Improvements in the traditional therapeutic options available to mesothelioma patients have led to longer median survival times for a subset of these individuals, but the overall effectiveness of these treatments is still quite disappointing—especially when compared to the great advances that have been made in the treatment of other forms of cancer. Because of this, a number of researchers are actively investigating the development of alternative treatment strategies in the hope that more effective therapeutic management of the disease will one day be available to people diagnosed with pleural mesothelioma and peritoneal mesothelioma. One of these alternative strategies involves the use of gene therapy to combat tumor genesis.

Gene therapy is a disease-fighting technique where genes are inserted into a patient’s cells to replace defective or mutated alleles with functional ones. Although a relatively recent invention, it has already shown great promise in the treatment of a variety of disorders. It is an active area of research for mesothelioma treatments and this research is being conducted in a number of institutions around the world. One of the latest articles in the field, which describes a study on the efficacy of “suicide gene therapy” on individual mesothelioma cell lines, was recently published in the journal Onkologie.

Overview of the Study

The article describes a study by German researchers who conducted a number of interesting investigations of three mesothelioma cell lines. Histologically, two of the lines presented with a biphasic subtype, while the histological type of the third line was not known. To analyze the individual lines’ genetic makeup and particular chromosomal structure, the authors utilized multiplex fluorescene in situ hybridization (M-FISH) analysis. They also studied the tumorgenicity of each line by injecting mice with the one of the cell lines and then tracking the course of its health after injection. The cell lines were then studied for their susceptibility to genetic changes introduced by a rAAV2-based vector (recombinant adeno-associated virus 2-based vector). In molecular biology, a vector refers to a piece of foreign DNA that is used to transfer gene sequences from one organism to another, so the authors were interested in the extent to which the mesothelioma cell lines were reactive to the gene sequences that were inserted into the lines. The final phase of the study was to investigate the feasibility of using in vivo therapy to precisely target and attack these rAAV2-transduced mesothelioma cell lines.

Results

M-FISH analysis of the cell lines revealed a number of aberrations in each of the individual cell lines’ chromosomal structures, as well as clear differences in the underlying structures between the cell lines themselves. One of the cell lines, H-Meso-1, exhibited more aberrations than did the other two lines, but all lines exhibited non-standard genetic structures. After H-Meso-1, the cell line MSTO-211H exhibited the most aberrations, while the cell line NCI-H28 exhibited the least. When the authors compared the particular aberrations within each of the lines, they sometimes found that two of the lines shared the same recurrent aberrations, but the exact aberrations were not found among all three lines.

When the authors investigated the tumorgenicity of each of the lines, they discovered that H-Meso-1 was also the most tumorgenic of them. The NCI-H28 line did not cause any tumors at all. All of the cell lines were found to be rAAV2 susceptible, with H-Meso-1, again, exhibiting the highest gene transfer and expression rate. To study the feasibility of the in vivo gene therapy, the authors injected mice with the H-Meso-1 cell line and then separated them into groups treated with GVC and NaCl. The GVC group was the study group in this setting, because it should activate the rAAV2-vector. This is just what the authors found. Their analysis showed that GVC-treated mice demonstrated a near doubling of median survival time as compared to the NaCl group. This is a statistically significant finding, with the authors noting that future optimizations of the protocol could likely give even better survival figures.

Conclusion

The authors conclude their article by calling for additional research into the development of rAAV2-based treatments for patients with pleural mesothelioma. The results as presented in their paper were designed as a proof-of-feasibility test, not as an official clinical modality. Much more work is necessary before more comprehensive studies could even be considered, but the encouraging results as presented here certainly warrant this further research. The question of whether these therapies will be effective for humans is still years from being answered, but this study, as well as the numerous other studies that are investigating the creation of novel treatments, is another sign that improving the efficacy of mesothelioma treatments remains a top priority for researchers the world over.

Labels: mesothelioma