Researchers at NCI, other institutions, and biotechnology companies have been exploring various avenues to utilize mesothelin - a glycoprotein found on the surface of normal mesothelial cells that line the abdominal, lung, and heart cavities - as a target for antibody- and vaccine-based therapies.

"The limited distribution of mesothelin on normal tissues, combined with the fact that it is highly expressed on the surface of many human tumors, makes it an attractive target for tumor-specific therapy," explains Dr. Ira Pastan, chief of the Laboratory of Molecular Biology at the NCI Center for Cancer Research. Most notably, high levels of mesothelin are found in mesothelioma, pancreatic cancer, and ovarian cancer.

Mesothelin also appears to play a role in malignancy, adds Dr. Raffit Hassan, a principal investigator in Dr. Pastan's lab. "These characteristics make it a very important molecule for targeted therapies," he says.

The protein, thought to play a role in cellular adhesion, is also being studied as a cancer vaccine target to trigger a tumor-specific immune response, and as a diagnostic marker to indicate the presence and progression of certain malignancies. Mesothelin was discovered by Drs. Kai Chang, Mark Willingham, and Pastan at NCI; the team then cloned the gene encoding mesothelin, aided by a lab-generated monoclonal antibody, K1, that specifically recognizes mesothelin. Dr. Pastan, with Drs. David Fitzgerald and Partha Chowdhury, took the research a step further, combining the Fv portion of an antibody to mesothelin with a portion of a highly toxic protein, Pseudomonas exotoxin A, to create an immunotoxin called SS1P.

Preclinical studies of SS1P demonstrated antitumor activity against mesothelin-expressing tumors in animal models as well as tumor cells obtained directly from patients with mesothelioma and ovarian cancer. Drs. Robert Kreitman, Hassan, and Pastan are conducting two phase I studies to determine the safety and efficacy of SS1P in patients with advanced cancers whose tumors express mesothelin.

"Preliminary results indicate that SS1P is well tolerated, shows promising clinical activity, and may be useful in patients with small-volume disease who have failed standard chemotherapy," says Dr. Hassan. NCI has entered into a Collaborative Research and Development Agreement (CRADA) with Enzon Pharmaceuticals, Inc., to further develop SS1P for mesothelioma, ovarian, and pancreatic cancers as the immunotoxin moves into phase II trials.

Meanwhile, at the Johns Hopkins Kimmel Cancer Center, Dr. Elizabeth Jaffee and colleagues have had some success with an experimental vaccine that indicates mesothelin could be an important component of a therapeutic vaccine. During a clinical trial using tumor vaccinations for patients with pancreatic cancer, the Hopkins team discovered that three patients had a strong anti-mesothelin T-cell immune response. Six years after vaccination, all three patients are still alive and tumor free. Based on these findings, the researchers have initiated preclinical studies in collaboration with Cerus Corp. to develop a therapeutic listeria-based, mesothelin-targeted cancer vaccine for use against mesothelin-expressing cancers.

Mesothelin also may prove useful in the diagnostic arena. For example, a mesothelin variant has been detected in very small quantities in the blood of patients with malignant mesothelioma and ovarian cancer. A study led by Dr. Ingegerd Hellstrom of the Pacific Northwest Research Institute, showed that the level of these soluble mesothelin-related proteins (SMR) in the blood could potentially be useful to diagnose and measure progression of mesotheliomas. According to their study, 84 percent of patients with mesothelioma had elevated SMR, with increased levels of SMR noted in patients with increased stage and tumor burden. Their results also indicated that SMR could potentially be helpful in screening asbestos-exposed individuals for early evidence of developing mesothelioma. Fujirebio Diagnostics, Inc., is currently trying to develop a commercial diagnostic based on this research.

"Pancreatic cancer and mesothelioma are both aggressive and deadly cancers with no effective treatments currently available," says Dr. Pastan. "The new interventions in development could change that scenario considerably."

By Sunil Jani