Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma

Abstract

Background:Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus.Methods:In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence.Results:Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis.Conclusions:In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Time-Based Switching Control of Genetic Regulatory Networks: Toward Sequential Drug Intake for Cancer Therapy

“…This suggests that the drugs are effective when taken simultaneously or sequentially based on the reduction in the expression levels of the proteins and complexes. However, toxicity becomes a concern in the simultaneous intake case as already investigated in the previous studies 3–8. This suggests that the proposed sequential or switched drug inputs approach is a promising solution.…”

“…Experimental data have suggested that MTDs for combination therapy drugs are different from those of monotherapy in which the drugs are given sequentially or individually3–5,8 and toxicity of drug combinations are higher than single-drug treatments. The model presented in this work is based on some previous studies 3–8.…”

“…The model presented in this work is based on some previous studies 3–8. It is shown that the sequential treatment schedule has lower drug-related toxicity when compared with the drugs taken simultaneously 13.…”

“…The state-space trajectory depicts that both the simultaneous drug intake and sequential drug intake significantly reduced the expression levels of the diseased genes. Although they are both effective against the diseased genes, toxicity is a concern with the simultaneous drug intake 3–8. Therefore, this study is focused on time-based switching control and stability analysis for the sequential drug intake approach due to the reduced toxicity associated with such drug intake methods.…”

Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations

“…The underlying rationale for drug combination treatment in cancer has been to coadminister drugs that act by different mechanisms, thereby increasing tumor cell killing while reducing the likelihood of drug resistance (Al-Lazikani et al, 2012). To rapidly move drug combinations to the clinic, studies need to compare the effects of simultaneous versus sequential administration of targeted therapy and select the best approach based on a solid mechanistic justification (Wang et al, 2012(Wang et al, , 2013Fung et al, 2013;Wild et al, 2013;Dos Santos et al, 2015;Song et al, 2015). If sequential administration is as effective as simultaneous administration, existing clinical trial toxicity data can be used to expedite clinical testing.…”