WorldCare Consortium® MSO providers Dana-Farber and Boston Children’s Hospital develop a preventive measure to breast cancer
Concept shows great potential to help at-risk women
Researchers and doctors alike recognize the importance of preventing or reversing cancer before patients are in the position of having to treat more advanced cases. Michael Goldberg, Ph.D., of Dana-Farber has contributed to a collaborative group effort into research that demonstrates how particular cancer cases could be prevented and or treated before becoming malignant.
Goldberg in collaboration with the Wyss Institute of Biological Inspired Engineering at Harvard University used gene-knockdown strategy to partially reverse early cases of ductal carcinoma in situ (DCIS) using lab mice prone to the condition. The findings from this study were published in Science Translational Medicine. Following these results, the Wyss Institute encouraged Goldberg to devise a delivery system that could successfully carry gene-silencing snippets called siRNA into breast cells. The strategy behind this was to turn off a gene that researchers had previously pinpointed as the leading gene in DCIS growth. This delivery tool is known as RNA interference (RNAi), which is a natural biological system for reducing gene activity.
Ductal carcinoma in situ is a non-invasive cancer in the milk duct that is non-life threatening unless of course the cells escape the ducts and enter and invade the breast and other tissues. This non-invasive cancer was critical to research because 25 percent of all breast cancer diagnoses are DCIS and of those patients, half will become invasive. Many patients will opt for lumpectomy or mastectomy and may receive radiation to prevent cancer from becoming invasive. Donald Ingber, MD, Ph.D., founding director of Wyss and a pathologist at Boston Children’s Hospital sought an alternative that would prevent such a serious preventive measure.
Ingber strategized the possibility of hunting through a network of genes to identify kingpins in breast cancer, searching abnormal genes that order other genes to misbehave and then block them with targeted molecular agents. Working with Jim Collins, Ph.D., a Wyss faculty member and professor at Boston University, and Hu Li, a postdoctoral fellow on Collins team, they used computers to search through networks of genes looking for a gene that acts suspiciously right before milk-duct cells in the breast begin to grow. This resulted in the identification of a prime suspect, a gene known as HoxA1, which has a statistical link to breast cancer that had not previously been linked to the disease. Post-Doctoral fellow Amy Brock, Ph.D. on Ingber’s team, used siRNA to treat cells from both mice and humans and found that they muted the HoxA1 gene and made the cells reverse back to malignancy. However, siRNA cannot cross the cell membrane, so they turned back to Goldberg who had synthesized molecules called lipidoids that could be used as a delivery mechanism for siRNA.
Goldberg’s approach, referred to as The Trojan Horse approach caused genes to be silenced for weeks inside the body. Now that a delivery mechanism was functional Goldberg had the researchers inject these siRNA-loaded nanoparticles directly into the milk duct through the nipple of the infected mice. Resulting in the infected mice remaining healthy while untreated mice developed breast cancer. Goldberg stated “through a tremendous multidisciplinary collaboration, our team successfully prevented the development of breast cancer in mice that were genetically predisposed to develop the disease. Though this concept is years away from being implemented into clinics, it shows great potential to administer the siRNA to women at increased risk for breast cancer to prevent cancer from ever developing.”
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