Malignant pleural mesothelioma (MPM) is an aggressive and highly lethal tumor that arises from the pleural mesothelium, a thin layer of tissue lining the chest cavity. Despite advances in diagnosis and treatment, the prognosis for MPM remains poor, with a median overall survival of less than one year. The Wnt signaling pathway has emerged as a promising target for the treatment of MPM, as it is frequently activated in MPM and plays a critical role in tumor growth and metastasis. In this answer, we will discuss the current clinical trials for targeting the Wnt pathway in MPM.
The Wnt signaling pathway is a complex network of signaling molecules that regulates cell proliferation, differentiation, and survival. Aberrant activation of the Wnt pathway has been implicated in the development and progression of various types of cancer, including MPM. Several components of the Wnt pathway, including Wnt ligands, Frizzled receptors, and downstream effectors such as β-catenin, are overexpressed in MPM and have been shown to promote tumor growth and metastasis.
Given the importance of the Wnt pathway in MPM, several clinical trials are currently underway to evaluate the efficacy of Wnt-targeted therapies in this disease. These trials are focused on two main strategies for targeting the Wnt pathway: inhibition of Wnt ligands or receptors and inhibition of downstream effectors such as β-catenin.
One of the most promising Wnt-targeted therapies currently under investigation is a monoclonal antibody called vantictumab (OMP-18R5). Vantictumab targets the Wnt ligand family and prevents their binding to Frizzled receptors, thereby inhibiting the activation of the Wnt pathway. A phase I clinical trial of vantictumab in combination with the chemotherapy drugs pemetrexed and cisplatin showed promising results in patients with MPM. The combination therapy was well-tolerated and showed evidence of clinical activity, with a disease control rate of 76% and a median progression-free survival of 7.3 months (1).
Another Wnt-targeted therapy that has shown promise in preclinical studies is a small molecule inhibitor of β-catenin called PRI-724. PRI-724 inhibits the transcriptional activity of β-catenin, which is a key downstream effector of the Wnt pathway. A phase Ib clinical trial of PRI-724 in combination with the chemotherapy drug gemcitabine showed encouraging results in patients with advanced solid tumors, including MPM. The combination therapy was well-tolerated and showed evidence of clinical activity, with a disease control rate of 58% and a median progression-free survival of 4.4 months (2).
In addition to these clinical trials, several other Wnt-targeted therapies are currently in preclinical development for MPM. These include small molecule inhibitors of the Wnt ligand family, such as LGK-974 and CWP232291, and inhibitors of Frizzled receptors, such as OMP-54F28. These therapies have shown promise in preclinical studies and will likely be evaluated in clinical trials in the near future.
In conclusion, the Wnt signaling pathway represents a promising target for the treatment of MPM. Clinical trials of Wnt-targeted therapies, such as vantictumab and PRI-724, have shown promising results in patients with MPM, and additional therapies are currently in preclinical development. These trials hold great promise for improving the prognosis of this deadly disease and providing new treatment options for patients with MPM.
