Dr. Menon’s research is focused on developing new cell based drug delivery systems for continuous delivery of drug/biological agents at tumor site. Two major concerns in cancer therapy are the short half-life, availability or excessive toxicity of the drugs, and the extreme invasiveness of the malignant tumor cells to infiltrate into the surrounding tissue and recur locally near the neurosurgical resection site. The goal is the direct targeting and eradication of these disseminated tumor cells in the brain. Stem cell-based therapies provide a promising approach for treatment of tumors in humans. Human bone marrow derived mesenchymal stromal cells (hMSC) is an excellent source, as these cells can be genetically modified to express proteins/drugs and also have an exceptional migratory or homing ability towards tumors, injury or inflammation.
This project will study the use genetically modified human mesenchymal stromal cells as a local therapeutic drug delivery vehicle for the targeted delivery and secretion of chemotherapeutic/biologic agents for treatment of brain tumors. This therapeutic strategy employs genetic modification of hMSC and exploits the tumor tropic behavior, for tracking to sites of tumor cell invasion and allows on-site generation of drug to control tumor growth. This approach will allow the cells to migrate to dispersed tumor cells near the surgical site and also to track down tumor cells migrated to the normal brain parenchyma.
For this study, hMSC will be genetically engineered to express a prodrug enzyme, Cytosine Deaminase (CD). CD is an enzyme found in bacteria and fungi that converts nontoxic drug 5-fluorocytosine (5-FC) to form the highly cytotoxic 5-fluorouracil (5-FU). The 5-FU produced locally will diffuse through cellular membranes thereby increasing the cytotoxicity to neighboring tumor cells without increasing the risk of harmful systemic effects. This is a novel treatment approach for a disease in which outcomes are exceptionally poor and options are limited. Developing innovative therapeutic approaches can help us to improve survival and quality-of-life for patients with this devastating neoplasm. hMSC is an ideal candidate and compatible for clinical use as these cells can be harvested by bone marrow aspiration from individual patients without difficulty, processed ex vivo very efficiently, and later transplanted back into the same patients during surgery thereby reducing immunological consequences.
The results at the conclusion of this project will provide us all the information necessary for a pilot phase I feasibility and safety study for treating brain tumor patients with mesenchymal stem cells that have been engineered to express cytosine deaminase (MSC-CD) followed by 5-FC therapy.