In today’s current state, 90% of failures in chemotherapy are during the invasion and metastasis of cancers related to drug resistance.1 Cancer recurrence following cytoreductive surgery is incredibly common, a large number of patient tumors develop a resistance to the drug, this is an especially common occurrence in aggressive peritoneal cancers, such as mesothelioma. Despite aggressive treatment with chemotherapy and surgery, around 85% of patients develop recurrent disease at 18 months, even after a complete clinical response to first-line therapy.2  Verticillin A is a novel selective histone methyltransferase inhibitor that is thought to induce the expression of epigenetically silenced tumor suppressor genes, leading to suppression of cancer growth and resensitisation of cancer cells to traditional chemotherapy. By combining verticillin A and a stimuli resposive particle drug delivery system, The Colson Lab, in partnership with the Grinstaff Lab,  proposes that cancer drug resistance may be overcome as this allows for highly specific tumoral accumulation. The project develops a nanoparticle based solution to cancer recurrence, a common point of treatment failure. By delivering Verticillin with a chemotherapeutic using expansile Nanoparticles (eNPs) to mesothelioma tumours will not only overcome drug resistance but also extend survival compared to the delivery of verticillin or the chemotherapeutics alone. For this project, we will begin by evaluating the epigenetic activity of verticillin A and five of its analogs in human mesothelioma cells collected from patient pleural effusions, in addition to the toxicity profile via in vitro assays for hepatotoxicity, cardiotoxicity, and mitochondrial toxicity. Once that evaluation has been completed, we plan to optimize the co-formulation of two verticillin agents with paclitaxel, cisplatin, or pemetrexed to achieve the maximum cytotoxic effect in drug resistant mesothelioma cell lines and tumor cells collected from patient pleural effusions. Further continuations of this study will focus on assessing toxicity in healthy mice and the optimised formulation in patient-derived xenograft murine models of the drug resistant mesothelioma. Together, this proposal, if successful, will provide a promising direction for drug delivery methods, and conduct a more “materials-based targeting” for improving drug delivery to peritoneal carcinomatosis, specifically. 

References

1. Mansoori, Behzad et al. “The Different Mechanisms of Cancer Drug Resistance: A Brief Review.” Advanced pharmaceutical bulletin vol. 7,3 (2017): 339-348. doi:10.15171/apb.2017.041
2. Mahvi, David A et al. “Local Cancer Recurrence: The Realities, Challenges, and Opportunities for New Therapies.” CA: a cancer journal for clinicians vol. 68,6 (2018): 488-505. doi:10.3322/caac.21498