“I live to cure cancer.”
Losing a sister to breast cancer over a decade ago inspired Karen S. Aboody, M.D., to make the battle against cancer her life's work.
Dr. Aboody is at the forefront of research into using neural stem cells to assist in the delivery of chemotherapy to brain tumors, a critical step in attacking invasive tumors that cannot be successfully treated through surgery or other means.
A member of the City of Hope staff since 2003, Dr. Aboody received her medical degree at New York's Mount Sinai School of Medicine and received further training at Harvard Medical School.
Overview: Neural stem cells (NSCs) have a natural ability to home to malignant tumors and invasive tumor cells, making them an ideal delivery vehicle for transporting therapeutic agents to tumor sites. Dr. Aboody and colleagues at COH were the first in the world to move this therapeutic strategy from “bench to bedside” for brain tumor patients, demonstrating safety of their NSCs.
My translational research laboratory focuses on neural stem cells (NSCs) and their therapeutic applications for primary and metastatic tumors. Our novel findings have demonstrated the inherent tumor-tropic property of NSCs, and their use as cellular delivery vehicles to effectively target and deliver therapeutic payloads to invasive tumor sites, including brain tumors and metastatic cancers. Their capacity for tracking infiltrating tumor cells and localizing to distant micro-tumor foci make NSCs a novel and attractive tumor selective delivery vehicle with tremendous clinical potential. In effect, the NSCs serve as a platform for tumor-localized therapy, which should also minimize toxicity to normal tissues. Our current research focuses on modifying human NSCs to deliver different therapeutic agents to tumor sites in animal models.
Clinical Trials: In 2013, we completed a first in-human FDA approved safety/feasibility NSC clinical trial at City of Hope in patients with recurrent high-grade gliomas (clinical PI: Dr. Jana Portnow, MD). The NSCs delivered an enzyme (cytosine deaminase; CD) that converts an inactive prodrug (5-flurocytosine; 5-FC) to an active chemotherapeutic agent (5-Flurouracil; 5-FU). The 5-FU produced by the NSCs diffuses into surrounding brain tumor tissue, selectively killing dividing tumor cells. By producing the chemo drug only at the tumor sites, systemic side effects are minimized. Results of this study demonstrated: 1) safety of administering therapeutic NSCs into the brain tumor resection cavity or biopsy site; 2) proof of concept for tumor-localized chemotherapy production – demonstrating that the CD-expressing NSCs were able to convert oral 5-FC to the active chemo drug 5-FU, locally in the brain; and 3) no significant immune response following one round of treatment. A phase I dose escalation, multi-treatment round study is currently accruing patients at COH.
1. NSCs delivering a prodrug activating enzyme for tumor-localized chemotherapy production: CD-NSCs + 5-FC → 5-FU
Funding: STOP Cancer, COH, The Rosalinde and Arthur Gilbert Foundation, The Ziman Family Foundation, NIH-NCI (Portnow, Aboody)
NSCs are genetically modified to express cytosine deaminase (CD). When the inactive prodrug 5-FC is administered, it crosses the BBB and gets converted to the active chemotherapeutic 5-FU by the CD expressing NSCs locally at the brain tumor sites. In effect, allowing for tumor localized chemotherapy production, and reducing toxic side effects to normal tissues.
2. NSCs delivering a prodrug activating enzyme for tumor-localized chemotherapy production: CE-NSCs + IRN → SN-38
Funding: California Institute of Regenerative Medicine, NIH-U01, The Rosalinde and Arthur Gilbert Foundation, STOP Cancer, Mary Kay Foundation (Berlin, Aboody)
NSC-mediated CE/Irinotecan (CPT-11) enzyme/prodrug therapy. NSCs localize to metastatic tumor sites and express the CE enzyme. CE converts the intravenously administered CPT-11 (irinotecan) prodrug to the active chemotherapeutic drug SN-38. SN-38 is highly toxic to the surrounding tumor cells
In 2010, we were granted an $18M CIRM Disease Team Award to move a 2nd generation enzyme/prodrug therapeutic toward clinical trials (Co-PIs: Jana Portnow, MD and Larry Couture, PhD). Collaborators include the Synold lab for pharmacology, the Barish lab for 3D tumor reconstruction, the Forman lab (C Brown) for xenogen imaging and tumor modeling, and the Moats lab at Children’s Hospital Los Angeles for MRI imaging. We also work closely with the Center for Biomedicine & Genetics and the Office of IND Development and Regulatory Affairs. An IND has been submitted and we expect to initiate a phase I study for this NSC-mediated brain tumor therapy in 2015. We are also funded $4.7M by an NIH-U01 (in collaboration with CHLA and St. Jude) to move this same product to clinical trial for pediatric patients with metastatic neuroblastoma by 2017.
3. NSCs delivering internalized gold nanoparticles for thermal ablative therapy
in collaboration with Jacob Berlin laboratory, COH
After loading NSCs with gold nanorods (NSC-AuNPs), they are administered (current preclinical investigations focusing on bladder and prostate cancer). Following migration of NSCs to tumor sites, localizing the gold particles, near infrared laser is applied, causing the gold nanoparticles to vibrate and generate heat – ‘burning’ surrounding tumor tissue.
Funding: COH, The Rosalinde and Arthur Gilbert Foundation, STOP Cancer, Alvarez Family Charitable Foundation, Mary Kay Foundation (Berlin, Aboody), Ladies Auxiliary Veteran’s Grant (Mooney)
4. NSCs delivering external nanoparticles for small molecule drug delivery
in collaboration with Jacob Berlin laboratory, COH
In collaboration with Dr. Berlin we are constructing NSC-NP hybrids, where the NPs are being constructed to release drug after NSCs reach the tumor. The NPs will be externally bound to the NSCs. Our initial preclinical studies are focused on peritoneal ovarian cancer metastases, for potential translation tp patients with Stage III ovarian carcinoma.
Funding: COH, Anthony F. & Susan M. Markel Fund, NIH, The Rosalinde and Arthur Gilbert Foundation, STOP Cancer, Alvarez Family Charitable Foundation. Ladies Auxillary Veteran’s Grant (R Mooney)
5. NSC Oncolytic Virotherapy
in collaboration with Maciej Lesniak laboratory, University of Chicago
Funding: NIH-U01 (PI, Lesniak)
We are further modifying our clinically relevant NSC line to produce conditionally replication competent oncolytic virus, CRAd-Survivan-pk7, for application to newly diagnosed glioma patients.
Translational Research Overview
Additional research investigations early in the pipeline include:
Aboody Lab 2015
Margarita Gutova, M.D.
Associate Research Professor
Rachael Mooney, Ph.D.
Post-doctoral CIRM Scholar
Marianne Metz, Ph.D.
Staff Scientist, Lab Manager
Research Associate II, Small Animal Surgery Supervisor
Zhongqi Li, Ph.D.
Research Associate II
Revathiswari Tirughana-Samban, B.S.
Research Associate II
Ali-Asghar Zhumkhawala, MD
Urology Surgical Research Fellow
City of Hope Graduate Student
CIRM Masters Intern, CSU Pomona
CIRM Masters Intern, CSU Channel Islands
CIRM Intern, CSU Pomona
Senior Secretary, Dr. Aboody
November 17, 2014
September 29, 2014
March 28, 2014
Information listed here is obtained from Pubmed, a public database; City of Hope is not responsible for its accuracy.