ingenious new way to get neural stem cells to rid brain of bc mets (with built-in

[Lani]

self-destruct mechanism!_

PUBLIC RELEASE: 24-APR-2015
Stem-cell-based therapy promising for treatment of breast cancer metastases in the brain
New animal model of breast-to-brain cancer spread allows testing of therapeutic stem cell approach

MASSACHUSETTS GENERAL HOSPITAL


IMAGE: TAGGED THERAPEUTIC STEM CELLS (GREEN) ARE TARGETING BREAST CANCER METASTASES (RED) IN THE BRAIN OF A MOUSE MODEL.e

CREDIT: KHALID SHAH, MS, PHD, MASSACHUSETTS GENERAL HOSPITAL

Investigators from Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute have developed an imageable mouse model of brain-metastatic breast cancer and shown the potential of a stem-cell-based therapy to eliminate metastatic cells from the brain and prolong survival. The study published online in the journal Brain also describes a strategy of preventing the potential negative consequences of stem cell therapy.

"Metastatic brain tumors - often from lung, breast or skin cancers - are the most commonly observed tumors within the brain and account for about 30 percent of advanced breast cancer metastases," says Khalid Shah, MS, PhD, director of the Molecular Neurotherapy and Imaging Laboratory in the MGH Departments of Radiology and Neurology, who led the study. "Our results are the first to provide insight into ways of targeting brain metastases with stem-cell-directed molecules that specifically induce the death of tumor cells and then eliminating the therapeutic stem cells."

In their search for novel, tumor-specific therapies that could target multiple brain metastases without damaging adjacent tissues, the research team first developed a mouse model that more closely mimics what is seen in patients. They found that injecting into the carotid artery breast cancer cells that express markers allowing them to enter the brain - cells labelled with bioluminescent and fluorescent markers to enable tracking by imaging technologies - resulted in the formation of many metastatic tumors throughout the brain, mimicking what is seen in advanced breast cancer patients. Current therapeutic options for such patients are limited, particularly when there are many metastases.

To devise a potential new therapy, the investigators engineered a population of neural stem cells to express a potent version of a gene called TRAIL, which codes for a molecule that activates cell-death-inducing receptors found only on the surface of cancer cells. Previous research by Shah and his colleagues had shown that two types of stem cells are naturally attracted toward tumors in the brain. After first verifying in their model that stem cells injected to the brain would travel to multiple metastatic sites and not to tumor-free areas, the team implanted TRAIL-expressing stem cells into the brains of metastasis-bearing mice, which reduced the growth of tumors. Injecting the TRAIL-expressing stem cells into the carotid artery, a likely strategy for clinical application, led to significantly slower tumor growth and increased survival, compared with animals receiving unaltered stem cells or control injections.

The safe use of a stem-cell-based therapy against brain metastasis would require preventing the engineered cells from persisting within the brain, where they could affect normal tissue and possibly give rise to new tumors. To facilitate removal of the therapeutic stem cells from the brain at the conclusion of therapy, the researchers created cells that, in addition to TRAIL, express a viral gene called HSV-TK, which renders them susceptible to the effects of the antiviral drug ganciclovir. Several tests in cultured cells indicated that ganciclovir would cause the death of HSV-TK-expressing stem cells, and testing in the mouse model confirmed that administration of the drug after successful treatment of brain metastases successfully eliminated therapeutic stem cells that also expressed HSV-TK.

Shah and his team are currently developing similar animal models of brain metastasis from lung cancers and from melanoma. They also are working to improve understanding of the therapeutic efficacy of simultaneously targeting multiple tumor-specific molecules on the surface of metastatic cells within the brain and anticipate that their findings will make a major contribution towards developing novel targeted therapies for metastatic tumors in the brain.

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In addition to Shah, who is an associate professor at Harvard Medical School and a principal faculty member at Harvard Stem Cell Institute, the authors of the Brain report are co-lead authors Wanlu Du, PhD, and Tugba Bagci-Onder, PhD, along with Jose-Luiz Figueiredo, MD, and Jordi Martinez-Quintanilla, PhD - all of the MGH Molecular Neurotherapy and Imaging Laboratory. The study was supported by National Institutes of Health grants CA138922 and NS071197 and a grant from the James McDonald Foundation.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $760 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

[KDR]

This is the future! I'm going for it! Please friends, do your research and search out facilities doing immunotherapy! Do not be afraid! The cure is within YOU!

Karen

[Dakini52]

Thanks for continuing to post the NEWS on this board. I learn something new every day.

[Lani]

ABSTRACT: Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells
[Brain: A Journal of Neurology]
Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications.