Mesothelioma and Molecular Pathways

A recently published review* looks at some of the molecular signaling pathways currently being investigated in mesothelioma.

The challenge of developing disease-specific treatments.

The goal is to develop more – and more effective – treatments, says co-author Dan J. Raz, MD, of the University of California, San Francisco’s Division of Thoracic Surgery.

“The options for mesothelioma patients have primarily been surgery, conventional chemotherapy, and radiation therapy,” Raz says. “But even when a combination of treatments is used, the outcomes aren’t great.”

While several drugs have been approved for treating mesothelioma, there aren’t a lot – largely because researchers simply haven’t been able to conduct many clinical drug trials.

This is in part because, with some 5,000 Americans diagnosed with the disease annually, mesothelioma is fairly uncommon compared with other cancers. This factor, combined with mesothelioma’s typically swift progression, has made it difficult to enroll enough people in drug studies.

Another obstacle has been the large spectrum of disease. “When patients present with mesothelioma, we often don’t know how long they’ve had it, which can make it difficult to differentiate people with different levels of disease, and to know what the best treatment options might be,” Raz says.

So instead of waiting for drugs to be approved for other cancers to conduct clinical trials for their use in mesothelioma – which is how it currently works – researchers are striving to develop drugs specifically for the disease.

Which brings us back to the study of its molecular signaling pathways.

Pathways to understanding

Clinical trials of several angiogenesis drugs (those that target the blood vessels that fuel tumor growth) known to be effective for other diseases suggest that two signaling pathways examined in the article – vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) – can be disrupted by these drugs.

The review also looked at the Wnt pathway, which – because it is believed to play an important role in activating mesothelioma stem cells – also shows promise as a treatment target. By learning how to target problems in this initiating pathway, scientists may discover ways to essentially nip mesothelioma in the bud, Raz says. Several Wnt antibodies will soon enter clinical trials.

Other signaling pathways currently being studied include P53 and pRB, as well as the BCL-2 family. Also significant to the molecular makeup of mesothelioma, these pathways hold valuable clues for developing effective disease-specific therapies.

In the meantime, a number of trials for drugs developed for other cancers are underway, says Raz, and many new angiogenesis therapies are in the pipeline.

Another promising avenue – for countless medical conditions, not just cancer – is genomic medicine, of which knowledge is growing every day.

“By learning about the genetic patterns of individuals, we’ll eventually be able to know how someone’s genes interact with the biology of tumors, which signaling pathways play which roles in different people, and how patients will respond to different therapies,” Raz says. “Genetic medicine and drug development go hand in hand, and most people in the scientific community agree that this is the future of medical treatment.”

Raz encourages patients diagnosed with mesothelioma to look into clinical trials, and to seek treatment from physicians with specialized training and experience, at centers with recognized mesothelioma programs.

A growing number of centers fit the bill – UCSF, Brigham and Women’s Hospital, and Memorial Sloan Kettering Cancer Center, to name a few – which translates into more treatment options for patients.

“This is a very exciting time for advances in mesothelioma, and slow but definite progress is being made,” Raz says. “The scientific community is starting to understand a lot more about the biology of this terrible disease, which means that more targeted therapies are being introduced that could potentially help people.”

* Lee AY, Raz DJ, He B, Jablons DM, Update on the Molecular Biology of Malignant Mesothelioma. Cancer, 2007 Mar 8:109(8):1454-1461