The use of AONYS®-API microemulsions will allow effective delivery of APIs targeting specific genes or proteins in tumors, resulting in tumor growth inhibition and shrinkage. Once the therapeutic potential of the Aonys®-API combination has been validated in the mouse model, clinical development will be initiated.
Medesis Pharma is actively engaged in the systemic delivery of new anticancer therapeutic agents, including siRNAs and peptides, using the AONYS® technology.
RNA interference in the treatment of resistant tumor cells
Resistance to anticancer drugs is a huge problem in many cancers including breast, colorectal and brain cancers. Combining several approaches including radiation therapy and chemotherapy is currently the major option in therapeutic oncology. However, the efficiency of chemotherapy is often limited due to inherent and/or acquired resistance of tumor cells. The mechanisms of resistance are numerous and include notably (but not exclusively) overexpression of genes encoding metabolic enzymes, efflux transporters, DNA repair enzymes, apoptosis controlling proteins, etc.
RNA interference (RNAi) represents a new perspective for the treatment of resistant tumors. Indeed, the use of siRNAs has been shown to sensitize tumors to chemotherapeutics treatments. However, this strategy is hampered by major problems of delivery of siRNAs including: i) degradation of siRNA by serum nucleases, ii) renal clearance, iii) host-innate immune response, iv) efficient targeting to the tissue and/or cell type of interest and v) efficient loading on the RNAi machinery (RISC). Published (see full article here: Lehmann et al. 2014) and current investigations (Champagne et al. 2017) have revealed that siRNAs can be efficiently delivered to the brain and tumors via our Aonys® technology. The aim of this project is to use this technology to develop new siRNA/APIs for the treatment of resistant tumors in breast, colorectal and brain cancers.
Breast cancer is the most common cause of cancer deaths in women in industrialized countries. Women with advanced breast cancer live as long as their tumors respond to chemotherapy. However, patients with breast cancer whose tumor is or becomes resistant to chemotherapy have a poor prognosis. The most aggressive form of breast cancer is the triple negative breast cancer (TNBC) subtype, which does not express the receptors to oestrogen (ER) and progesterone, and HER2. These tumors have no therapeutic targets, so that cytotoxic chemotherapy is the only therapy. Resistance to chemotherapy is associated with rapid progression to death in these patients.
Colorectal cancer (CRC) is one of the most common human malignancies and remains the third leading cause of malignancy-related mortality in Western countries. Approximately 40%–50% of all CRC patients will develop metastatic tumors after resection of the primary CRC. Tumor invasion, metastasis and resistance to chemotherapy weaken the effect of treatment and are a major reason in the death of CRC patients. Identification of novel strategies for the treatment and prevention of CRC is therefore urgently needed.
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Median survival is 14.6 months and the percentage of patients living for five years or more is less than 10%. Current therapy includes surgical intervention, radiotherapy and chemotherapy with temozolomide. However, despite the advances made during the past few years, the prognosis of this disease has not significantly improved mainly because these tumors acquire a resistance phenotype.
A consortium has been gathered by Medesis Pharma, including the following groups:
– Dr Gerald Batist, Lady Davis Institute, McGill University, Montreal
– Dr Mark Basik, Lady Davis Institute, McGill University, Montreal
– Dr Sylvie Mader, Institute for Research in Immunology and Cancer, University of Montreal
– Dr Stefano Stifani, Dept. of Neurology and Neurosurgery, McGill University
The project is based on the following steps:
– academic groups have constructed “next generation bio-banks” composed of serial biopsies of metastasis from chemotherapy-resistant tumors from cancer patients before treatment and at the time of therapeutic resistance to the most effective chemotherapeutic agents (Diaz 2013). These banks are continuously enriched with newly collected specimen.
– gene profiling of these resistant tumors using next generation sequencing (Lemieux 2017) has been or is currently carried out.
– gene candidates possibly responsible for the chemoresistance of the tumors whose therapeutic targeting should delay, overcome or avoid resistance, have been or will be identified.
– these candidates have been or will be validated through high-throughput shRNA screens in a pannel of drug-resistant breast, colic and glioblastoma cell lines (Ye 2012;Deschenes 2007).
– feasibility of stable siRNAs-Aonys® nanoemulsion formulations will be assessed.
– siRNAs formulated in Aonys® nanoemulsions will be tested in mouse xenograft models (nude mice transplanted with resistant human tumor cells) for their capacity to develop RNAi-based tumor chemosensitization to anticancer drugs of reference as a proof of concept of reversing or preventing the development of resistance.