Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.

Background: Regulation of cell adhesion is important for embryonic development and to prevent cancer metastasis.Results: Zeb1 controls cell adhesion in zebrafish embryos and human cancer cell lines through transcriptional repression of E-cadherin, Epcam, and miR-200s.Conclusion: Zeb1 fine-tunes E-cadherin- and Epcam-mediated cell adhesion to control cell behavior during gastrulation.Significance: Conserved cell adhesion regulation mechanisms are crucial for understanding development and cancer invasion.

Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection of JPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, which result in poor bioavailability, may prohibit its use for stand-alone treatment of solid mammary cancers and their lung metastases.

Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.

<b><i>Introduction:</i></b> Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect persisting after completion of neurotoxic chemotherapies. This observational study was designed to evaluate the effectiveness of the dietary supplement OnLife® (patented mixture of specific fatty acids and palmitoylethanolamide) in improving symptoms of CIPN in breast and colon cancer patients. <b><i>Methods:</i></b> Improvement of CIPN was evaluated in adult patients, previously treated with (neo)adjuvant paclitaxel- (breast cancer) or oxaliplatin-based (colon cancer) therapies, receiving OnLife® for 3 months after completion of chemotherapy. The primary endpoint was to compare the severity of peripheral sensory neuropathy (PSN) and peripheral motor neuropathy (PMN) before and at the end of OnLife® treatment. Secondary endpoints included the assessment of patient-reported quality of life and CIPN symptoms as assessed by questionnaires. <b><i>Results:</i></b> 146 patients (<i>n</i> = 75 breast cancer patients and <i>n</i> = 71 colon cancer patients) qualified for analysis; 31.1% and 37.5% of breast cancer patients had an improvement of PSN and PMN, respectively. In colon cancer patients, PSN and PMN improved in 16.9% and 20.0% of patients, respectively. According to patient-reported outcomes, 45.9% and 37.5% of patients with paclitaxel-induced PSN and PMN, and 23.9% and 22.0% of patients with oxaliplatin-induced PSN and PMN experienced a reduction of CIPN symptoms, respectively. <b><i>Conclusion:</i></b> OnLife® treatment confirmed to be beneficial in reducing CIPN severity and in limiting the progression of neuropathy, more markedly in paclitaxel-treated patients and also in patients with oxaliplatin-induced CIPN.

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e23143 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, long-term side effect of many antineoplastic agents and has a detrimental impact on patients (pts)’ quality of life and functional activities of daily living. Currently, preventive measures and treatment options for CIPN are quite limited. OnLife is a dietary supplement that contains a patented mixture of fatty acids with anti-inflammatory, neuroprotective and antinociceptive properties. Methods: The STEFANO study – an observational, prospective, two-cohort, multicenter study of dietary supplementation – was designed to evaluate the potential of OnLife to improve CIPN in adult pts with completed neo-/adjuvant chemotherapy and manifest CIPN (grade 1-3) (Cohort A: colon cancer, oxaliplatin-containing therapy; cohort B: breast cancer, paclitaxel therapy). Pts received OnLife for 3 months. The primary objective – assessment of changes in CIPN – was evaluated by comparing the severity of sensory and motor CIPN according to CTCAE v4.03 before, during and after treatment with OnLife. Secondary endpoints included patient-reported experience of symptoms and functional limitations related to CIPN. Descriptive statistics were used to analyze data. Results: In total, 75 breast cancer pts with paclitaxel-induced and 71 colon cancer pts with oxaliplatin-induced peripheral neuropathy, respectively, received OnLife. Based on physician-rated CTCAE grades, 21.3% of breast cancer pts and 12.7% of colon cancer pts had a sustained improvement of sensory CIPN after OnLife treatment. Concerning motor CIPN, the proportions were 12.0% and 9.9%, respectively. According to patient-reported outcomes, 45.3% of breast cancer pts and 23.9% of colon cancer pts had less symptoms and functional limitations related to sensory CIPN after OnLife treatment. Concerning motor CIPN, the proportions were 32.0% and 22.5%, respectively. Conclusions: STEFANO provides indications of the potential of OnLife to reduce severity of objective and subjective CIPN-related symptoms. Therefore, it is a promising agent to meet the unmet medical need of management options for patients with established CIPN. Clinical trial information: NCT03065478.

Background Prognosis of patients with multiple myeloma (MM) who have relapsed on or become refractory to immunomodulators and bortezomib is poor, and treatment options are limited. While pomalidomide plus low‐dose dexamethasone (POM/DEX) has demonstrated efficacy in clinical trials, real‐world evidence is scarce. Patients and Methods POSEIDON was a prospective non‐interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of POM/DEX in patients with relapsed or refractory MM (R/RMM) pretreated with at least two prior therapy lines including both lenalidomide and bortezomib in real world in Germany. Patients received POM/DEX according to physicians’ choice. Data were analyzed descriptively. Results Between 2014 and 2017, 151 patients were enrolled, 144 patients with a median of three prior therapy lines qualified for effectiveness analysis. Median age was 73.2 years. Median progression‐free and overall survival were 6.3 months [95% confidence interval (CI) 5.2, 8.6] and 12.9 months [95% CI 10.6, 15.1]. Most frequent grade 3/4 adverse events were leukopenia (8.2%), pneumonia (7.5%) and anemia (5.5%). QoL was maintained after start of POM/DEX. Conclusion The results of POSEIDON support the effectiveness and safety of POM/DEX in R/RMM patients pretreated with lenalidomide and bortezomib and highlight the clinical value of the POM/DEX regimen in the real‐world setting. Registered at clinicaltrials.gov (NCT02075996).