The Engineered Drug 3'UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer.

c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3'UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target.

Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2.

Non-small cell lung cancer (NSCLC) caused more deaths in 2017 than breast cancer, prostate, and brain cancers combined. This is primarily due to their aggressive metastatic nature, leading to more fatal rates of cancer patients. Despite this condition, there are no clinically approved drugs that can target metastasis. The NSCLC with EGFR T790M-overexpressing HER2 shows the resistance to osimertinib and trastuzumab starting 10-18 months after the therapy, and thus prospects are grim to these patients. To target the recalcitrant ERBB2 driver oncogene, we developed two engineered destabilizing 3'UTR ERBB2 constructs that degrade the endogenous ERBB2 transcript and proteins by overwriting the encoded endogenous ERBB2 mRNA with the destabilizing message. When iron oxide nanocages (IO nanocages) were used as vehicles to deliver them to tumors and whole tissues in mice bearing tumors, it was well tolerated and safe and caused no genome rearrangement whereas they were integrated into genome deserts (non-coding regions). We achieved significant reduction of the primary tumor volume with desARE3'UTRERBB2-30, achieving 50% complete tumor lysis and inhibiting 60%-80% of liver metastasis, hepatomegaly, and 90% of lung metastasis, through ERBB2 downregulation. These constructs were distributed robustly into tumors, livers, lungs, kidneys, and spleen and mildly in the brain and not in the heart. They caused no abnormality in both short- and long-term administrations as well as in healthy mice. In summary, we accomplished significant breakthrough for the therapeutics of intractable lung cancer patients whose cancers become resistant and metastasize.

How Accurately FNAC Reflects the Breast Papillary Lesions?

Context: Diagnosis of papillary lesions of the breast by fine needle aspiration cytology (FNAC) is problematic. For this reason, it is situated in the indeterminate zone in classification systems. Aims: To ascertain the accuracy of cytological diagnosis of papillary lesions in distinguishing papillary lesions from non-papillary lesions and to determine whether papillomas can be reliably distinguished from malignant papillary lesions by FNAC. Material and Methods: A total of 346 cases with the diagnoses of breast papillary lesions were selected among 5112 breast FNAC procedures performed in our center. One hundred and thirty-nine cases with excised lesions were included in this study, and their corresponding histology was reviewed. Results: Papillary lesion diagnosis was confirmed by histopathology in 103 (74.1%) of 139 patients. Cytology and histopathology results were not found to be compatible in 35 (25.2%) cases. The diagnostic accuracy of distinguishing papillary breast lesions as malignant or benign was assessed statistically. According to the cytology-histology comparison, one case was evaluated as false negative (FN) and twelve cases as false positive (FP). Overall accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FNAC in distinguishing papillary lesions as benign or malignant were calculated as 87%, 97%, 83%, 72%, and 98%, respectively. Conclusions: The diagnostic accuracy of papillary breast lesions classified by FNAC might be improved by careful evaluation together with cytological, radiological, and clinical findings (triple test). Cell block may allow more accurate evaluation of the papillary lesion and can be applied to immunohistochemical examination. It may also facilitate the differentiation of benign/malignant papillary lesions.