STX140, but Not Paclitaxel, Inhibits Mammary Tumour Initiation and Progression in C3(1)/SV40 T/t-Antigen Transgenic Mice

Abstract

Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer.

Role of 2-methoxyestradiol, an Endogenous Estrogen Metabolite, in Health and Disease

“…Interestingly, STX140 did not affect cell viability in a non-tumorigenic human breast cell line [154]. This compound also inhibited initiation and progression of mammary tumors in adult mice [155] suggesting that STX140 is a promissory 2ME 2 analog that can be potentially used in human breast cancer.…”

Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade

“…Furthermore, favourable pharmacokinetic properties of STX140, including good bioavailability and low metabolism in rodents 105 , have proved its major clinical advantages 106 also for chemotherapy-resistant tumours 107 . In 2013, in vivo studies with three breast cancer models 108 demonstrated that STX140 had greater anticancer efficacy and therapeutic index as well as reduced neurotoxicity compared to paclitaxel (clinically used for hormone-refractory breast cancer), which may bring significant benefits to patients with breast cancer. Furthermore, a 2-[ 11 C]methoxy derivative of STX140 has been reported as a new potential imaging agent of STS in tumours in the positron emission tomography technique 109 .…”

Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents

“…Moreover, β3-tubulin overexpression has also been reported to confer resistance to paclitaxel and vinorelbine, but with no effect to the resistance to colchicine-site binding agents [ 25 ]. Lastly, STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in transgenic mice [ 26 ].…”