People often speak mistakenly of cancer as if it were a single disease that just happens to target different areas of the body. In fact, cancer is not a single disease, but a family of diseases whose propagation is driven by a breakdown of the same cellular processes that are normally responsible for keeping people healthy. When these processes are undermined by aberrant cellular activity, the strict regulation of cell division and growth is compromised and the malignant cells that do develop are ones that put the health of the entire body into question. This is the reason why no single cure for cancer exists—and probably never will exist—and why cancer research requires both great scientific understanding and great creativity.

The key to treating individual forms of cancer is to understand the particular molecular and biological features involved in the genesis of these specific tumor types and to then develop targeted agents that attack the structures upon which tumors can grow. In the quest for a cure for mesothelioma, scientists have discovered a number of proteins that are overexpressed in malignant tissue and they hope a better understanding of the structures which produce these proteins will lead to better treatments for mesotheloima patients.

One such protein that has received a great amount of attention is mesothelin, which is a membrane-bound glycoprotein that has been implicated not only in all forms of mesothelioma, especially pleural mesothelioma and peritoneal mesothelioma, but in pancreatic and ovarian cancer, as well as in lung adenocarcinoma. Now considered a therapeutic target for treatment, mesothelin is the subject of a number of research programs, one of which we will now be covering. An international team of researchers has recently released the results of a pre-clinical study of a monoclonal antibody they developed, MORAb-009, that targets tumor-associated mesothelin.

Introduction to the Study

Monoclonal antibody therapy is a treatment method where antibodies specific to a particular substance or cell-type are created that will then bind to this substance or cell-type and stimulate the immune system to attack the entire cell-antibody domain. In the case of cancer research, monoclonal antibodies are created for specific tumors or the receptors which stimulate tumor growth and then the tumor-antibody domain is attacked and, ideally, removed from the system.

As we noted above, mesothelin has been identified as significantly over-expressed in all pancreatic adenocarcinomas and in all mesotheliomas, as well as ovarian cancers and lung adenocarcinoma and non-small cell lung cancer. Its expression in normal tissues is limited to the mesothelial cells in the pleura, pericardium and peritoneum, so targeting agents that can bind with tumor-related mesothelin are potentially beneficial for a number of different cancers.

The researchers developed a monoclonal antibody called MORAb-009 to bind to mesothelin-expressing tumor surfaces, but not to other membrane-bound proteins that have been implicated in tumor genesis. Using immunohistochemical analysis, the authors were able to show that MORAb-009 was able to bind to tumor-associated mesothelin and then become internalized into the cell surface. They were also able to show that MORAb-009 could disrupt cell adhesion between mesothelin and its ligand (i.e., a smaller molecule that binds to a larger one, such as a receptor protein) CA125/MUC16—a combination thought to facilitate metastasis to the peritoneum.

Another phase of their research had the authors studying its toxicity and its anti-tumor effects. In toxicity tests on cynomolgus monkeys, MORAb-009 was well-tolerated and exhibited a favorable toxicity profile. While on its own MORAb-009 only showed moderate anti-tumor activity, when researchers combined it with the chemotherapy agents Taxol® and gemcitabine, they found significantly enhanced activity. Although the precise mechanism of this multiplicative effect is presently unknown, the authors still hypothesize that due to its low toxicity and its overall efficacy, the MORAb-009-chemotherapy axis is potentially quite useful for the treatment of cancers expressive of mesothelin.

Conclusion

In light of their successful pre-clinical studies, the authors have commenced a Phase I clinical study with patients who present with one of the aforementioned cancers: pancreatic and ovarian cancers, lung adenocarcinomas and all forms of mesothelioma. However, as the pre-clinical phase was made up of entirely non-human subjects, this Phase I trial is simply the first of much more research that needs to be completed on the feasibility of MORAb-009 therapy in humans before any firm conclusions can be drawn regarding its efficacy.

Labels: mesothelioma