Specific genetic markers need to be identified to allow for personalized treatment of malignant mesothelioma that can be applied once first-line therapy fails, according to a review exploring why newly developed targeted therapies have largely failed to provide new treatments.
The study, “The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?” was published in the journal Critical Reviews in Oncology/Hematology.
To understand the failure of targeted therapies in mesothelioma, researchers at the University of Palermo in Italy reviewed published studies focusing on targeted molecular therapy and resistance to treatment.
The review showed that there was no lack in efforts exploring new treatment options. Drugs that benefit patients with other types of cancers, including drugs that block blood vessel growth into the tumor, immunotherapies, and other molecular interventions known to trigger cell death, have all been tried, either in clinical or preclinical trials.
But the unifying theme of the studies — in addition to the fact that most of them failed to show any beneficial effect of the treatment in mesothelioma patients — was that all explored treatments in unselected and uncharacterized groups of patients.
Although researchers have identified mutations that are common in mesothelioma patients, the mutations responsible for driving disease are not known. The same is true when it comes to the mechanisms mediating resistance to drug treatment. While these mechanisms are well-studied, researchers do not know enough to circumvent them.
The team also pointed out that another factor behind the high failure rate is the lack of reliable preclinical models. Most often, new treatment approaches are developed in either lab dishes or mice carrying human tumors. Neither model can adequately mirror the cellular complexity of human tumors.
But what it all comes down to, according to the review, is that no attempts have been made to identify differences between patients that are linked to a treatment response — in other words, an almost complete lack of personalized treatment.
“In the era of personalized medicine, when each cancer patient receives therapies tailored on the individual tumor characteristics and host factors, MPM [malignant pleural mesothelioma] is still largely managed as a single disease,” the research team wrote.
They also called for smaller clinical trials to avoid faulty conclusions by larger trials that do not have a comparison treatment. Also, they highlighted that combination treatments may give better results than single drugs, proposing that drugs targeting specific molecular pathways should be combined with more general approaches to anti-cancer and immunotherapy.