Jennifer Macdiarmid

Separation of epidermal tissue from underlying dermis and primary keratinocyte culture

The epidermis shares many structural similarities to other epithelia throughout the body. All epithelia function as a barrier protecting the internal organs. The epidermis of the skin protects the exterior of the body, whereas other forms of epithelia line the airways, blood vessels, and gastrointestinal, urinary, and reproductive tracts. Some glandular epithelia secret substances such as sweat, mucus, and hormones. All epithelia are avascular and consist of closely packed cells, which are tightly attached to one another via cell junctions. This tight structure allows all epithelia to closely regulate the movement of materials such as ions, nutrients, and secretory products

Abstract 3976: Targeted delivery of a synthetic microRNA-based mimic as an approach to cancer therapy

MicroRNA expression is commonly suppressed in cancer, contributing to tumor cell biology. Recently we demonstrated that multiple members of the miR-15/16 family are downregulated and have tumor suppressor functions in malignant pleural mesothelioma (MPM), an asbestos-related cancer for which few treatments are available. These results are similar to previous findings in prostate and non-small cell lung cancer (NSCLC). Using mimics to restore levels of miR 15a, miR-15b or miR-16 led to growth inhibition and induction of apoptosis of MPM cells in vitro. The miR-16 mimic, packaged in bacterially-derived, EGFR antibody-targeted, EDV(TM)nanocells, inhibited xenograft tumor growth in vivo. As multiple microRNAs from the same family are downregulated in MPM, we investigated whether a single synthetic mimic based on the consensus sequence of all family members could restore activity of the entire family. To this end we generated four novel mimics derived from the consensus sequence of the miR-15/16 family and tested them in a range of tumor cell lines. Compared with a mimic corresponding in sequence to native miR-16, the consensus mimics had enhanced growth inhibitory activity in MPM, NSCLC and prostate cancer lines, three tumor types in which miR-15/16 expression is suppressed. They were also active in cell lines derived from breast and colon cancer. When packaged in minicells, the synthetic mimics inhibited growth of MPM xenograft tumors in vivo. Based on these preclinical studies a Phase I clinical trial has been initiated for patients with MPM or NSCLC failing standard therapy. This represents only the second trial of microRNA replacement as a cancer therapy, and the first for thoracic cancer. Citation Format: Glen Reid, Marissa Williams, Michaela B. Kirschner, Nancy Mugridge, Jocelyn Weiss, Himanshu Brahmbhatt, Jennifer MacDiarmid, Nico van Zandwijk. Targeted delivery of a synthetic microRNA-based mimic as an approach to cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3976. doi:10.1158/1538-7445.AM2015-3976

Translational applications of microRNAs in cancer, and therapeutic implications

The search for targeted novel therapies for cancer is ongoing. MicroRNAs (miRNAs) display a number of characteristics making them an attractive and realisable option. In this review, we explore these applications, ranging from diagnostics, prognostics, disease surveillance, to being a primary therapy or a tool to sensitise patients to treatment modalities such as chemotherapy and radiotherapy. We take a particular perspective towards miRNAs and their impact on rare cancers. Advancement in the delivery of miRNAs, from viral vectors and liposomal delivery to nanoparticle based, has led to a number of pre-clinical and clinical applications for microRNA cancer therapeutics. This is promising, especially in the setting of rare cancers.