Targeting of melanoma brain metastases using engineered neural stem/progenitor cells1

Abstract

Brain metastases are an increasingly frequent and serious clinical problem for cancer patients, especially those with advanced melanoma. Given the extensive tropism of neural stem/progenitor cells (NSPCs) for pathological areas in the central nervous system, we expanded investigations to determine whether NSPCs could also target multiple sites of brain metastases in a syngeneic experimental melanoma model. Using cytosine deaminase-expressing NSPCs (CD-NSPCs) and systemic 5-fluorocytosine (5-FC) pro-drug administration, we explored their potential as a cell-based targeted drug delivery system to disseminated brain metastases. Our results indicate a strong tropism of NSPCs for intracerebral melanoma metastases. Furthermore, in our therapeutic paradigm, animals with established melanoma brain metastasis received intracranial implantation of CD-NSPCs followed by systemic 5-FC treatment, resulting in a significant (71%) reduction in tumor burden. These data provide proof of principle for the use of NSPCs for targeted delivery of therapeutic gene products to melanoma brain metastases.

Stem and progenitor cell-mediated tumor selective gene therapy

“…This tropism has been exploited to deliver multiple therapeutic genes or cDNAs selectively to tumor foci (summarized in Table 1; stem and progenitor cells for tumor-selective therapy). 3,10,[15][16][17][23][24][25][26][27][28][29][30][31] The central question to be addressed then becomes whether we can exploit the inherent ability of these cells to migrate to, infiltrate and-when desirable-engraft to 'correct' pathologies in patients. The long-range goal is complete cure without toxic side effects or relapse.…”

Human neural stem cells transduced with IFN-β and cytosine deaminase genes intensify bystander effect in experimental glioma

“…In NSC-based gene therapy strategies targeting brain tumors, NSCs were mostly used to transport the CD/5-FC prodrug system to the tumor cells. [3][4][5][6][7][8] Recently, Dickson et al 21 showed that in mice, F3 human NSCs transiently expressing human IFN-b displayed tropism for sites of disseminated neuroblastoma, resulting in significant tumor growth. The sustained expression of IFN-b at disseminated sites of microscopic disease represents a novel therapeutic approach.…”

“…In particular, NSCs that are retrovirally transduced with suicide genes such as the cytosine deaminase (CD) gene show a remarkable 'bystander killer effect' on 5-fluorocytosine (5-FC)-treated glioma cells. 3,[5][6][7][8] Interferon-b (IFN-b) is known for its ability to interfere with viral replication and also for its antiproliferative effects on a variety of cancer cells. However, the efficacy of IFN-b is limited because of its extremely short half-life after intravenous administration as well as the systemic toxicity when this protein is administered at doses required to achieve the desired antitumor effect.…”

Synergistic effects of genetically engineered stem cells expressing cytosine deaminase and interferon-β via their tumor tropism to selectively target human hepatocarcinoma cells

“…As neural stem cells (NSCs) are able to target tumor cells, molecular therapies using these cells can be used to produce antitumor effects in tumor lesions. 8,9 As gene/prodrug systems can be designed to more selectively target tumor cells than normal cells, 10 the application of enzyme/ prodrug systems to minimize side effects has received much attention. The cytosine deaminase (CD)/5-fluorocytosine (5-FC) system, 11--13 one of the gene-directed enzyme/prodrug therapies (GEPT), metabolically converts non-toxic 5-FC into the toxic metabolite 5-FU 14 and inhibits DNA synthesis in cancer cells.…”