Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study

Milosevic, Michael; Townsley, Carol; Chaudary, Naz; Clarke, Blaise A.; Pintilie, Melania; Fan, Stacy; Glicksman, Rachel; Haider, Masoom A.; Kim, Sunmo; Mackay, Helen; Yeung, Ivan; Hill, Richard P.; Fyles, Anthony; Oza, Amit M.

doi:10.1016/j.ijrobp.2015.09.009

Cited by 28 publications

(17 citation statements)

References 21 publications

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“…Yet another study using the same drug, almost identical dose schedule (3 × 45 mg/kg), and similar hypoxic specific marker, found that 2 days after treatment, MCa4/MCa35 mammary carcinomas were significantly more hypoxic (99). This same controversy was seen in the limited clinical studies in which both a decrease (100) and an increase (101,102) in tumor hypoxia have been reported. Such findings clearly argue against making sweeping statements about the effects of AIs on tumor hypoxia and that either measurements of the oxygenation status need to be routinely made when AIs are administered or that they be given in such a way as to avoid any negative influence on the conventional treatment with which they are combined.…”

Section: Vascular Targeting Agents and Hypoxiamentioning

confidence: 80%

Tumor Hypoxia: Impact on Radiation Therapy and Molecular Pathways

2020

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Tumor hypoxia is a common feature of the microenvironment in solid tumors, primarily due to an inadequate, and heterogeneous vascular network. It is associated with resistance to radiotherapy and results in a poorer clinical outcome. The presence of hypoxia in tumors can be identified by various invasive and non-invasive techniques, and there are a number of approaches by which hypoxia can be modified to improve outcome. However, despite these factors and the ongoing extensive pre-clinical studies, the clinical focus on hypoxia is still to a large extent lacking. Hypoxia is a major cellular stress factor and affects a wide range of molecular pathways, and further understanding of the molecular processes involved may lead to greater clinical applicability of hypoxic modifiers. This review is a discussion of the characteristics of tumor hypoxia, hypoxia-related molecular pathways, and the role of hypoxia in treatment resistance. Understanding the molecular aspects of hypoxia will improve our ability to clinically monitor hypoxia and to predict and modify the therapeutic response.

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Section: Vascular Targeting Agents and Hypoxiamentioning

confidence: 80%

Tumor Hypoxia: Impact on Radiation Therapy and Molecular Pathways

2020

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“…Treatment with the negative control 7C1-siLUC (silencing luciferase mRNA) did not change tumor growth or immune cell infiltration, and there was Furthermore, we find that immunosuppression, rather than angiogenesis, in the tumor microenvironment is the key mechanism conferring resistance to anti-VEGF therapy exerted by Ly6C Some reports show that low doses of anti-VEGF therapy can induce vascular normalization and improve antitumor immunity (63,64). It is also known that high dose or prolonged treatment of anti-VEGF therapy promotes hypoxia and immunosuppression in the tumor microenvironment in both clinical and preclinical studies (1,6,24,(65)(66)(67)(68). The latter case explains one mechanism of anti-VEGF therapy resistance in patients, which is consistent with our observations in CRC models.…”

Section: Ly6c Lo Monocytes and Neutrophils Produce Il-10 And Inhibit mentioning

confidence: 85%

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

Jung¹,

Heishi²,

Khan³

et al. 2017

Journal of Clinical Investigation

131

142

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“…The therapeutic outcome of HCC with transarterial chemoembolization of RT could be improved when combined with sorafenib [14–16]. Sorafenib has been shown to sensitize both human colorectal and oral carcinomas to RT in tumor-bearing mouse models via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and its downstream effector proteins [17, 18].…”

Section: Introductionmentioning

confidence: 99%

Sorafenib pretreatment enhances radiotherapy through targeting MEK/ERK/NF-κB pathway in human hepatocellular carcinoma-bearing mouse model

et al. 2016

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Patients with unresectable hepatocellular carcinoma (HCC) usually have poor prognosis because current monotherapy including surgery, chemotherapy and radiotherapy (RT) are not effective. Combination therapy may be effective to overcome this clinical problem. Here, we proposed the combination of sorafenib and RT, which have been applied in HCC treatment, could improve the treatment outcome of HCC. Our previous study showed that sorafenib could suppress the expression of NF-κB which is related to the chemo- and radio-resistance. Nevertheless, the expression of NF-κB is oscillatory and is affected by the treatments. Thus, understanding the oscillation of NF-κB expression would be beneficial for determining the optimal treatment schedule in combination therapy. Here established Huh7/NF-κB-tk-luc2/rfp cell line, in which NF-κB indicates a NF-κB promoter, was utilized to noninvasively monitor the expression of NF-κB overtime in vitro and in vivo. The results show that pretreatment of sorafenib with RT suppresses the expressions of NF-κB and its downstream proteins induced by radiation through downregulation of phosphorylated extracellular signal-regulated kinase (pERK) most significantly compared with other treatment schedules. The results were further verified with Western blotting, EMSA, and NF-κB molecular imaging. These findings suggest that pretreatment of sorafenib with RT may be the ideal treatment schedule for the treatment of HCC.

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Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study

Cited by 28 publications

References 21 publications

Tumor Hypoxia: Impact on Radiation Therapy and Molecular Pathways

Tumor Hypoxia: Impact on Radiation Therapy and Molecular Pathways

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

Sorafenib pretreatment enhances radiotherapy through targeting MEK/ERK/NF-κB pathway in human hepatocellular carcinoma-bearing mouse model

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