Background: Industry, society or clinical need for project and scientific rationale
Adrenocortical carcinoma (ACC) is a rare disease which occurs with an annual incidence of 2-4 cases per million with a five-year survival of less than 16-38%. The incidence of this disease is maximal in adults of 40-50 years and in children but can occur at any age. The mainstay of treatment for ACC is surgical resection; however 50% of patients have distant metastasis at presentation and will not be cured by surgery. Currently mitotane is the only effective adjuvant treatment however only 20% of patients respond to this drug. Failing mitotane, patients may be offered high dose multi-agent chemotherapy however the median survival is less than 15 months.
microRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression through RNA degradation and translational inhibition. miRNAs demonstrate distinctive expression signatures in cancer cells compared to normal tissues and act as tumour suppressors or oncogenes. Each individual miRNA modulates a cohort of cancer-relevant genes, involved in several cancer-related pathways. The potential of using miRNAs as a ‘one-hit multi-target’ therapy is a significant advance over traditional chemotherapy which initiates indiscriminate cell death in both normal and malignant tissue. However, one of the major obstacles for the therapeutic use of miRNAs in the clinic is the lack of a cancer-specific delivery system and poor cellular uptake. The innovative EnGeneIC delivery vesicles (EDVs), which utilize a bi-specific antibody, offer a solution to achieve target-specific delivery of therapeutic agents, such as miRNAs and both supervisors have close collaborations with EngeneIC.
Research challenge and specific research questions, to include description of multidisciplinary aspects, and potential applications and benefits
Professor Stan Sidhu and his team have identified the role of microRNAs (miRNAs) in the development of ACC and the potential of miRNAs as therapeutic targets for advanced and chemo-resistant ACC will now be studied. By performing a variety of studies in cell lines and animal xenograft models, examining how these miRNAs play a critical role in ACC development and chemo-resistant modulation, and how the miRNA can be delivered specifically to the tumour site, the research team aims to develop a novel miRNA-based therapy option, either alone or in combination with current chemotherapy to improve treatment response and patient survival. This research will potentially open a new frontier in cancer therapy and provide proof of principal for miRNA therapy in other cancer types.(Glover Oncotargets 2015,Kwok Oncologist 2019,Hassan Endocrine Rel Cancer 2019) Professor Gyorgy Hutvagner and his team have worked in the basic biology of miRNAs for many years.Recently they have undertaken translational cancer work in breast cancer and brain cancer and developed a novel model of miRNA isomiRs that can be used as biomarkers in the identification of different breast cancer subtypes, and in addition, provide new insights into the diverse molecular mechanisms of breast cancers. They have also shown that the classification of different subtypes of breast cancer based on isomiRs expression is more effective than using published gene expression profiling( Lan BMC Medical Genomics 2018).
Combining the expertise of these 2 groups-one with access to adrenocortical cancer samples and clinical outcome data and one with demonstrated outcomes in analysis of RNA seq data in miRNA isoforms, allows for expansion in our knowledge in this field to identify miRNA isomers involved in diagnosis, prognosis and therapy.
Project Description: aims, objectives.
To this end, within the time frame of three years, the specific aims of this project are:
1. Undertake next generation sequencing of a cohort of adrenocortical cancers, adrenal adenomas and normal adrenal glands to identify miRNA isoforms in these 3 tissue types.
2. Undertake analysis of isoform results results in order to develop an algorithm that discriminates benign from malignant tumours , provides prognostic data and informs for therapeutic response.
3. Undertake functional investigation of miRNA isoforms to compare therapeutic efficacy as a solo or adjuvant agent to wild type miRs.
$30k consumable support has been established at the Kolling institute