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Aboody, Karen S., M.D.

Laboratory of Karen S. Aboody, M.D.
Neural Stem Cells and Cancer Treatment
My translational research laboratory focuses on neural stem cells (NSCs) and their therapeutic clinical applications for invasive brain tumors and metastatic solid tumors. Our novel findings have demonstrated the inherent tumor-tropic properties of NSCs, and their use as delivery vehicles to selectively target therapeutic agents to invasive tumors, including primary and secondary brain tumors, neuroblastoma, and breast carcinoma. We and others have demonstrated their ability to track and localize to infiltrating tumor cells when delivered into the brain, and metastatic tumor sites when delivered intravenously - making NSCs an attractive gene therapy vehicle with tremendous clinical potential.
 
In 2010, we received FDA approval for a first-in-human clinical trial for NSC-mediated therapy for high-grade glioma patients. This phase I study is ongoing at COH, supported by NCI/NIH funding.  Selected members of my laboratory are HIPAA and GMP trained, and prepare the NSCs for patient transplantation. In 2010, we also received an $18MM California Institute of Regenerative Medicine (CIRM) Disease Team Award to develop a second-generation enzyme/prodrug stem cell-mediated cancer therapy. (PI: K Aboody, Co-PIs: J Portnow, L Couture). This milestone driven translational research project is planned to result in a new FDA IND submission for brain tumor treatment in 2014. The therapeutic paradigm uses NSCs to deliver a CPT-11 (irinotecan) activating enzyme to increase its tumor-killing effect up to 1000 fold at the tumor sites. We believe this NSC-mediated treatment may have applications for other cancers as well.
 
We use various preclinical tumor models to test intracranial and intravenous delivery of NSCs to target various therapeutic agents to tumor sites. Therapeutic approaches being explored include enzyme/prodrug, oncolytic virus, antibody, and small molecule drug delivery.  Our lab has many leading-edge, collaborate projects in progress, including an NIH/NINDS U-01 with Univ. of Chicago (PI: M Lesniak), that is planned to lead to a new NSC-mediated clinical trial in 2014.  We are also working closely with CHLA, USC (R Moats) on iron labeling of NSCs for MRI cellular tracking. We have currently completed toxicity studies, and have submitted an amendment to the FDA to add this iron-labeling of NSCs to our current clinical trial. This would be a first in human use of ferumoxytol (Feraheme) as a cell tracker in patients.  In collaboration with Drs. M Barish and C Glackin, we are also trying to 1) identify the biological mechanisms and signally pathways involved in the directed migration of NSCs to tumor cells; 2) investigate the endogenous stem cell response to tumors; and 3) investigate the origin and progression of brain and breast cancers. The field of stem cell research is at the frontier of medical research – there are many exciting directions of investigations to pursue in order to better understand their function and development, with a wide array of potential clinical applications to explore.
 
For more information about Dr. Aboody, click here.
 

Research

Neural Stem Cells Target Human Primary and Metastatic Tumors in Animal Models: Therapeutic Strategies
 
Introduction and Preliminary Data
Neural Stem Cells (NSCs), by virtue of their inherent migratory and tumor-tropic properties, represent a unique and potentially powerful approach for the treatment of invasive tumors. Utilized as a delivery vehicle to target and disseminate therapeutic gene products to tumor sites, NSCs may meet two major challenges facing current gene therapy strategies: effective delivery and distribution of a therapeutic agent throughout the tumor masses and to aggressive infiltrative tumor cells.  We previously demonstrated that murine C17.CD2 NSCs could deliver a bioactive therapeutically relevant molecule to effect a significant anti-tumor response in experimental intracranial glioma models. Further studies demonstrated retention of tumor-tropic properties when these NSCs were injected into the peripheral vasculature, even when the tumor was established outside the cranial vault, i.e. subcutaneous flank. When injected into the tail vein of animals with intracranial and/or subcutaneous flank tumors, the murine NSCs localized to both tumor sites, with little accumulation in normal tissues.
 
We previously demonstrated that murine C17.CD2 NSCs could deliver a bioactive therapeutically relevant molecule to effect a significant anti-tumor response in experimental intracranial glioma models. Further studies demonstrated retention of tumor-tropic properties when these NSCs were injected into the peripheral vasculature, even when the tumor was established outside the cranial vault, i.e. subcutaneous flank. When injected into the tail vein of animals with intracranial and/or subcutaneous flank tumors, the murine NSCs localized to both tumor sites, with little accumulation in normal tissues.
 
Neural Stem Cells Distribute Efficiently throughout Primary Brain Tumor Mass
CNS-1.GFP invasive rodent glioma cells, were implanted into the frontal lobe of adult nude mice followed 6 days later by transplantation of NSCs directly into the main tumor bed. Note efficient distribution of NSCs throughout main tumor bed, and localizing to invasive tumor islands and cells, and not seen elsewhere in the brain.
 
Neural Stem Cells Selectively Track Infiltrating Tumor Cells
Of note, whether NSCs are injected directly into tumor bed, or at a distance form main tumor (including ventricular or intravascular administration), they are able to localize to main tumor sites, invading tumor islands, and individual tumor cells in the brain.
 
Therapeutic Proof of Concept
The NSCs in the above figures were expressing a reporter gene. These NSCs can also be engineered to stably express therapeutic genes. We can therefore utilize them as cellular delivery vehicles to target therapeutic agents directly to tumor sites. In the following proof-of-concept paradigm, we achieve production of localized chemotherapy to produce a significant therapeutic effect in a metastatic brain tumor model. NSCs are engineered to produce an enzyme, cytosine deaminase, which can convert a systemically administered pro-drug (5-FC) to an active chemotherapeutic agent (5-FU), which diffuses out of the stem cells to selectively kill the surrounding dividing tumor cells. in vivo example shown in Figure 3, schematic representation of paradigm shown below:
 
NSCs expressing cytosine deaminase were injected into brain parenchyma of animals with established melanoma metastasis. After 3 days, in which time NSCs localized specifically to tumor sites, animals received tail vein injections of 5-FC prodrug for eight days. Representative brain tissue sections of untreated vs. treated animals shown. Tumor area is dark purple delineated by red outline.
 
Therapeutic Paradigm Schematic
In this case, stem cells were engineered to express the pro-drug activating enzyme, cytosine deaminase. Once cells are injected into animal tumor models, and localize to tumor sites, the 5-FC pro-drug is given systemically. Result is production of chemotherapeutic agent localized to tumor sites.
 

Lab Members

Lucy Ghoda Ph.D.
CIRM Disease Team Project Manager
 
Joseph Najbauer, Ph.D.
Associate Research Professor
 
Margarita Gutova, M.D.
Assistant Research Professor
 
Rachael Mooney, Ph.D.
Post-doctoral CIRM Scholar
 
Donghong Zhao, Ph.D.
Post-doctoral Fellow
 
Marianne Metz
Staff Scientist
 
Elizabeth Garcia, R.V.T.
Research Associate II
 
Soraya Aramburo
Research Associate II
 
Zhongqi Li, Ph.D.
Research Associate II
 
Kelsey Herrmann, B.S.
Research Associate II
 
Tien Vo
Research Associate I
 
Revathiswari Tirughana, B.S.
Research Associate I
 
Yelena Abramyants,
Laboratory Technician
 
Valerie Valenzuela,
Laboratory Technician
 
Monika Polewski, B.A.,
City of Hope Graduate Student
 
Patrick Perrigue, B.S
City of Hope Graduate Student
 
Megan Gilchrist
CIRM Bridges Intern
 
Michael Silva
CIRM Bridges Intern
 
Kenna Schnaar
CIRM Bridges Intern
 
Elizabeth Ochoa
Senior Secretary, Dr. Aboody’s Laboratory
 
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