The novel low molecular weight MYC antagonist MYCMI-6 inhibits proliferation and induces apoptosis in breast cancer cells.

Background The MYC oncogene is one of the most frequently altered driver genes in cancer. MYC is thus a potential target for cancer treatment as well as a biomarker for the disease. However, as a target for treatment, MYC has traditionally been regarded as "undruggable" or difficult to target. We set out to evaluate the efficacy of a novel MYC inhibitor known as MYCMI-6, which acts by preventing MYC from interacting with its cognate partner MAX. Methods MYCMI-6 response was assessed in a panel of breast cancer cell lines using MTT assays and flow cytometry. MYC gene amplification, mRNA and protein expression was analysed using the TCGA and METABRIC databases. Results MYCMI-6 inhibited cell growth in breast cancer cell lines with IC50 values varying form 0.3 µM to >10 µM. Consistent with its ability to decrease cell growth, MYCMI-6 was found to induce apoptosis in two cell lines in which growth was inhibited but not in two cell lines that were resistant to growth inhibition. Across all breast cancers, MYC was found to be amplified in 15.3% of cases in the TCGA database and 26% in the METABRIC database. Following classification of the breast cancers by their molecular subtypes, MYC was most frequently amplified and exhibited highest expression at both mRNA and protein level in the basal subtype. Conclusions Based on these findings, we conclude that for patients with breast cancer, anti-MYC therapy is likely to be most efficacious in patients with the basal subtype.

Effects of HER Family-targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer.

PURPOSE: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2+) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC. EXPERIMENTAL DESIGN: Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2+ (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array-determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry-based protocols. RESULTS: Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy (P = 0.03) and associated with trastuzumab response (P = 0.01). TKI treatment altered mAb-induced NK cell-mediated ADCC in vitro, but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone. CONCLUSIONS: TKIs differentially alter tumor cell phenotype which can impact NK cell-mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.

Adaptation of CARE (CAse REport) guidelines on published case reports in the Saudi Journal of Anesthesia.

BACKGROUND: Toward improving the reporting quality of clinical case reports in the Saudi Journal of Anesthesia, we conducted this audit. The aim of this paper is to provide an overview of the different objectives for clinical case reports and to identify those subordinate items which seem most relevant from the CAse REport (CARE) checklist. METHODS: We performed this pilot study on clinical case reports published in the Saudi Journal of Anesthesia (SJA) in the past 5 years from 2013 to 2017. The journal publishes 4 issues/year that means 20 issues were studied. We used one online source to gather the clinical case reports which is the SJA website. A total of 84 case reports were studied. We have applied the 13th items in the CARE checklist on the case reports to determine their representations. Two reviewers abstracted data from all included papers to determine the adaptation of the CARE checklist. Data are presented as percentages of different subordinate items of the CARE guidelines. RESULTS: None of the 84 case reports met all subordinate items of CARE guidelines, and only 5 subordinate items were reported fully met (100%). Patient perspective subordinate item was not mentioned in our series due to lack of data in the studied case reports. Therefore, only 12 subordinate items were included. We reported those adaptation percentages of the 12th subordinate items of the CARE checklist as follows: (a) title, keywords, abstract patient's biodata, and conclusion 100%; (b) main symptoms of the patients 97.6%; (c) timeline 78.5%; (d) diagnosis 94.0%; (e) treatment 97.6%; (f) strengths 85.7%; (g) literature review 94.0%; and (h) patient consent 33.4%. CONCLUSION: We believe that the CAse REport guidelines can provide an international framework for the authors to follow in writing their case reports and for the editors to use to ensure the completeness and readiness of the peer-reviewed case reports for publication. For the SJA, we have to apply the CARE checklist and to ensure all subordinate items are adapted including the patient's perspective subordinate item and to make sure that the consent form obtained and accompanied each submitted case reports.