Combination with Stereotactic Body Radiotherapy Offers a Promising Strategy to Overcome Resistance to Immunotherapy in Advanced Renal Cell Cancer

Sun, Xiaowen; Gan, Lu; Aru, Na; Ge, Liang; Chen, Baoqing; Liu, Jiaming

doi:10.1155/2019/1483406

Cited by 19 publications

(13 citation statements)

References 74 publications

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“…Presently, investigation of the metabolic mechanisms is ongoing. HIF-1 signaling can also be activated by IR through damage to endothelial cells, producing hypoxia and regulating VEGF (vascular endothelial growth factor) and CXCL12 (C-X-C motif chemokine 12) 354 . HIF-1 is involved in the mitochondria-mediated RR of cancer stem cells 355 .…”

Section: Targeting Dna Damage Repair To Sensitize Cancer Cells To Radiationmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

608

457

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Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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Section: Targeting Dna Damage Repair To Sensitize Cancer Cells To Radiationmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

608

457

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“…Clear cell RCC (ccRCC) is the most common subtype among the malignant RCCs, accounting for 70-80% followed by papillary (15%), chromophobe (4-5%) and other less subtypes [2]. The onset of RCC is hidden and 16% of patients have metastasized at rst diagnosis with a 5-year survival of 9-12% [3]. Traditional chemotherapy and radiotherapy have limited effect in RCC, and molecular biomarkers are more targetable to guide treatment decisions.…”

Section: Introductionmentioning

confidence: 99%

C1QBP regulates apoptosis of renal cell carcinoma via modulating xanthine dehydrogenase (XDH) mediated ROS generation

Wang¹,

Cui²,

Wang³

et al. 2020

Preprint

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Background Complement component 1 Q subcomponent binding protein (C1QBP) is a multifunctional protein and plays a vital role in the progression and metabolism of cancer. Our previous study has revealed that the low expression of C1QBP in renal cell carcinoma (RCC) and knockdown of C1QBP promotes the adhesion and invasion of RCC cells. However, its functions in the metabolism, oxidative stress and apoptosis of RCC cells have not yet been explored. Methods Metabolomics assay was applied to investigate the role of C1QBP in RCC metabolism. C1QBP knockdown and overexpression cells were established via lentiviral infection and subjected to apoptosis and ROS assay in vitro. RNA stability assay and pre-mRNA detection were applied to characterize the mechanism of C1QBP regulating XDH transcription. In vivo, orthotopic tumor xenografts assay was performed to investigate the role of C1QBP progression. Results Metabolomics investigations revealed that C1QBP dramatically diminished the hypoxanthine content in RCC cells. C1QBP promoted the mRNA and protein expression of hypoxanthine catabolic enzyme xanthine dehydrogenase (XDH). Meanwhile, C1QBP regulated the expression of XDH gene at the pre-transcriptional level by regulating XDH transcriptional stimulators IL-6, TNF-α and IFN-γ. Moreover, the expression of C1QBP and XDH was lower in RCC tumors compared with the para-tumor normal tissues, and their down-regulation was associated with higher levels of Fuhrman grade. In RCC cells, C1QBP significantly increased produces reactive oxygen species (ROS) levels, apoptosis, and the expression of apoptotic proteins cleaved caspase-3 and bax/bcl2 via regulating XDH.Conclusions C1QBP promotes the catabolism of hypoxanthine and elevates the apoptosis of RCC cells by modulating XDH-mediated ROS generation.

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“…Still, a considerable proportion of patients did not obtain a clinically effective response. Also, some patients who initially obtained a durable response to ICI therapy showed significant progression in the follow-up , and more than 55% of RCC patients who did not receive combined treatments developed resistance to different immunotherapies (59,61). These findings were supported by the results of Chowdhry et al's study.…”

Section: Immunotherapy and Sbrt Have A Synergistic Antitumor Effectmentioning

confidence: 70%

The promising role of radiotherapy in the treatment of advanced or metastatic renal cell carcinoma: a narrative review

Wei

et al. 2020

Transl Androl Urol

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Traditionally, renal cell carcinoma (RCC) has been regarded to be "radioresistant". Conventional fractionated radiation (CFRT) has played a limited role in RCC as a palliative treatment to relieve pain and bleeding. Succeed to the rapid development of precise radiotherapy techniques, realizing safe delivery of high-dose radiotherapy, an increasing amount of convincing data suggests that the delivery of high-dose-perfraction radiation through stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR) can help to overcome resistance to radiotherapy.Herein, we summarized and analyzed the data from randomized controlled trials, retrospective and prospective studies, and meta-analyses relating to the treatment of advanced and metastatic RCC (mRCC) with CFRT, SBRT, or SBRT combined with systemic therapy. CFRT has a limited effect on local control (LC) of advanced RCC and mRCC, but it is a major palliative treatment which could obviously relieve pain caused by cancer. SBRT and SRS have the significant advantage of being able to precisely deliver a high dose of radiation to the target tissues. SBRT could cause a higher LC for advanced and metastatic RCC and could be used as an alternative to surgery for patients with oligometastatic RCC. The combination of SBRT with systemic therapy, such as targeted therapy or immunotherapy, is safe and tolerable. Concurrent immunotherapy and SBRT is a promising treatment strategy for patients with advanced or metastatic RCC. However, research on radiotherapy combined with systemic therapy is still limited and further studies to explore this treatment for RCC are urgently needed.

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Combination with Stereotactic Body Radiotherapy Offers a Promising Strategy to Overcome Resistance to Immunotherapy in Advanced Renal Cell Cancer

Cited by 19 publications

References 74 publications

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

C1QBP regulates apoptosis of renal cell carcinoma via modulating xanthine dehydrogenase (XDH) mediated ROS generation

The promising role of radiotherapy in the treatment of advanced or metastatic renal cell carcinoma: a narrative review

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