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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

Science China Life Sciences 2025年第1期 204-218页

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang Xie Qian Hao Xiang Zhou fudan university shanghai cancer center and Institutes of Biomedical Sciences Fudan University Department of oncology Shanghai Medical CollegeFudan University Department of Breast Surgery Fudan University Shanghai Cancer CenterFudan University Department of oncology First Affiliated Hospital of Nanchang University Beijing Institute of Hepatology Beijing Youan HospitalCapital Medical University Beijing Engineering Research center for Precision Medicine and Transformation of Hepatitis and Liver cancer Key Laboratory of Breast cancer in shanghai Fudan University Shanghai Cancer CenterFudan University shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology)Institutes of Biomedical SciencesFudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or si RNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

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CapOX as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: a prospective single-arm phase Ⅱ trial

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Chinese Journal of cancer Research 2016年第6期28卷 589-597页

作者： Fangqi Liu Li Yang Yuchen Wu Cong Li Jiang Zhao Adili Keranmu Hongtu Zheng Dan Huang Lei Wang Tong Tong Junyan Xu Ji Zhu Sanjun Cai Ye Xu Department of Colorectal Surgery Fudan University Shanghai Cancer Center Department of oncology Shanghai Medical College Fudan University Department of Pathology Fudan University Shanghai Cancer Center Department of Radiology Fudan University Shanghai Cancer Center Department of Nuclear Medicine Fudan University Shanghai Cancer Center Department of radiation oncology Fudan University Shanghai Cancer Center Clinical Statistics center Fudan University Shanghai Cancer Center

Objective： The aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy（NAC） using oxaliplatin plus capecitabine（Cap OX） for patients with operable locally advanced colon cancer（CC）.Methods： Patients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1,plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade（TRG） score. The primary endpoint was pathologic tumor response. This trial is registered in Clinical ***（No： NCT02415829）.Results： Forty-seven patients were enrolled in the study. Forty-two patients completed the planned *** total radiological response rate was 68%（32/47）, including complete and partial response rates of 2%（1/47）and 66%（31/47）, respectively. Stable disease was observed in 32%（15/47） and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1（2%）, 2（4%）, and 29（62%） patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation（1/47, 2%）. There was no treatment-related ***： Our results suggest that NAC with Cap OX is an effective and safe treatment option for patients with locally advanced CCs.

关键词： Colon cancer neoadjuvant chemotherapy phase II trial surgery

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Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage Ⅲ non-small cell lung cancer:a preliminary report

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Chinese Journal of cancer Research 2015年第2期27卷 172-180页

作者： Di Liu Yu-Xin Shen Wei-Xin Zhao Guo-Liang Jiang Jia-Yan Chen Min Fan Department of radiation oncology Fudan University Shanghai Cancer Center Department of radiation oncology The First Affiliated Hospital of Nanjing Medical University

Objective： In recent years, the combination of cetuximab and chemoradiotherapy （CRT） has been used to treat stage III non-small cell lung cancer （NSCLC）; however, limited data are available for Chinese patients. Herein, we report preliminary data from a phase I/II study testing the combination of cetuximab with inductive chemotherapy, followed by concurrent CRT （CCRT） in Chinese patients with stage III NSCLC. Methods： Eligibility criteria were Zubrod performance status （PS） 0-1, forced expiratory volume in 1 second （FEV1）〉_1.2 L and adequate organ function. Enrolled patients received weekly cetuximab （initial dose of 400 mg/m2 on day 1 of week 1 and a maintenance dose of 250 mg/m2 on week 2 to the end of CCRT） with cisplatin/vinorelbine （NP） chemotherapy （every 3 weeks for 2 cycles from week 2, followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy （TRT）（60-66 Gy/2 Gy）. The primary endpoints were toxicity and feasibility. All patients received positron emission tomography- computerized tomography （PET-CT） scans within the 2 weeks prior to enrollment. Univariate analyses were used to assess the correlation between SUV-T, SUV-N, SUV-TOTAL, gender, age, histology, tumor-node- metastasis （TNM） stage, PS and smoking status and survival. Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test. Results： Seventeen patients were enrolled and 16 completed the full regime. The overall response rate （ORR） was 58.8% and 82.3% after the induction and CCRT phases, respectively. With a median follow-up duration of 27.6 months, the median survival was 27.6 months [95% confidence interval （CI）： 11.3-43.9 months] with 1- and 2-year survival rates of 88.2% （95% CI, 60.6-96.9%） and 58.8% （95% CI, 60.6-77.8%）, respectively. Three patients remain progression-free to date, and the median progression-free survival （PFS） was 13.5 months （95% CI, 6.8-20.2 months）. No treatment-rela

关键词： Cetuximab induction chemotherapy concurrent chemoradiotherapy (CRT) positron emission tomography-computerized tomography (PET-CT) locally advanced non-small cell lung cancer (NSCLC)

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Advanced gastric cancer achieving major pathologic regression after chemoimmunotherapy combined with hypofractionated radiotherapy: A case report

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World Journal of Gastrointestinal oncology 2023年第6期15卷 1096-1104页

作者： Meng-Long Zhou Ruo-Ne Xu Cong Tan Zhen Zhang Jue-Feng Wan Department of radiation oncology Fudan University Shanghai Cancer CenterShanghai 200032China Department of oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China shanghai Key Laboratory of radiation oncology Fudan UniversityShanghai 200032China Department of Pathology Fudan University Shanghai Cancer CenterShanghai 200032China

BACKGROUND Currently,chemotherapy combined with immunotherapy is the established firstline standard treatment for advanced gastric cancer(GC).In addition,the combination of radiotherapy and immunotherapy is considered a promising treatment *** SUMMARY In this report,we present a case of achieving nearly complete remission of highly advanced GC with comprehensive therapies.A 67-year-old male patient was referred to the hospital because he presented with dyspepsia and melena for several *** on fluorodeoxyglucose positron emission tomography/computed tomography(FDG PET/CT),endoscopic examination and abdominal CT,he was diagnosed with GC with a massive lesion and two distant metastatic *** patient received mFOLFOX6 regimen chemotherapy,nivolumab and a short course of hypofractionated radiotherapy(4 Gy×6 fractions)targeting the primary *** the completion of these therapies,the tumor and the metastatic lesions showed a partial *** having this case discussed by a multidisciplinary team,the patient underwent surgery,including total gastrectomy and D2 lymph node *** pathology showed that major pathological regression of the primary lesion was *** therapy started four weeks after surgery,and examination was performed every three *** surgery,the patient has been stable and healthy with no evidence of *** The combination of radiotherapy and immunotherapy for GC is worthy of further exploration.

关键词： Gastric cancer Oligometastasis Immunotherapy Hypofractionated radiotherapy Gastrectomy Case report

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Diffusion-weighted magnetic resonance imaging for predicting the response of rectal cancer to neoadjuvant concurrent chemoradiation

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World Journal of Gastroenterology 2013年第33期19卷 5520-5527页

作者： Gang Cai Ye Xu Ji Zhu Wei-Lie Gu Shuai Zhang Xue-Jun Ma San-Jun Cai Zhen Zhang Department of radiation oncology Fudan University Shanghai Cancer Center Department of oncology Shanghai Medical CollegeFudan University Department of Colorectal Surgery Fudan University Shanghai Cancer Center Department of Endoscopic center Zhongshan HospitalFudan University Department of Radiology Fudan University Shanghai Cancer Cente

AIM:To evaluate the clinical value of diffusion-weighted magnetic resonance imaging(DW-MRI)in predicting the response of rectal cancer to neoadjuvant ***:This prospective study was approved by our institutional review board,and informed consent was obtained from each *** patients(median age 56 years)with locally advanced rectal cancer were treated in our hospital from June 2006 to December *** patients were stageⅢB-C according to the results of MRI and endorectal ultrasound *** patients underwent pelvic irradiation with 45 Gy/25 fx per 35 *** concurrent chemotherapy regimen consisted of capecitabine 625mg/m2,bid(Monday-Friday),and oxaliplatin 50 mg/m2,*** patients underwent surgery 5-8 wk after the completion of neoadjuvant therapy.T downstaging was defined as the downstaging of the tumor from cT3to ypT0-2 or from cT4 to *** regression was defined as TRG 3-4,and poor regression was defined as TRG ***-weighted magnetic resonance images were obtained prior to and weekly during the course of neoadjuvant chemoradiation,and the apparent diffusion coefficient(ADC)values were calculated from the acquired tumor ***:Comparison with the mean pretreatment tumor ADC revealed an increase in the mean tumor ADC during the course of neoadjuvant chemoradiation,especially at the 2ndweek(P=0.004).We found a strong negative correlation between the mean pretreatment tumor ADC and tumor regression after neoadjuvant chemoradiation(P=0.021).In the T downstage and tumor regression groups,we found a significant increase in the mean ADC at the 2ndweek of neoadjuvant therapy(P=0.011;0.004).CONCLUSION:DW-MRI might be a valuable clinical tool to help predict or assess the response of rectal cancer to neoadjuvant chemoradiation at an early timepoint.

关键词： Locally advanced rectal cancer Neoadjuvant chemoradiation Diffusion-weighted magnetic resonance imaging Apparent diffusion coefficient

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Genitourinary small-cell carcinoma： 11-year treatment experience

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Asian Journal of Andrology 2014年第5期16卷 705-709,I0007页

作者： Kun Chang Department of Urology Fudan University Shanghai Cancer Center Shanghai China Department of oncology Fudan University Shanghai Cancer Center Shanghai China Department of Pathology Fudan University Shanghai Cancer Center Shanghai China

The predictive factors of prognosis and treatment strategies for small-cell carcinoma （SCC） of the urinary tract are controversial. This study was aimed to investigate the clinical experience and management of patients with SCC of the urinary tract. We collected data of patients who were diagnosed with genitourinary SCC （GSCC） between 2002 and 2013 and were treated in the fudan university shanghai cancer center. A total of 18 patients were diagnosed with GSCC of which 10 originated from the prostate, seven from the bladder and one from the adrenal gland. The mean follow-up time was 15.5 months and progression-free survival （PFS） was 9.3 months. Primary tumor resection was attempted in 13 of 18 patients （72.2%） in whom radical surgery was performed in six of 14 （42.9%） limited disease patients. Most of the patients （13, 72.2%） received cisplatin-based chemotherapy. Patients who had normal lactic dehydrogenase （LDH） levels showed a significantly higher median PFS and overall survival （OS） compared with patients with high LDH levels （P = 0,030, P = 0.010）. Patients with limited disease treated with a radical operation experienced a non-significant （P = 0,211） longer PFS compared with patients who were not treated, but this reached statistical significance after analyzing OS （P = 0.211, P = 0.039）. Our patients showed a poor prognosis as reported previously. Serum LDH levels beyond the normal range indicate a poor prognosis. For GSCC patients who are diagnosed with limited disease, radical surgery is strongly recommended along with cisplatin-based chemotherapy,

关键词： bladder cancer diagnosis genitourinary small-cell carcinoma prognosis prostate cancer

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LRP5 polymorphism—A potential predictor of the clinical outcome in advanced gastric cancer patients treated with EOF regimen

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Chinese Journal of cancer Research 2014年第4期26卷 478-485页

作者： Xin Liu Ming-Zhu Huang Zhi-Yu Chen Xiao-Yin Zhao Chen-Chen Wang Wei Peng Ji-Liang Yin Jin Li Xiao-Dong Zhu Department of Medical oncology Fudan University Shanghai Cancer Center Department of oncology Shanghai Medical CollegeFudan University

Purpose： Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. The present study analyzed the polymorphism of lipoprotein-related receptor 5 （LRPS）（gene with key functions in Wnt signaling） and its impact on the response to chemotherapy and survival of patients with advanced gastric cancer （AGC）. Methods： A total of 107 consecutive patients with AGC treated with first-line chemotherapy of EOF regimen were enrolled in the present retrospective study. The association between single nucleotide polymorphism （SNP） of rs3736228 in LRP5 and the clinical outcomes of the patients was studied. Results： The CC genotype of rs3736228 was significantly correlated with a higher disease control rate when compared to the CT and TT genotypes （89.3% and 61.8%, respectively, P〈0.001）. A univariate survival analysis also showed that the progression free survival （PFS） and overall survival （OS） for the patients with the TC and TF genotypes of rs3736228 were worse than for the patients with the CC genotype （PFS： 3.3 and 6.7 months, respectively, HR =0.454, P〈0.001; OS： 8.1 months and 18.8 months, respectively, HR =3.056, P〈0.001）. A multivariate Cox model incorporates rs3736228 and clinical features, also identified rs3736228 was significantly associated with the PFS and OS. Conclusions： Our results firstly highlight the importance of LRPY gene of Wnt pathway in the treatment of AGC and identify polymorphism of rs3736228 as independent predictor of disease control rate, PFS and OS in AGC patients treated with first-line chemotherapy of EOF regimen in the Chinese Han population.

关键词： Gastric cancer chemotherapy biomarker lipoprotein-related receptor 5 (LRP5) rs3736228

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Particle therapy for cancers:a new weapon in radiation therapy

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Frontiers of Medicine 2012年第2期6卷 165-172页

作者： Guo-Liang Jiang Department of radiation oncology Fudan University Shanghai Cancer CenterShanghai 200032China

Particle irradiation started to draw attention in the past decade and has now become a hotspot in the radiation oncology *** article reviews the most advanced developments in particle irradiation,focusing on the characteristics of proton and carbon ions in radiation physics and *** Bragg peak of physical dose distribution causes proton and carbon beams to optimally meet the requirement for cancer irradiation because the Bragg peak permits the accurate concentration of the dose on the tumor,thus sparing the adjacent normal ***,carbon ion has more radiobiological benefits than photon and proton *** benefits include stronger sterilization effects on intrinsic radio-resistant tumors and more effective killing of hypoxic,G0,and S phase *** with the most advanced radiation techniques using photon,such as three-dimensional conformal radiation therapy and intensity-modulated radiation therapy,proton therapy has yielded more promising outcomes in local control and survival for head and neck cancers,prostate carcinoma,and pediatric *** therapy in Japan showed even more promising results than proton *** local controls and overall survivals were as good as that treated by surgery in early stages of non-small cell lung cancer,hepatocellular carcinoma,prostate carcinoma,and head and neck cancers,especially for such highly resistant tumors as *** non-invasive nature of particle therapy affords more patients with chances to receive and benefit from *** therapy is gradually getting attention from the oncology ***,the cost of particle therapy facilities has limited the worldwide use of this technology.

关键词： radiation therapy particle therapy proton carbon cancer

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RIFLE:a Phase II trial of stereotactic ablative radiotherapy combined with fruquintinib and tislelizumab in metastatic colorectal cancer

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Gastroenterology Report 2023年第1期11卷 454-461页

作者： Kun Wang Yajie Chen Zhiyuan Zhang Ruiyan Wu Menglong Zhou Wang Yang Juefeng Wan Lijun Shen Hui Zhang Yan Wang Xu Han Jiazhou Wang Zhen Zhang Fan Xia Department of radiation oncology Fudan University Shanghai Cancer CenterShanghaiP.R.China Department of oncology Shanghai Medical CollegeFudan UniversityShanghaiP.R.China shanghai Key Laboratory of radiation oncology ShanghaiP.R.China

Background:Currently,the prognosis for metastatic colorectal cancer(mCRC)still remains *** management of mCRC has become manifold because of the varied advances in the systemic and topical treatment *** patients with limited number of metastases,radical local therapy plus systemic therapy can be a good choice to achieve long-term tumor *** this study,we aimed to explore the efficacy and safety of the combination of fruquintinib,tislelizumab,and stereotactic ablative radiotherapy(SABR)in mCRC(RIFLE study).Methods:RIFLE was designed as a single-center,single-arm,prospective Phase II clinical trial.A total of 68 mCRC patients who have failed the first-line standard treatment will be recruited in the safety run-in phase(n=6)and the expansion phase(n=62),*** patients will receive SABR followed by fruquintinib(5 mg,d1–14,once every day)and tislelizumab(200 mg,d1,once every 3 weeks)within 2 weeks from completion of *** expansion phase starts when the safety of the treatment is determined(dose limiting toxicity occur in no more than one-sixth of patients in the run-in phase).The primary end point is the objective response *** secondary end points include the disease control rate,duration of response,3-year progression-free survival rate,3-year overall survival rate,and ***:The results of this trial will provide a novel insight into SABR in combination with PD-1 antibody and vascular endothelial growth factor receptor inhibitor in the systematic treatment of metastatic colorectal cancer,which is expected to provide new therapeutic strategies and improve the prognosis for mCRC *** registration:NCT04948034(***).

关键词： metastatic colorectal cancer SABR immunotherapy

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Development of scanning transmission ion microscopy computed tomography at fudan microbeam line

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Nuclear Science and Techniques 2013年第4期24卷 5-8页

作者： LI Yongqiang HABCHI Claire LIU Xue LIU Yiyang SHEN Hao deaprtmentof radiation oncology fudan university shanghai cancer center Department of oncology shanghai Medical Colloge Fudan Unversity Institute of Modern Physics Applied Ion Beam Physics Laboratory Fudan University university Bordeaux CENBGUMR 5797 F-33170 Gradignan France Research center of L aser Fusion CAEP

The computed tomography was applied to setting STIM(Scanning Transmission Ion Microscopy) projections recorded at the fudan Ion Beam *** this work,in order to visualize the three-dimensional mass density distribution in several specimens,example for a test structure of hollow gold cyliner was presented together with a detailed description of the developed system,including data reconstruction code(Tomorebuild 2) and image display software(AMIRA).Future development will allow the particle induced X-ray emission tomography for elemental analysis of micrometer-sized samples.

关键词：计算机断层扫描离子束透射线扫描开发微束 X射线发射 STIM

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