Sorafenib Decreases Tumor Exposure to an Anti-carcinoembryonic Antigen Monoclonal Antibody in a Mouse Model of Colorectal Cancer

Thomas, Veena A.; Balthasar, Joseph P.

doi:10.1208/s12248-016-9909-y

Cited by 13 publications

(8 citation statements)

References 40 publications

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“…Therefore we demonstrated that, by counteracting the action of miR-17-5p and miR-106b-5p by specific anti-miRs, the cells regained sensitivity to chemotherapeutic treatments. Significantly, cells became sensitive not only to Sorafenib and Axitinib, which are among Tyrosine Kinase Inhibitors currently in use for treatment of both renal and colorectal carcinoma [28, 30, 32, 34, 35], but also to Nutlin-3 and Cisplatin. This suggests that with the TRIM8-mediated recovery of the p53 tumour suppressor activity, a broader spectrum of chemotherapeutic agents may be taken into consideration to blunt tumorigenicity.…”

Section: Discussionmentioning

confidence: 99%

TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours

et al. 2017

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BackgroundTRIM8 plays a key role in controlling the p53 molecular switch that sustains the transcriptional activation of cell cycle arrest genes and response to chemotherapeutic drugs. The mechanisms that regulate TRIM8, especially in cancers like clear cell Renal Cell Carcinoma (ccRCC) and colorectal cancer (CRC) where it is low expressed, are still unknown. However, recent studies suggest the potential involvement of some microRNAs belonging to miR-17-92 and its paralogous clusters, which could include TRIM8 in a more complex pathway.MethodsWe used RCC and CRC cell models for in-vitro experiments, and ccRCC patients and xenograft transplanted mice for in vivo assessments. To measure microRNAs levels we performed RT-qPCR, while steady-states of TRIM8, p53, p21 and N-MYC were quantified at protein level by Western Blotting as well as at transcript level by RT-qPCR. Luciferase reporter assays were performed to assess the interaction between TRIM8 and specific miRNAs, and the potential effects of this interaction on TRIM8 expression. Moreover, we treated our cell models with conventional chemotherapeutic drugs or tyrosine kinase inhibitors, and measured their response in terms of cell proliferation by MTT and colony suppression assays.ResultsWe showed that TRIM8 is a target of miR-17-5p and miR-106b-5p, whose expression is promoted by N-MYC, and that alterations of their levels affect cell proliferation, acting on the TRIM8 transcripts stability, as confirmed in ccRCC patients and cell lines. In addition, reducing the levels of miR-17-5p/miR-106b-5p, we increased the chemo-sensitivity of RCC/CRC-derived cells to anti-tumour drugs used in the clinic. Intriguingly, this occurs, on one hand, by recovering the p53 tumour suppressor activity in a TRIM8-dependent fashion and, on the other hand, by promoting the transcription of miR-34a that turns off the oncogenic action of N-MYC. This ultimately leads to cell proliferation reduction or block, observed also in colon cancer xenografts overexpressing TRIM8.ConclusionsIn this paper we provided evidence that TRIM8 and its regulators miR-17-5p and miR-106b-5 participate to a feedback loop controlling cell proliferation through the reciprocal modulation of p53, miR-34a and N-MYC. Our experiments pointed out that this axis is pivotal in defining drug responsiveness of cancers such ccRCC and CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0634-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours

et al. 2017

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“…Similarly, the addition of bevacizumab to trastuzumab therapy in HER-2 positive breast cancer patients did not improve overall survival [394]. Muselaers et al used an imaging technique to show that 4-week sorafenib treatment (400 mg twice daily) in patients with renal cell carcinoma decreased microvessel density in tumor tissue and caused a 38.4% reduction in the uptake of 111In-girentuximab [395], in line with preclinical results [386].…”

Section: Alteration In Convective Transport and Tumor Uptakementioning

confidence: 91%

“…In another preclinical investigation, the effect of the small molecule anti-angiogenic agent sorafenib on T84.66 tumor disposition was evaluated. Sorafenib treatment decreased tumor microvessel density, decreased macromolecular extravasation in tumors, and decreased tumor exposure to T84.66 [386].…”

Section: Alteration In Convective Transport and Tumor Uptakementioning

confidence: 95%

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Thomas

Balthasar

2019

Antibodies

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Monoclonal antibodies (mAbs) are currently the largest and most dominant class of therapeutic proteins. Inter-individual variability has been observed for several mAbs; however, an understanding of the underlying mechanisms and factors contributing to inter-subject differences in mAb disposition is still lacking. In this review, we analyze the mechanisms of antibody disposition and the putative mechanistic determinants of inter-individual variability. Results from in vitro, preclinical, and clinical studies were reviewed evaluate the role of the neonatal Fc receptor and Fc gamma receptors (expression and polymorphism), target properties (expression, shedding, turnover, internalization, heterogeneity, polymorphism), and the influence of anti-drug antibodies. Particular attention is given to the influence of co-administered drugs and disease, and to the physiological relevance of covariates identified by population pharmacokinetic modeling, as determinants of variability in mAb pharmacokinetics.

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“…Therefore, sorafenib can also be expected to be effective for the treatment of patients with advanced CRC. The excellence of sorafenib as a targeted therapy for CRC was verified through non-clinical and clinical studies [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…As a single agent, sorafenib can decrease the viability of human CRC cells or reduce carcinoembryonic antigens. The antitumor effect of sorafenib in combination with erlotinib or cetuximab on human CRC cells was also investigated [4,5]. In patients with metastatic CRC, sorafenib has been found to increase the median progression-free survival and overall survival when single-treated or combined with an anti-angiogenic agent, such as bevacizumab [6,7].…”

Section: Introductionmentioning

confidence: 99%

Combination Antitumor Effect of Sorafenib via Calcium-Dependent Deactivation of Focal Adhesion Kinase Targeting Colorectal Cancer Cells

Jeong¹,

Park²,

Sim³

et al. 2020

Molecules

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Sorafenib has been recently used for the treatment of patients with advanced colorectal cancer (CRC) and is recognized for its therapeutic value. However, the continuous use of sorafenib may cause resistance in the treatment of cancer patients. In this study, we investigated whether sorafenib exerts an enhanced anticancer effect on CRC cells via the calcium-mediated deactivation of the focal adhesion kinase (FAK) signaling pathways. The appropriate dose of sorafenib and lactate calcium salt (CaLa) for a combination treatment were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Then, cell cycle analysis was performed following treatment with 2.5 μM sorafenib and/or 2.5 mM CaLa. CRC cells were found to be in the G1 phase by sorafenib treatment, and they accumulated in the sub-G1 phase with CaLa treatment. Western blots and enzyme-linked immunosorbent assays were performed to analyze the elements of the recombinant activated factor (RAF) and focal adhesion kinase (FAK) signaling cascades. Sorafenib-inhibited RAF-dependent signaling in CRC cells, however, either did not affect the expression of Akt or increased it. As the upstream signaling of FAK was suppressed by CaLa, we observed that the expression of the sub-signaling phospho (p) AKT and p-mammalian target of rapamycin was also suppressed. Treatment with a combination of sorafenib and CaLa enhanced the antitumor activity of CRC cells. The % viability of CRC cells was significantly decreased compared to the single treatment with sorafenib or CaLa, and the accumulation of Sub G1 of CRC cells was clearly confirmed. The migration ability of CRC cells was significantly reduced. The findings of this study indicate that sorafenib will show further improved antitumor efficacy against CRC due to overcoming resistance through the use of CaLa.

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Sorafenib Decreases Tumor Exposure to an Anti-carcinoembryonic Antigen Monoclonal Antibody in a Mouse Model of Colorectal Cancer

Cited by 13 publications

References 40 publications

TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours

TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Combination Antitumor Effect of Sorafenib via Calcium-Dependent Deactivation of Focal Adhesion Kinase Targeting Colorectal Cancer Cells

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