Epithelial-Mesenchymal Transition as a New Target

Anticancer drug discovery

In the May issue of Nature Reviews Drug Discovery, Fabrizio Marcucci and colleagues discuss the screening and classification of compounds that affect epithelial–mesenchymal transition (EMT), highlight some compounds of particular interest, and address issues related to their clinical application.

EMT is becoming a target of prime interest for anticancer therapy. The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype is a critical process for embryonic development that occurs particularly during tumour progression.

Tumour cells undergoing EMT acquire the capacity to disarm the body's antitumour defences, resist apoptosis and anticancer drugs, disseminate throughout the organism, and act as a reservoir that replenishes and expands the tumour cell population.

In their article the authors present classes and subclasses of inhibitors targeting stimuli and signalling pathways related to EMT, along with their current stage of development. However, most of these compounds were not developed with an anti-EMT purpose to begin with, but instead based on their potential to result in antitumour responses assessed by commonly accepted clinical response criteria.

Nevertheless, based on preclinical evidence, these compounds are expected to have anti-EMT activity when tested in the appropriate clinical setting. Several clinical trials are now incorporating biomarker assays that reflect the anti-EMT activity of investigated compounds.

Epithelial-Mesenchymal Transition as a New Target

Induction of epithelial–mesenchymal transition by stimuli from the tumour microenvironment.

Among the inhibitors of stimuli from the tumour microenvironment, the authors in this perspective article classified: HIF1α inhibitors which are up to phase II testing for cancer; carbonic anhydrase 9 inhibitors which are up to phase I for cancer; proton pump inhibitors which are up to phase II for cancer in combination with chemotherapy; and LOX2 inhibitors.

Among the inhibitors of extracellular mediators and their corresponding receptors the authors classified: TGFβ- TGFβ receptor inhibitors which are up to phase II testing for cancer; IL-6/IL-6R inhibitors from which siltuximab is approved for multicentric Castelman disease, other are up to phase II for cancer; HGF/MET inhibitors: from tyrosine kinase inhibitors (TKIs) crizotinib and cabozantinib have non-specific activity against MET and are approved for non-small cell lung cancer and medullary thyroid cancer, other are up to phase III for cancer, development of the HGF-targeted antibody rilotumumab was recently terminated; PDGF/PDGFR inhibitors: several TKIs that have non-specific activity against PDGFR (including imatinib, nilotinib, axitinib and dasatinib) are approved for haematological malignancies and solid tumours, PDGFR-specific monoclonal antibodies are up to phase II for cancer; FGF/FGFR inhibitors: several TKIs that have non-specific activity against FGFR (including lenvatinib, nintedanib, pazopanib and ponatinib) are approved for haematological malignancies and solid tumours, FGFR-specific monoclonal antibodies or monoclonal antibody-drug conjugates are up to phase II for cancer; Hedgehog/Smoothened inhibitors: vismodegib is approved for the treatment of basal cell carcinoma, other are up to phase II for cancer; Notch/Notch ligand (Delta-like and Jagged) inhibitors are up to phase II for cancer; WNT/Frizled inhibitors are up to phase II for cancer; and adhesion molecule inhibitors are up to phase II for cancer.

Among inhibitors or activators of intracellular signalling pathways, the authors included: SRC inhibitors: several TKIs that have non-specific activity against SRC (including bosutinib, dasatinib, ponatinib and vandetanib) are approved for haematological malignancies and solid tumours, other are up to phase II for cancer; FAK inhibitors are up to phase II for cancer; from PI3K/AKT/mTOR inhibitors, PI3K inhibitor idelalisib is approved for CLL, other are up to phase II for cancer, AKT inhibitors are up to phase II for cancer, mTOR inhibitor everolimus is approved for some cancer indications, temsirolimus is approved for renal cell cancer, several dual PI3K/mTOR  inhibitors are up to phase II for cancer; AXL inhibitors are up to phase II for cancer; among RAS/RAF/MAPK inhibitors, BRAF inhibitors, vemurafenib and dabrafenib are approved for late stage melanoma, RAF inhibitor sorafenib is approved for renal cell cancer and hepatocellular carcinoma, MEK inhibitor trametinib is approved for melanoma, other are up to phase III for cancer; and AMPK activators are up to phase III for cancer.

Among inhibitors of transcription factors that indirectly induce EMT, the authors categorised: NF-ƙB inhibitors from which acetylsalicylic acid is up to phase III for cancer prevention; STAT3 inhibitors are up to phase III for cancer, microRNA inducers of inhibitors are up to phase I for cancer; among compounds acting on epigenetic modulators the HDAC inhibitors vorinostat and romidepsin are approved for cutaneous T cell lymphoma, panobinostat is approved for multiple myeloma, other are up to phase III for cancer.

The authors concluded that despite some limitations, the oncology community can be optimistic about the clinical potential of anti-EMT compounds that are already available or will be in the near future.  

Reference

Marcucci F, Stassi G, De Maria R. Opinion: Epithelial–mesenchymal transition: a new target in anticancer drug discovery. Nature Reviews Drug Discovery 2016; 15:311-325. doi:10.1038/nrd.2015.13