text: Small molecules that are able to inhibit TGF-β induced EMT are under development. Silmitasertib (CX-4945) is a small molecule inhibitor of protein kinase CK2, which has been supported to be linked with TGF-β induced EMT, and is currently in clinical trials for cholangiocarcinoma (bile duct cancer), as well as in preclinical development for hematological and lymphoid malignancies. In January 2017, Silmitasertib was granted orphan drug status by the U.S. Food and Drug Administration for cholangiocarcinoma and is currently in phase II study. Silmitasertib is being developed by Senhwa Biosciences. Another small molecule inhibitor Galunisertib (LY2157299) is a potent TGF-β type I receptor kinase inhibitor that was demonstrated to reduce the size, the growth rate of tumors, and the tumor forming potential in triple negative breast cancer cell lines using mouse xenografts. Galunisertib is currently being developed by Lilly Oncology and is in phase I/II clinical trials for hepatocellular carcinoma, unresectable pancreatic cancer, and malignant glioma. Small molecule inhibitors of EMT are suggested to not act as a replacement for traditional chemotherapeutic agents but are likely to display the greatest efficacy in treating cancers when used in conjunction with them.
  Antagomirs and microRNA mimics have gained interest as a potential source of therapeutics to target EMT induced metastasis in cancer as well as treating many other diseases. Antagomirs were first developed to target miR-122, a microRNA that was abundant and specific to the liver, and this discovery has led to the development of other antagomirs that can pair with specific microRNAs present in the tumor microenvironment or in the cancer cells. A microRNA mimic to miR-655 was found to suppress EMT through the targeting of EMT inducing transcription factor ZEB1 and TGF-β receptor 2 in a pancreatic cancer cell line. Overexpression of the miR-655 mimic in the Panc1 cancer cell line upregulated the expression of E-cadherin and suppressed the migration and invasion of mesenchymal-like cancer cells. The use of microRNA mimics to suppress EMT has expanded to other cancer cell lines and holds potential for clinical drug development. However, microRNA mimics and antagomirs suffer from a lack of stability in vivo and lack an accurate delivery system to target these molecules to the tumor cells or tissue for treatment. Improvements to antagomir and microRNA mimic stability through chemical modifications such as locked nucleic acid (LNA) oligonucleotides or peptide nucleic acids (PNA) can prevent the fast clearing of these small molecules by RNases. Delivery of antagomirs and microRNA mimics into cells by enclosing these molecules in liposome-nanoparticles has generated interest however liposome structures suffer from their own drawbacks that will need to be overcome for their effective use as a drug delivery mechanism. These drawbacks of liposome-nanoparticles include nonspecific uptake by cells and induction of immune responses. The role that microRNAs play in cancer development and metastasis is under much scientific investigation and it is yet to be demonstrated whether microRNA mimics or antagomirs may serve as standard clinical treatments to suppress EMT or oncogenic microRNAs in cancers.