Klaus Fenchel

Targeting Developmental Pathways: The Achilles Heel of Cancer?

Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways.

Improved overall survival following tyrosine kinase inhibitor (TKI) treatment in NSCLC—are we making progress?

Non-small cell lung cancer (NSCLC; 80–85% of all lung cancers) continues to be one of the major causes of cancer related deaths around the world (1). The development of molecularly targeted therapies (small molecules and monoclonal antibodies) has, however, significantly improved outcomes in the metastatic setting for NSCLC patients harbouring activated oncogenes such as epidermal growth factor receptor (EGFR) and translocated anaplastic lymphoma kinase (ALK) (2). By targeting the main pathways of NSCLC signal transduction, these drugs dramatically improved progression-free survival (PFS) and quality of life (QoL) in this highly selected subgroup of NSCLC patients sparing them from toxic chemotherapy approaches (del16) (3).

Durvalumab for non-resectable stage IIIB non-small cell lung cancer—a small step or a big leap?

Over 70% of all non-small cell lung cancer (NSCLC) patients present with advanced or metastatic tumours at the time of diagnosis. Locally advanced (stage III) NSCLC is an important and controversial treatment subgroup comprising 25–30% of all NSCLC at diagnosis (1). Within this patient population, there is a considerable heterogeneity in both, tumour burden and the extent of lymph node involvement.

Programmed cell death ligand-1 (PD-L1) as a biomarker for nonsmall cell lung cancer (NSCLC) treatment—are we barking up the wrong tree?

Immunotherapy with monoclonal antibodies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) has become a standard of care treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) in first and later treatment lines with durable responses seen in approximately 10-20% of patients treated. However, the optimal selection of eligible patients who will benefit most, is far from being clear and the best biomarker has not yet been established. PD-L1 expression as a predictive biomarker for immunotherapy in NSCLC patients has shown some value for predicting response to immune checkpoint inhibitors in some studies, but not in others, and its use has been complicated by a number of factors which has prompted many researchers to establish better predictive biomarkers for immunotherapy of NSCLC. Most recently, two phase III first-line NSCLC studies have provided evidence that tumour mutational burden (TMB) correlates with the clinical response to the combination of nivolumab and ipilimumab (CheckMate-227; NCT02477826), whereas atezolizumab response was correlated with T effector gene signature expression (IMPower 150; NCT02366143). Both studies demonstrated a significant primary endpoint [progression-free survival (PFS)] benefit in the TMB group and in the group of patients expressing a T effector cell signature, respectively. However, PFS benefit in both studies was seen regardless of the PD-L1 status of all patients suggesting that TMB and T effector cell signatures may be more robust to predict clinical response following treatment with checkpoint inhibitors. The role of putative novel predictive biomarkers evaluated in the CheckMate-227 and the IMPower 150 trials may, if confirmed in future prospective studies, offer a new perspective for predicting immunotherapy treatment outcomes of NSCLC patients in the near future.

Targeting SHP-1,2 and SHIP pathways – a novel strategy for cancer treatment?

Well-balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in haematopoietic cells are SHP-1 and SHP-2. SHP-1, 2 promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP is another inhibitory phosphatase that is specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and SHIP deficiency results in myeloproliferation and B-cell lymphoma in mice. The validation of SHP-1, 2 and SHIP as oncology targets has generated interest in the development of inhibitors as potential therapeutic agents for cancers; however, SHP-1, 2 and SHIP have proven to be an extremely difficult target for drug discovery, primarily due to the highly conserved and positively charged nature of their PTP active site, and many PTP inhibitors lack either appropriate selectivity or membrane permeability. To overcome these caveats, novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and amongst them; some are already in clinical development which are discussed in this review.

Treating epidermal growth factor receptor-mutated non-small cell lung cancer—is dacomitinib the winner?

Non-small cell lung cancer (NSCLC) (80–85% of all lung cancers) continues to be one of the major causes of cancer related deaths around the world (1). The development of molecularly targeted therapies (small molecules and monoclonal antibodies) has, however, significantly improved outcomes in the metastatic setting for NSCLC patients harbouring activated oncogenes such as epidermal growth factor receptor (EGFR) and translocated anaplastic lymphoma kinase (ALK) (2). By targeting the main pathways of NSCLC signal transduction, these drugs dramatically improved progression-free survival (PFS) and quality of life (QoL) in this highly selected subgroup of NSCLC patients and thereby sparing them from toxic chemotherapy approaches (3).