Sitravatinib potentiates immune checkpoint blockade in refractory cancer models

Du, Wenting; Huang, Huocong; Sorrelle, Noah; Brekken, Rolf A.

doi:10.1172/jci.insight.124184

Cited by 88 publications

(111 citation statements)

References 20 publications

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“…In the present study, we report the potential interactions of sitravatinib with ABCB1 and ABCG2 in human multidrug-resistant cancer cells. First, the determined cytotoxicity of sitravatinib in our drug-sensitive and multidrug-resistant cell lines is comparable to the cytotoxic profile of sitravatinib reported by others in previous studies [25,53,54]. In contrast to imatinib [32] and dasatinib [34], we found that cells overexpressing ABCB1 or ABCG2 were not resistant to sitravatinib (Figure 1).…”

Section: Discussionsupporting

confidence: 89%

“…Sitravatinib is an orally bioavailable TKI that targets multiple receptor tyrosine kinases [25] and potentiates immune checkpoint blockade to help cancer patients that are resistant to immune therapy [53]. In the present study, we report the potential interactions of sitravatinib with ABCB1 and ABCG2 in human multidrug-resistant cancer cells.…”

Section: Discussionmentioning

confidence: 82%

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Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

Hsiao

Huang

et al. 2020

Cancers

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The development of multidrug resistance (MDR) in cancer patients driven by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells presents one of the most daunting therapeutic complications for clinical scientists to resolve. Despite many novel therapeutic strategies that have been tested over the years, there is still no approved treatment for multidrug-resistant cancers to date. We have recently adopted a drug repurposing approach to identify therapeutic agents that are clinically active and at the same time, capable of reversing multidrug resistance mediated by ABCB1 and ABCG2. In the present study, we investigated the effect of sitravatinib, a novel multitargeted receptor tyrosine kinase inhibitor, on human ABCB1 and ABCG2 in multidrug-resistant cancer cell lines. We discovered that at submicromolar concentrations, sitravatinib re-sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. We found that sitravatinib blocks the drug efflux function of ABCB1 and ABCG2 in a concentration-dependent manner but does not significantly alter the protein expression of ABCB1 or ABCG2 in multidrug-resistant cancer cells. In conclusion, we reveal a potential drug repositioning treatment option for multidrug-resistant cancers by targeting ABCB1 and ABCG2 with sitravatinib and should be further investigated in future clinical trials.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 82%

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

Hsiao

Huang

et al. 2020

Cancers

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“…Radiation can convert immunologically “cold” tumours or “cold” regions of tumour into “hot” tumours via several mechanisms, including overcoming an immunosuppressive tumour microenvironment, recruitment of antigen‐presenting and immune effector cells, and increasing antigenic expression on tumour cells, thus upregulating tumour immunogenicity . In contrast, radiation alone can cause marked immunosuppression through several mechanisms, such as disruption of vascular supply, excessive circulating lymphocyte death, and alteration in cell signals (ie, PDGFR, HIF‐1α, VEGF/VEGFR, and PD‐L1) …”

Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

“…[151][152][153][154][155] In contrast, radiation alone can cause marked immunosuppression through several mechanisms, such as disruption of vascular supply, excessive circulating lymphocyte death, and alteration in cell signals (ie, PDGFR, HIF-1α, VEGF/VEGFR, and PD-L1). 126,156 Single, large ablative doses of radiation may particularly hamper effective antitumour immune responses; thus, focus has been on fractionated radiation regimens and SBRT protocols. 60,157,158 SBRT is theoretically less systemically immunosuppressive than conventional radiation, in which patients have circulating lymphocytes that may be irradiated over 5 to 6 weeks.…”

Section: Rt and Immunotherapy For Sarcomasmentioning

confidence: 99%

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Borgatti

Dickerson

Lawrence

2019

Vet Comparative Oncology

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Sarcomas represent a group of genomically chaotic, highly heterogenous tumours of mesenchymal origin with variable mutational load. Conventional therapy with surgery and radiation therapy is effective for managing small, low‐grade sarcomas and remains the standard therapeutic approach. For advanced, high‐grade, recurrent, or metastatic sarcomas, systemic chemotherapy provides minimal benefit, therefore, there is a drive to develop novel approaches. The discovery of “Coley's toxins” in the 19th century, and their use to stimulate the immune system supported the application of unconventional therapies for the treatment of sarcomas. While promising, this initial work was abandoned and treatment paradigm and disease course of sarcomas was largely unchanged for several decades. Exciting new therapies are currently changing treatment algorithms for advanced carcinomas and melanomas, and similar approaches are being applied to advance the field of sarcoma research. Recent discoveries in subtype‐specific cancer biology and the identification of distinct molecular targets have led to the development of promising targeted strategies with remarkable potential to change the landscape of sarcoma therapy in dogs. The purpose of this review article is to describe the current standard of care and limitations as well as emerging approaches for sarcoma therapy that span many of the most active paradigms in oncologic research, including immunotherapies, checkpoint inhibitors, and drugs capable of cellular metabolic reprogramming.

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“…Nivolumab is a programmed death 1 immune checkpoint inhibitor with proven efficacy against clear cell renal cell carcinoma . Sitravatinib is an oral tyrosine kinase inhibitor that Du et al have shown in preclinical cancer models to potentiate immune checkpoint blockade when combined with drugs such as nivolumab, by targeting cell receptors known to contribute to an immunosuppressive tumor microenvironment. This motivates exploring the combination of nivolumab and sitravatinib clinically in metastatic renal cancer.…”

Section: Introductionmentioning

confidence: 99%

A phase I‐II design based on periodic and continuous monitoring of disease status and the times to toxicity and death

Thall

Msaouel

2020

Statistics in Medicine

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A Bayesian phase I-II dose-finding design is presented for a clinical trial with four coprimary outcomes that reflect the actual clinical observation process. During a prespecified fixed follow-up period, the times to disease progression, toxicity, and death are monitored continuously, and an ordinal disease status variable, including progressive disease (PD) as one level, is evaluated repeatedly by scheduled imaging. We assume a proportional hazards model with piecewise constant baseline hazard for each continuous variable and a longitudinal multinomial probit model for the ordinal disease status process and include multivariate patient frailties to induce association among the outcomes. A finite partition of the nonfatal outcome combinations during the follow-up period is constructed, and the utility of each set in the partition is elicited. Posterior mean utility is used to optimize each patient's dose, subject to a safety rule excluding doses with an unacceptably high rate of PD, severe toxicity, or death. A simulation study shows that, compared with the proposed design, a simpler design based on commonly used efficacy and toxicity outcomes obtained by combining the four variables described above performs poorly and has substantially smaller probabilities of correctly choosing truly optimal doses and excluding truly unsafe doses.

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Sitravatinib potentiates immune checkpoint blockade in refractory cancer models

Cited by 88 publications

References 20 publications

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

A phase I‐II design based on periodic and continuous monitoring of disease status and the times to toxicity and death

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