy reduced tumor volume and extended survival in mice with resistant breast cancer while sparing normal cells because the gene therapy package is tuned to stay silent in non-cancerous cells. It also increased the impact of the chemotherapy drug lapatinib, known commercially as Tykerb®å.

The gene therapy 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 that is planned for early 2012.

Hung and colleagues developed VISA, short for versatile expression vector, to deliver, selectively express and amplify gene therapy to tumor cells. VISA includes a promoter gene, which acts like a trigger, two components to amplify expression, and the payload - the enhanced Bik gene called BikDD.

BikDD is modified to more tightly bind and block three proteins in the Bcl-2 family that inhibit cell suicide.  All of these components are packaged in a fatty ball called a liposome.

Any cell can take up the liposome, but it only launches BikDD in breast cancer cells because the promoter gene claudin4, which triggers the therapy, is expressed only in breast cancer cells. In cells without claudin4 expression, the VISA-claudin4-BikDD liposome breaks down harmlessly.

MD Anderson news release: Gene Therapy Kills Breast Cancer Stem Cells, Boosts Chemotherapy

Genetic Engineering & Biotechnology News:  Scientists Use Mutant Protein to Inhibit Cancer Stem Cells and Resensitize Tumors to Lapatinib

Cancer Cell: BikDD Eliminates Breast Cancer Initiating Cells and Synergizes with Lapatinib for Breast Cancer Treatment