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Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself

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Abstract

Bone and soft tissue sarcomas are rare malignant tumors originated from mesenchymal tissues. They harbor more than 50 distinct subtypes and differ in pathological features and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed diseases. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis, and VEGF/VEGFR pathway is considered as the most prominent player in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy to retard neovascularization. Several VEGFR inhibitors have been developed and revealed their favorable anti-neoplastic effects in various cancers, but such desirable anti-tumor effects are not obtained in advanced sarcomas because of multiple reasons, such as drug tolerance, short duration of response, and severe adverse effects. Fortunately, preclinical and clinical studies have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Especially, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, and enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas.

Graphic abstract

Bone and soft tissue sarcomas are rare but malignant tumors originated from mesenchymal tissues. They harbor more than 100 distinct subtypes and differ in features of pathologies and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed lesions. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis and VEGF/VEGFR pathways play a pivotal role in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy. Several VEGFR inhibitors have been developed and verified in clinical trials but with unfavorable outcomes. Fortunately, preclinical studies and clinical trials have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Actually, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas.

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Abbreviations

ABC transporters:

ATP-binding cassette (ABC) transporters

ALK :

Anaplastic lymphoma kinase

cMet:

Cellular mesenchymal–epithelial transition

CQ:

Chloroquine

CRC:

Colorectal cancer

DCR:

Disease control rate

DOR:

Duration of response

EGFR:

Epidermal growth factor receptor

EML4 :

Echinoderm microtubule-associated protein-like 4

FGFR:

Fibroblast growth factor receptor

HCC:

Hepatocellular carcinoma

HGF:

Hepatocyte growth factor

HGFR:

Hepatocyte growth factor receptor

ICIs:

Immune checkpoint inhibitors

IGF-1:

Insulin growth factor 1

IGF-1R:

Insulin growth factor 1 receptor

IRE-1α:

Inositol-requiring enzyme 1 alpha

KIF5B:

Kinesin family member 5B

MDR:

Multidrug resistance

MRP1:

Multidrug resistance associated protein-1

NMPA:

National Medical Products Administration

NSCLC:

Non-small-cell lung carcinoma

ORR:

Objective response rate

OS:

Overall survival

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death ligand 1

PFS:

Progression-free survival

RCC:

Renal cell carcinoma

RET:

Ret proto-oncogene

STAT:

Signal transducer and activator of transcription

TAMs:

Tumor-associated macrophages

TGF-β:

Transforming growth factor-β

TILs:

Tumor-infiltrated lymphocytes

TKI:

Tyrosine kinase inhibitor

TME:

Tumor microenvironment

TTF:

Time to failure

VEGF:

Vascular endothelial growth factor

VEGFRs:

Vascular endothelial growth factor receptors

VEGFRIs:

Vascular endothelial growth factor receptor inhibitors

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Acknowledgements

This work was fully supported by grants from the National Natural Science Foundation of China (No. 31371147) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. We sincerely thank Xue Yang for providing help in language editing.

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Q-KY and S-QW collected materials and wrote this manuscript. Q-KY extracted, analyzed, and interpreted the data from the collected articles. TC is responsible for the schematic diagram within this article. Z-XY and X-JZ provided professional support and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiao-Jing Zhang or Zhong-Xiang Yao.

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Yang, QK., Chen, T., Wang, SQ. et al. Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself. Angiogenesis 23, 279–298 (2020). https://doi.org/10.1007/s10456-020-09716-y

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