Targeted agents are revolutionizing the cancer therapy. From monoclonal antibodies (MoAb) to small molecule inhibitors (SMIs) and immunoconjugates, more and more targeted agents are quickly migrating from bench to bedside. Rituximab, a MoAb against CD20, has essentially changed the natural history of diffuse large B cell lymphoma, and is effective in other B-cell disorders such as rheumatoid arthritis. Trastuzumab, a MoAb blocking Her2/neu, is an indispensible agent for Her2/neu positive breast cancer and metastatic gastric cancer. Bevacizumab, a MoAb binding vascular endothelial growth factor (VEGF), has been approved for the treatment of a broad spectrum of advanced malignancies such as colorectal, brain, kidney and non-small cell lung cancer (NSCLC). Brentuximab vedotin (SGN-35), an immunotoxin conjugate, is now available for CD30 positive anaplastic large cell lymphoma and Hodgkin lymphoma. BCR-ABL genetic rearrangement has served as a diagnostic biomarker for chronic myelogenous leukemia (CML). Imatinib, a SMI of ABL, has led the way toward modern-era therapy for CML, essentially changing allogeneic stem cell transplantation to the backseat. The discovery of CD 117 expression on gastrointestinal stromal tumor (GIST) escalated SMI therapy to another level, turning the once most chemo-resistant malignancy to a stunning success of targeted therapy [1, 2]. Chemo-resistant renal cell carcinoma (RCC) became sensitive to SMIs, such as sorafenib, sunitinib, and pazopanib. Everolimus and temsirolimus, the class of mTOR inhibitors, have also shown significant activity toward RCC and other malignancies. SMI and MoAb of epidermal growth factor receptor (EGFR) such as gefitinib, erlotinib, cetuximab, panitumumab, are widely used for the treatment of lung, colon, and pancreatic cancers. Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is another biomarker targeting agent against NSCLC harboring ALK translocation, which is mutually exclusive from EGFR mutation.
There are several novel targeted therapies available or in late clinical development for advanced melanoma, one of the most chemo-refractory cancers . Vemurafenib, an inhibitor of BRAF V600E mutant, has been approved for advanced melanoma therapy. Ipilimumab, a MoAb against CTLA-4, has demonstrated efficacy in patients with advanced melanoma. Trametinib, a SMI against MEK, has shown promising activity against BRAF mutated melanoma and may provide an alternative for patients who are resistant to BRAF targeting therapy in the future
JAK2 V617F mutation is the most important biomarker in myeloproliferative neoplasms (MPN). Ruxolitinib, a JAK inhibitor, has been shown to decrease splenomegaly and alleviate symptoms associated with MPN associated with advanced myelofibrosis. More JAK2 –specific inhibitors are undergoing clinical trials.
With the vast knowledge of signal transduction pathways, SMIs are being developed for many known biomarkers, such as PI3K, Bruton’s tyrosine kinase, c-MET, RET, etc.