Selumetinib for the treatment of cancer.

Introduction: The MAPK pathway is essential for regulation of cellular proliferation, differentiation and survival. Multiple human cancers have demonstrated activation of Raf-mitogen-activated kinase kinase (MEK)-extracellular signal-related kinase signaling, a hallmark of these tumors. Efforts to inhibit various protein kinases in this pathway have led to the development of MEK inhibitors. Selumetinib is one such drug, functioning as an oral, selective non-ATP-competitive MEK1/2 inhibitor. Areas covered: In this article, the authors discuss the underlying biology of MEK inhibition and its rationale in cancer treatment. Furthermore, the authors summarize the clinical development of selumetinib in various tumor types, from initial Phase I studies to randomized Phase II studies, both as monotherapy or in combination with other chemotherapeutics. Expert opinion: Given the frequency of activated MAPK signaling in multiple tumor types, the potent MEK inhibitor selumetinib had strong preclinical and early clinical rationale, particularly in those tumors harboring KRAS or BRAF mutations. While efficacy signals have been seen in various tumor types treated with selumetinib, better biomarkers are needed to select patients most likely to respond favorably to this agent. Furthermore, combinatorial therapy with selumetinib and other targeted agents can likely be optimized to maximize the antitumor effect of inhibiting RAS/MAPK signaling.

Emerging treatments in recurrent and metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) is a prevalent disease for which many new therapies have been developed over the past decade. Currently, standard of care chemotherapeutic regimens for mCRC include doublet cytotoxic chemotherapy with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab with or without chemotherapy, and single-agent cytotoxic chemotherapy or targeted therapy for patients intolerant of combination regimens. Recent studies have investigated the efficacy of triplet cytotoxic chemotherapeutic regimens, bevacizumab in combination with chemotherapy beyond first-line therapy disease progression, dual anti-VEGF and anti-EGFR antibody therapy, and the more novel agents ziv-aflibercept and regorafenib for treatment of mCRC. Furthermore, molecular profiling of CRC has identified several genetic alterations for which targeted therapies are currently being developed. Optimal drug combinations and treatment sequences have yet to be defined, but an expanding armamentarium of therapies with which to treat CRC offers a promising future.

Advances in the management of biliary tract cancers.

Biliary tract cancers, although uncommon, are highly fatal malignancies. Current treatments fail to cure or control the majority of tumors. Given the complexity of the anatomy and the often aggressive nature of the disease, multidisciplinary treatment, including palliation, is often required. However, systemic therapy with cytotoxics and/or targeted agents is routinely the mainstay of treatment for patients with advanced biliary tract cancers, and new targets and agents provide hope for this disease. This article focuses on recent advances in the management of biliary tract cancers, with a special focus on the molecular basis for current therapeutic investigation in this disease.

Management of small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive type of lung cancer characterized by rapid growth and early metastasis. It is chemosensitive and radiosensitive, yet decades of research investigating multimodality treatments have failed to control or cure this disease in most patients. First-line treatment of limited-stage disease consists of chemotherapy (often etoposide/cisplatin or etoposide/carboplatin) combined with thoracic radiation therapy (TRT), followed by prophylactic cranial irradiation to decrease brain metastases as a site of disease progression for those who experience complete remission or a very good partial response to multimodality treatment. In a Japanese trial, the combination of irinotecan and cisplatin had initially shown promise in treating patients with extensive-stage SCLC, but a confirmatory trial in the United States did not find a difference in overall survival with irinotecan/cisplatin versus etoposide/cisplatin. Adding a third drug to the etoposide/cisplatin combination, as well as other triplet therapies, has mostly been ineffective in improving outcomes. Variables in chemotherapy administration, including maintenance therapy, alternating non-cross-resistance regimens, and dose intensification, have not been shown to increase survival at large. In terms of radiation therapy, early administration of TRT concurrent with chemotherapy, and hyperfractionation, have been beneficial in treatment of limited-stage disease. In patients who relapse, second-line therapy options consist of reinduction of previous chemotherapy or administration of a single agent. Targeted biological therapies for SCLC are now being investigated, and although a great deal of research remains to be done, these agents and their derivatives may provide the most hope for future treatment of SCLC.