Claudins in Cancer: A Current and Future Therapeutic Target.

Claudins are a family of 27 proteins that have an important role in the formation of tight junctions. They also have an important function in ion exchange, cell mobility, and the epithelial-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evidence shows improved outcomes when combining monoclonal antibodies against claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently, chimeric antigen receptor T-cells targeting claudin 18 are under investigation. In this review, we will discuss the major functions of claudins, their distribution in the normal as well as cancerous tissues, and their effect in cancer metastasis, with a special focus on the therapeutic targeting of claudins to improve cancer outcomes.

Folate Receptor Alpha-A Novel Approach to Cancer Therapy.

Folate receptor α (FR) was discovered many decades ago, along with drugs that target intracellular folate metabolism, such as pemetrexed and methotrexate. Folate is taken up by the cell via this receptor, which also targeted by many cancer agents due to the over-expression of the receptor by cancer cells. FR is a membrane-bound glycosyl-phosphatidylinositol (GPI) anchor glycoprotein encoded by the folate receptor 1 (FOLR1) gene. FR plays a significant role in DNA synthesis, cell proliferation, DNA repair, and intracellular signaling, all of which are essential for tumorigenesis. FR is more prevalent in cancer cells compared to normal tissues, which makes it an excellent target for oncologic therapeutics. FRα is found in many cancer types, including ovarian cancer, non-small-cell lung cancer (NSCLC), and colon cancer. FR is widely used in antibody drug conjugates, small-molecule-drug conjugates, and chimeric antigen-receptor T cells. Current oncolytic therapeutics include mirvetuximab soravtansine, and ongoing clinical trials are underway to investigate chimeric antigen receptor T cells (CAR-T cells) and vaccines. Additionally, FRα has been used in a myriad of other applications, including as a tool in the identification of tumor types, and as a prognostic marker, as a surrogate of chemotherapy resistance. As such, FRα identification has become an essential part of precision medicine.

Novel advances in pancreatic cancer treatment.

Little progress has been made on the treatment of advanced pancreatic cancer. Gemcitabine has been an acceptable standard for more than a decade. The benefit of single-agent gemcitabine in advanced and metastatic pancreatic cancer is small. Adding other chemotherapy agents to gemcitabine has not resulted in meaningful improvement in survival. The randomized trials studying the addition of molecular targeting agents (cetuximab, bevacizumab, farnesyl transferase inhibitors and metalloproteinase inhibitors) to gemcitabine compared with gemcitabine alone have been disappointing. A small gain in median survival by adding erlotinib to gemcitabine has recently been reported. We herein review novel agents in pancreatic cancer that may change the current nihilistic approach in the management of this challenging disease.

Technology evaluation: mapatumumab, Human Genome Sciences/GlaxoSmithKline/Takeda.

Human Genome Sciences and GlaxoSmithKline, under license from Cambridge Antibody Technology, are developing mapatumumab, the intravenously administered lead from a series of human monoclonal antibody tumor necrosis factor-related apoptosis-inducing ligand receptor 1 agonists, for the potential treatment of cancer. The therapy is currently undergoing phase II clinical trials. Takeda is developing mapatumumab in Japan.

Molecular biological design of novel antineoplastic therapies.

Novel therapies represent a new strategy for the development of anticancer agents. New targets derived from the knowledge of the molecular structure and genetic defects has been useful in developing anticancer drugs that prolong or stabilise the progression of tumours with minimal systemic toxicities. In this review, the mechanism of action and the most significant trials regarding monoclonal antibodies, tyrosine kinase inhibitors, angiogenesis and cyclooxygenase inhibitor-based therapies, farnesyl transferase inhibitors and proteasome inhibitors are discussed. The potential biological end points and toxicities are also described. In conclusion, novel therapies present a promising class of anticancer agents, acting through different mechanisms and offering a new perspective in the treatment of cancer.