The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib

Wilding, Christopher P; Elms, Mark L.; Judson, Ian; Tan, Aik Choon; Jones, Robin L.; Huang, Paul H.

doi:10.1080/14737140.2019.1686979

Cited by 34 publications

(27 citation statements)

References 168 publications

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“…In the past 5 years the multi-kinase and chaperone inhibitor pazopanib was FDA approved for treatment of the majority of STS subtypes ( 6 ). Pazopanib, alone or in combination with other agents in our hands utilizes endoplasmic reticulum stress signaling and autophagosome formation as key components of its mechanisms of action ( 7 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

et al. 2020

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GZ17-6.02 (602) is presently under phase I clinical evaluation (NCT03775525). We defined the mechanisms by which it interacted with a standard of care therapeutic doxorubicin to kill sarcoma cells. Doxorubicin and 602 interacted to rapidly activate ATM and c-MET, inactivate mTOR, AKT, and p70 S6K, enhance the expression of Beclin1 and reduce the levels of K-RAS and N-RAS. This was followed later by the drugs interacting to reduce expression of MCL-1, BCL-XL, and HDAC6. Knock down of ATM prevented the drugs alone or in combination inactivating mTOR or activating ULK1. Knock down of c-MET significantly enhanced [doxorubicin + 602] lethality. Knock down of ATM and to a greater extent ULK1, Beclin1, or ATG5 significantly reduced killing by 602 alone or when combined with doxorubicin. Expression of an activated mTOR mutant suppressed killing, autophagosome formation and prevented autophagic flux. In the absence of Beclin1, knock down of CD95, or FADD, or over-expression of c-FLIP-s or BCL-XL abolished tumor cell killing. We conclude that 602 and doxorubicin interact to increase autophagosome formation and autophagic flux as well as causing elevated death receptor signaling resulting in mitochondrial dysfunction and tumor cell death.

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Section: Introductionmentioning

confidence: 99%

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

et al. 2020

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“…TKIs target tyrosine kinases, which are key mediators of intracellular signaling cascades. Consequently, aberrations in these proteins have been implicated as drivers of oncogenesis via the dysregulation of fundamental cellular processes, including proliferation, migration, and apoptosis [20]. TKI-based therapy has led to significant advances in the treatment of many malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…• m-PFS 7.9 m • m-OS 17 m Axitinib PDGFRα < PDGFRβ < KIT < VEGFR1 < VEGFR2 < < FGFR2 < RET < VEGFR3 < FGFR3 < FGFR1 < < MET << NTRK1 [20] 64 patients with progressive advanced solitary fibrous tumor [23] • ORR 41%…”

Section: Discussionmentioning

confidence: 99%

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Retrospective review of the activity and safety of apatinib and anlotinib in patients with advanced osteosarcoma and soft tissue sarcoma

et al. 2020

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Summary Background Previous studies have demonstrated the efficacy of apatinib and anlotinib for the treatment of sarcomas. However, more clinical data and evidence are needed to support clinical treatment selection and study design. Here, we evaluated the effectiveness and safety of these two drugs for the treatment of sarcomas. Methods We retrospectively reviewed the data of 110 patients with advanced osteosarcoma (n = 32) or soft tissue sarcoma (STS, n = 78) who received oral apatinib or anlotinib therapy during May 2016–February 2019 at two centers. Patients were divided into the apatinib and anlotinib groups. Results Among osteosarcoma patients, the objective response rates (ORRs) for the apatinib and anlotinib groups were 15.79% (3/19) and 7.69% (1/13), respectively. The disease control rates (DCRs) were 63.16% (12/19) and 30.77% (4/13), and the median progression-free survival (m-PFS) was 4.67 ± 3.01 and 2.67 ± 1.60 months, respectively. Among STS patients, ORRs for the apatinib and anlotinib groups were 12.24% (6/49) and 13.79% (4/29), respectively. The DCRs were 59.18% (29/49) and 55.17% (16/29), and m-PFS was 7.82 ± 6.90 and 6.03 ± 4.50 months, respectively. Regarding adverse events (AEs), apatinib was associated with a higher incidence of hair hypopigmentation and pneumothorax, while anlotinib was associated with a higher incidence of pharyngalgia or hoarseness. Conclusion Both apatinib and anlotinib were effective for the treatment of sarcomas. However, the effectiveness of the two drugs and associated AEs varied based on the histological type of sarcoma. These differences may be due to their different sensitivities to targets such as RET, warranting further study.

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“…Many of the TKIs inhibit several RTKs as the intracellular domain is relatively conserved among RTKs ( 14 ). The targeted drugs that showed efficacy in osteosarcoma treatment are these multi-target TKIs ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

2020

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Recent clinical trials have shown several multi-target tyrosine kinase inhibitors (TKIs) to be effective in the treatment of osteosarcoma. However, these TKIs have a number of targets, and it is yet unclear which of these targets has a key role in osteosarcoma treatment. In this review, we first summarize the TKIs that were studied in clinical trials registered on ClinicalTrials.gov. Further, we compare and discuss the targets of these TKIs. We found that TKIs with promising therapeutic effect for osteosarcoma include apatinib, cabozantinib, lenvatinib, regorafenib, and sorafenib. The key targets for osteosarcoma treatment may include VEGFRs and RET. The receptor tyrosine kinases (RTKs) MET, IGF-1R, AXL, PDGFRs, KIT, and FGFRs might be relevant but unimportant targets for osteosarcoma treatment. Inhibition of one type of RTK for the treatment of osteosarcoma is not effective. It is necessary to inhibit several relevant RTKs simultaneously to achieve a breakthrough in osteosarcoma treatment. This review provides comprehensive information on TKI targets relevant in osteosarcoma treatment, and it will be useful for further research in this field.

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The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib

Cited by 34 publications

References 168 publications

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

Retrospective review of the activity and safety of apatinib and anlotinib in patients with advanced osteosarcoma and soft tissue sarcoma

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

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