Regional Delivery of CAR-T Effectively Controls Tumor Growth in Colorectal Liver Metastasis Model

2022 ◽  
Vol 272 ◽  
pp. 37-50
Author(s):  
Louis F. Chai ◽  
John C. Hardaway ◽  
Kara R. Heatherton ◽  
Kyle P. O'Connell ◽  
Jason P. LaPorte ◽  
...  
Author(s):  
Jinhua Wang ◽  
Yajing Xing ◽  
Yingying Wang ◽  
Yundong He ◽  
Liting Wang ◽  
...  

Abstract Background Cancer-initiating cell (CIC), a functionally homogeneous stem-like cell population, is resonsible for driving the tumor maintenance and metastasis, and is a source of chemotherapy and radiation-therapy resistance within tumors. Targeting CICs self-renewal has been proposed as a therapeutic goal and an effective approach to control tumor growth. BMI-1, a critical regulator of self-renewal in the maintenance of CICs, is identified as a potential target for colorectal cancer therapy. Methods Colorectal cancer stem-like cell lines HCT116 and HT29 were used for screening more than 500 synthetic compounds by sulforhodamine B (SRB) cell proliferation assay. The candidate compound was studied in vitro by SRB cell proliferation assay, western blotting, cell colony formation assay, quantitative real-time PCR, flow cytometry analysis, and transwell migration assay. Sphere formation assay and limiting dilution analysis (LDA) were performed for measuring the effect of compound on stemness properties. In vivo subcutaneous tumor growth xenograft model and liver metastasis model were performed to test the efficacy of the compound treatment. Student’s t test was applied for statistical analysis. Results We report the development and characterization of a small molecule inhibitor QW24 against BMI-1. QW24 potently down-regulates BMI-1 protein level through autophagy-lysosome degradation pathway without affecting the BMI-1 mRNA level. Moreover, QW24 significantly inhibits the self-renewal of colorectal CICs in stem-like colorectal cancer cell lines, resulting in the abrogation of their proliferation and metastasis. Notably, QW24 significantly suppresses the colorectal tumor growth without obvious toxicity in the subcutaneous xenograft model, as well as decreases the tumor metastasis and increases mice survival in the liver metastasis model. Moreover, QW24 exerts a better efficiency than the previously reported BMI-1 inhibitor PTC-209. Conclusions Our preclinical data show that QW24 exerts potent anti-tumor activity by down-regulating BMI-1 and abrogating colorectal CICs self-renewal without obvious toxicity in vivo, suggesting that QW24 could potentially be used as an effective therapeutic agent for clinical colorectal cancer treatment.


2018 ◽  
Vol 500 (3) ◽  
pp. 731-737 ◽  
Author(s):  
Abhishek Kumar ◽  
Madhuri Cherukumilli ◽  
Seyed Hamidreza Mahmoudpour ◽  
Karsten Brand ◽  
Obul Reddy Bandapalli

Cytokine ◽  
2012 ◽  
Vol 57 (1) ◽  
pp. 46-53 ◽  
Author(s):  
Obul R. Bandapalli ◽  
Franziska Ehrmann ◽  
Volker Ehemann ◽  
Matthias Gaida ◽  
Stephan Macher-Goeppinger ◽  
...  

2014 ◽  
Vol 207 (4) ◽  
pp. 493-498 ◽  
Author(s):  
Rafael S. Pinheiro ◽  
Paulo Herman ◽  
Renato M. Lupinacci ◽  
Quirino Lai ◽  
Evandro S. Mello ◽  
...  

2015 ◽  
Vol 23 (S2) ◽  
pp. 257-265 ◽  
Author(s):  
Yusuke Matsumoto ◽  
Hironori Tsujimoto ◽  
Satoshi Ono ◽  
Nariyoshi Shinomiya ◽  
Hiromi Miyazaki ◽  
...  

2020 ◽  
Author(s):  
Lungwani Muungo

A 72-year-old woman with a sigmoid colon cancer anda synchronous colorectal liver metastasis (CRLM), whichinvolved the right hepatic vein (RHV) and the inferiorvena cava (IVC), was referred to our hospital. Themetastatic lesion was diagnosed as initially unresectablebecause of its invasion into the confluence of theRHV and IVC. After she had undergone laparoscopicsigmoidectomy for the original tumor, she consequentlyhad 3 courses of modified 5-fluorouracil, leucovorin,and oxaliplatin (mFOLFOX6) plus cetuximab. Computedtomography revealed a partial response, and theconfluence of the RHV and IVC got free from cancerinvasion. After 3 additional courses of mFOLFOX6 pluscetuximab, preoperative percutaneous transhepaticportal vein embolization (PTPE) was performed tosecure the future remnant liver volume. Finally, a righthemihepatectomy was performed. The postoperativecourse was uneventful. The patient was dischargedfrom the hospital on postoperative day 13. She hadneither local recurrence nor distant metastasis 18 moafter the last surgical intervention. This multidisciplinarystrategy, consisting of conversion chemotherapy usingFOLFOX plus cetuximab and PTPE, could contributein facilitating curative hepatic resection for initiallyunresectable CRLM.Key words: Initially unresectable; Colorectal liver metastasis;Conversion chemotherapy; Cetuximab; Percutaneoustranshepatic portal vein embolization


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