Abstract
PurposeRecurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity for tumour repair. Cantrixil targets this sub-population of cells and is being developed as an intraperitoneal therapy to be used as first-line therapy in combination with carboplatin for epithelial ovarian cancer. The studies presented here justify further development.MethodsA GLP dog CV study using a 4 × 4 Latin Square Crossover study was conducted using telemetric ECG recordings from dogs post IP administration to assess for cardiac abnormalities. Mutagenic potential was assessed using the bacterial reverse mutation assay. Clastogenicity was assessed by determining micronuclei formation in the bone marrow of SPF Arc(S) Swiss mice dosed at clinical concentrations. TRX-E-002-1 toxicology was evaluated in GLP-compliant MTD and 28-day repeat-dose studies in rats and dogs.ResultsIn vitro TRX-E-002-1 has potent cytotoxic activity against human cancer cells including CD44+/MyD88+ ovarian cancer stem cells. TRX-E-002-1 increased phosphorylated c-Jun levels in these cancer cells resulting in caspase-mediated apoptosis. In vivo, Cantrixil was active in a model of disseminated ovarian cancer as a monotherapy and in combination with Cisplatin. Cantrixil was active as maintenance therapy in a model of drug-resistant, recurrent ovarian cancer and in an orthotopic model of pancreatic cancer.ConclusionsIn animals, this clinical formulation and route of administration of Cantrixil demonstrated acceptable activity, safety pharmacology, genotoxicity and toxicology profile and constituted a successful Investigational New Drug application to the US Food and Drug Administration.
Highlights
With an age-standardised incidence of 9.4 women developing epithelial ovarian cancer (EOC) per 100,000 in the USA equating to 22,500 women developing the disease annually, approximately 14,200 of those women will die each year [1,2,3]
The introduction of combination chemotherapy several decades ago has had little impact on ovarian cancer patient survival rates, where patients who initially respond to standard of care eventually relapse with recurrent disease presenting with chemo-resistant carcinomatosis
Research indicates that tumour recurrence is caused by the expansion of chemo-resistant cancer stem cells that survive initial chemotherapy by residing in a niche microenvironment within the tumour mass
Summary
With an age-standardised incidence of 9.4 women developing epithelial ovarian cancer (EOC) per 100,000 in the USA equating to 22,500 women developing the disease annually, approximately 14,200 of those women will die each year [1,2,3]. Phytochemicals have been shown to modulate signalling pathways (i.e. Hedgehog, Wnt/β-catenin and Notch) in cancer stem cells which display enhanced DNA damage repair mechanisms, amplified anti-apoptotic activity, enhanced xenobiotic efflux and skewed production of certain pre-inflammatory cytokines [12]. Phytochemicals such as the flavonoid genistein are polyphenolic compounds found in plants characterised by a simple benzopyran structure. Several discrete sub-families of these SBPs have been identified on the basis of chemical
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