Positron emission tomography/computed tomography(PET/CT)with radiolabeled fibroblast activation protein inhibitors(FAPI)is an increasingly relevant molecular diagnostic image in oncology given the high expression of F...Positron emission tomography/computed tomography(PET/CT)with radiolabeled fibroblast activation protein inhibitors(FAPI)is an increasingly relevant molecular diagnostic image in oncology given the high expression of FAP in cancer associated fibroblast,being present in almost 90%of the epithelial carcinomas,which allows imaging with excellent diagnostic performance and can also become a therapeutic strategy.This review summarizes the literature on FAPIPET/CT for the cancer evaluation and compares it in some scenarios with the 18FFluorodeoxyglucose PET/CT.展开更多
AIM: To examine fibroblast activation protein (FAP) expression in pancreatic ductal adenocarcinoma (PDAC) and to analyze its relationship with the clinicopathology of PDAC. METHODS: FAP expression was examined in 134 ...AIM: To examine fibroblast activation protein (FAP) expression in pancreatic ductal adenocarcinoma (PDAC) and to analyze its relationship with the clinicopathology of PDAC. METHODS: FAP expression was examined in 134 PDAC specimens by immunohistochemistry, and in four pancreatic cancer cell lines (SW1990, Miapaca-2, AsPC-1 and BxPC-3) by Western blotting assay. We also analyzed the association between FAP expression in PDAC cells and the clinicopathology of PDAC patients. RESULTS: The results showed that the FAP was expressed in both stromal fibroblast cells (98/134, 73.1%) and carcinoma cells (102/134, 76.1%). All 4 pancreatic cancer cell lines expressed FAP protein at different levels. Protein bands corresponding to the proteolytically active 170-kDa seprase dimer and its88-kDa seprase subunit were identif ied. Higher FAP expression in carcinoma cells was associated with tumor size (P < 0.001), fi brotic focus (P = 0.003), perineural invasion (P = 0.009) and worse clinical outcome (P = 0.0085). CONCLUSION: FAP is highly expressed in carcinoma cells and f ibroblasts in PDAC tissues, and its expression is associated with desmoplasia and worse prognosis.展开更多
Quinoline-based fibroblast activation protein(FAP)inhibitor(FAPI)-based positron emission tomography(PET)imaging and radioligand therapy(RLT)are being investigated for use in a wide variety of diseases,and recent resu...Quinoline-based fibroblast activation protein(FAP)inhibitor(FAPI)-based positron emission tomography(PET)imaging and radioligand therapy(RLT)are being investigated for use in a wide variety of diseases,and recent results have been promising.This review summarizes the current status of FAPI radiopharmaceuticals in PET imaging of malignant tumors and benign conditions and compares their diagnostic efficacy with ^(18)F-fluorodeoxyglucose.In addition,we summarize the previously published FAP-targeted RLT data and discuss its current clinical use and future potential.Our qualitative summary can inform future research directions,medical guidelines,and optimal clinical decision-making.展开更多
Hepatectomy is a critical treatment for liver cancer,but achieving complete tumor removal remains challenging.The development of tumor-targeting probes capable of accurately identifying tumor locations and providing r...Hepatectomy is a critical treatment for liver cancer,but achieving complete tumor removal remains challenging.The development of tumor-targeting probes capable of accurately identifying tumor locations and providing real-time intraoperative navigation is of significant clinical importance.We synthesize a tumor-targeted probe by conjugating a fibroblast activation protein inhibitor(FAPI)with near-infrared organic room temperature phosphorescence(RTP)material.We then analyze its surgical navigation performance in the liver cancer model and its imaging performance in fresh patient-derived samples.In vivo validation reveals that the probe exhibits optimal phosphorescence intensity within 48 h(8.53×10^(5)p s^(−1)cm^(−2)sr^(−1))and an average signal-to-noise ratio of 16.The probe could effectively identify FAP-positive samples from liver cancer patients.The successful application of phosphorescence-guided surgery suggests that the near-infrared RTP probe holds significant clinical translational value and could serve as an auxiliary tool for the surgical treatment of liver cancer.展开更多
The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the prolifer...The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.展开更多
Targeted alpha therapy(TAT)is an innovative approach in cancer treatment that aims to selectively deliver high-energy radiation to cancer cells while minimizing damage to healthy tissues.^(225)Ac,an alpha radionuclide...Targeted alpha therapy(TAT)is an innovative approach in cancer treatment that aims to selectively deliver high-energy radiation to cancer cells while minimizing damage to healthy tissues.^(225)Ac,an alpha radionuclide with a half-life of 10 days and emitting 4 alpha particles and 2 beta particles in its decay chain,has shown promise for TAT.Fibroblast activation protein(FAP)has emerged as a valuable target for the development of radiopharmaceuticals in the context of TAT,given its expression in various cancers.However,a challenge arises when using FAPtargeting agents such as FAP inhibitors(FAPIs)in combination with^(225)Ac due to their rapid clearance from the tumor.To address this challenge,the FAP-targeting antibody PKU525 was developed as a TAT drug.The conjugation ratios of the chelator and the labeling procedure were systematically investigated,resulting in an efficient and stable radiolabeling method.Biodistribution studies were conducted using[^(225)Ac]Ac-DOTA-PKU525 with average drug-to-antibody ratios(DARs)of 1.85,3.87,and 7.72.A single dose of 11.1 kBq of[^(225)Ac]Ac-DOTA-PKU525 with DAR 3.87 demonstrated significant inhibition of 4T1-hFAP tumor growth.No significant weight changes were observed throughout the treatment period,and histological examination of the major organs revealed no adverse side effects.In conclusion,[^(225)Ac]Ac-DOTA-PKU525 exhibited both safety and efficacy in 4T1-hFAP tumor-bearing mice,indicating its potential for clinical translation in FAP-targeted alpha therapy.Further development and evaluation of this TAT approach hold promise for improving cancer treatment outcomes.展开更多
BACKGROUND This report describes a rare case of a small gastric cancer lesion with widespread bone metastases and markedly elevated alkaline phosphatase levels that was initially misdiagnosed as rheumatoid arthritis,a...BACKGROUND This report describes a rare case of a small gastric cancer lesion with widespread bone metastases and markedly elevated alkaline phosphatase levels that was initially misdiagnosed as rheumatoid arthritis,as the patient’s sole clinical manifestation was chronic bone pain persisting for 1 year.CASE SUMMARY An 83-year-old man was admitted due to worsening generalized joint pain over 1 year.Serum alkaline phosphatase levels were markedly elevated,and technetium-99m methylene diphosphonate single-photon emission computed tomography(CT)and fluorine-18 sodium fluoride positron emission tomography(PET)/CT images showed symmetrical diffuse uptake of the radiotracers throughout the skeleton.Initially,Paget’s disease was suspected,but abnormal hematologic tumor markers and bone biopsy confirmed metastatic adenocarcinoma.Fluorine-18-fluorodeoxyglucose PET/CT did not reveal a primary tumor.The patient had a history of colon polypectomy and tubulovillous adenoma with atypical hy-perplasia on pathological examination 10 years prior.Further investigation using gallium-68-labeled fibroblast-activation protein inhibitor PET/CT images showed increased punctate uptake in the gastric antrum.Gastroscopy demonstrated a 1.0 cm ulcerated mass in the prepyloric region,and histopathological evaluation of the biopsy specimen revealed poorly differentiated adenocarcinoma.The incidence of bone metastases from gastric cancer is very low,especially with such extensive involvement.CONCLUSION Occult gastric carcinomas with bone metastases necessitate proactive high-risk surveillance and multidisciplinary integration to improve diagnostic accuracy and clinical outcomes.展开更多
Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy ap...Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy approaches,these methods rely on direct destruction of tumor cells with minimal impact on the aggregate of nearby non-tumor cells,the extracellular matrix,and blood vessels that form the tumor microenvironment(TME).The TME is known to be heterogeneous and dynamic,exerting both antitumor and pro-tumor effects depending on the specific features and stage of carcinogenesis.TME has been shown in several studies to promote malignancy,angiogenesis,and metastasis in tumors in general and melanoma in particular.Consequently,a significant number of studies in thefield of melanoma therapy have been redirected to investigate the effects of individual TME constituents,their prognostic significance for patients,and the potential of therapeutic intervention to improve overall patient survival.This review highlights novel therapeutic approaches targeting two key resident cell types in the melanoma microenvironment:tumor-associated macrophages(TAMs)and cancer-associatedfibroblasts(CAFs).The review discusses their role in disease progression and summarizes the results of preclinical and clinical trials of targeted therapies against these cell types in the melanoma TME.展开更多
Pancreatic ductal adenocarcinoma(PDA)is among the deadliest cancers in the United States and in the world.Late diagnosis,early metastasis and lack of effective therapy are among the reasons why only 6%of patients diag...Pancreatic ductal adenocarcinoma(PDA)is among the deadliest cancers in the United States and in the world.Late diagnosis,early metastasis and lack of effective therapy are among the reasons why only 6%of patients diagnosed with PDA survive past 5 years.Despite development of targeted therapy against other cancers,little progression has been made in the treatment of PDA.Therefore,there is an urgent need for the development of new treatments.However,in order to proceed with treatments,the complicated biology of PDA needs to be understood first.Interestingly,majority of the tumor volume is not made of malignant epithelial cells but of stroma.In recent years,it has become evident that there is an important interaction between the stromal compartment and the less prevalent malignant cells,leading to cancer progression.The stroma not only serves as a growth promoting source of signals but it is also a physical barrier to drug delivery.Understanding the tumor-stroma signaling leading to development of desmoplastic reaction and tumor progression can lead to the development of therapies to decrease stromal activity and improve drug delivery.In this review,we focus on how the current understanding of biology of the pancreatic tumor microenvironment can be translated into the development of targeted therapy.展开更多
Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accura...Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accurate controls,making the results less specific and less confirmative.This study aimed to establish a pair of cell lines,in which one highly expresses FAP(HT1080-hFAP)and the other has no detectable FAP(HT1080-vec)as control,to accurately evaluate the specificity of the FAP-targeted theranostics in vitro and in vivo.Methods The cell lines of the experimental group(HT1080-hFAP)and no-load group(HT1080-vec)were obtained by molecular construction of the recombinant plasmid pIRES-hFAP.The expression of hFAP in HT1080 cells was detected by PCR,Western blotting and flow cytometry.CCK-8,Matrigel transwell invasion assay,scratch test,flow cytometry and immunofluorescence were used to verify the physiological function of FAP.The activities of human dipeptidyl peptidase(DPP)and human endopeptidase(EP)were detected by ELISA in HT1080-hFAP cells.PET imaging was performed in bilateral tumor-bearing nude mice models to evaluate the specificity of FAP.Results RT-PCR and Western blotting demonstrated the mRNA and protein expression of hFAP in HT1080-hFAP cells but not in HT1080-vec cells.Flow cytometry confirmed that nearly 95%of the HT1080-hFAP cells were FAP positive.The engineered hFAP on HT1080 cells had its ability to retain enzymatic activities and a variety of biological functions,including internalization,proliferation-,migration-,and invasion-promoting activities.The HT1080-hFAP xenografted tumors in nude mice bound and took up^(68)GA-FAPI-04 with superior selectivity.High image contrast and tumor-organ ratio were obtained by PET imaging.The HT1080-hFAP tumor retained the radiotracer for at least 60 min.Conclusion This pair of HT1080 cell lines was successfully established,making it feasible for accurate evaluation and visualization of therapeutic and diagnostic agents targeting the hFAP.展开更多
In recent years,fibroblast activation protein(FAP)has emerged as an attractive target for the diagnosis and radiotherapy of cancers using FAP-specific radioligands.Herein,we aimed to design a novel^(18)Flabeled FAP tr...In recent years,fibroblast activation protein(FAP)has emerged as an attractive target for the diagnosis and radiotherapy of cancers using FAP-specific radioligands.Herein,we aimed to design a novel^(18)Flabeled FAP tracer([^(18)F]Al F-P-FAPI)for FAP imaging and evaluated its potential for clinical application.The[^(18)F]Al F-P-FAPI novel tracer was prepared in an automated manner within 42 min with a non-decay corrected radiochemical yield of 32±6%(n=8).Among A549-FAP cells,[^(18)F]Al F-P-FAPI demonstrated specific uptake,rapid internalization,and low cellular efflux.Compared to the patent tracer[^(18)F]FAPI-42,[^(18)F]Al F-P-FAPI exhibited lower levels of cellular efflux in the A549-FAP cells and higher stability in vivo.Micro-PET imaging in the A549-FAP tumor model indicated higher specific tumor uptake of[^(18)F]Al F-P-FAPI(7.0±1.0%ID/g)compared to patent tracers[^(18)F]FAPI-42(3.2±0.6%ID/g)and[68 Ga]Ga-FAPI-04(2.7±0.5%ID/g).Furthermore,in an initial diagnostic application in a patient with nasopharyngeal cancer,[^(18)F]Al F-P-FAPI and[^(18)F]FDG PET/CT showed comparable results for both primary tumors and lymph node metastases.These results suggest that[^(18)F]Al F-P-FAPI can be conveniently prepared,with promising characteristics in the preclinical evaluation.The feasibility of FAP imaging was demonstrated using PET studies.展开更多
Late-stage functionalization is an attractive strategy that allows chemists to bypass lengthy synthetic processes,facilitating the rapid generation of drug analogs with potentially enhanced pharmacokinetic and pharmac...Late-stage functionalization is an attractive strategy that allows chemists to bypass lengthy synthetic processes,facilitating the rapid generation of drug analogs with potentially enhanced pharmacokinetic and pharmacological properties.This study describes a novel approach for cross-dehydrogenative oxyalkylation,leveraging a unique g-ray-enabled photoredox process to generate oxyalkyl radicals,followed by a Minisci-type addition in an aqueous solution.The metal-and oxidant-free aqueous conditions,coupled with excellent functional group compatibility,establish this method as a versatile protocol for the late-stage oxyalkylation of unprotected,structurally complex drug molecules.Notably,this method demonstrated improved pharmacokinetics in hydroxymethylated fibroblast activation protein inhibitor(FAPI)molecules,highlighting its potential to accelerate drug discovery efforts.展开更多
Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant ant...Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant anticancer properties,particularly through immune modulation.In this study,we explored the therapeutic potential of Ginsenoside Rg3 hydrogel in the treatment of gastric cancer,focusing on its ability to target fibroblast activation protein(FAP),a key mediator of tumor progression.Using reverse molecular docking and gene expression analysis,we identified FAP as a primary molecular target of Rg3.Preclinical evaluations revealed that Rg3 hydrogel effectively inhibited the proliferation and invasion of gastric cancer cells in vitro.Furthermore,the hydrogel promoted immunogenic cell death,resulting in a robust immune response against the tumor.Our findings suggest that Ginsenoside Rg3 hydrogel holds promise as a novel immune-based therapeutic strategy for gastric cancer,offering a potential pathway to improved clinical outcomes and treatment strategies.展开更多
Pancreatic cancer is one of the most lethal malignancies in the world.Cancer-associated fibroblasts are one of the main components of tumor microenvironment in pancreatic cancer and play an essential role in tumor pro...Pancreatic cancer is one of the most lethal malignancies in the world.Cancer-associated fibroblasts are one of the main components of tumor microenvironment in pancreatic cancer and play an essential role in tumor progression.Fibroblast activation protein that is expressed in specific subtypes of cancer-associated fibroblasts promotes tumor growth and is related to poor survival.Recent researches have preliminarily demonstrated a promising potential of radiopharmaceuticals targeting fibroblast activation protein in diagnosis and therapy of pancreatic cancer.This article comprehensively reviews the current development and clinical translation of fibroblast activation protein inhibitor-targeting radiopharmaceuticals in pancreatic cancer and provides significant perspectives for future investigations.展开更多
Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently...Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently,there are no molecular targeted drugs approved for osteosarcoma treatment,particularly effective drugs for osteosarcoma with pulmonary metastases.It has been reported that fibroblast activation protein alpha(FAPa)is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis,demonstrating that FAPa-targeted agents might be a promising therapeutic strategy for osteosarcoma.In the present study,we reported that the FAPa-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPa-positive osteosarcoma cells in vitro and in vivo.Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells.Importantly,it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition(EMT)of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo.Mechanistically,Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway,leading to inhibition of the growth and metastatic spread of osteosarcoma cells.These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPa-positive osteosarcoma,particularly osteosarcoma with pulmonary metastases.展开更多
文摘Positron emission tomography/computed tomography(PET/CT)with radiolabeled fibroblast activation protein inhibitors(FAPI)is an increasingly relevant molecular diagnostic image in oncology given the high expression of FAP in cancer associated fibroblast,being present in almost 90%of the epithelial carcinomas,which allows imaging with excellent diagnostic performance and can also become a therapeutic strategy.This review summarizes the literature on FAPIPET/CT for the cancer evaluation and compares it in some scenarios with the 18FFluorodeoxyglucose PET/CT.
基金Supported by The National Key Project of Scientific and Technical Supporting Programs of China, No. 2006BAI02A14National Natural Science Foundation of China, No. 30770996 and No. 81172310
文摘AIM: To examine fibroblast activation protein (FAP) expression in pancreatic ductal adenocarcinoma (PDAC) and to analyze its relationship with the clinicopathology of PDAC. METHODS: FAP expression was examined in 134 PDAC specimens by immunohistochemistry, and in four pancreatic cancer cell lines (SW1990, Miapaca-2, AsPC-1 and BxPC-3) by Western blotting assay. We also analyzed the association between FAP expression in PDAC cells and the clinicopathology of PDAC patients. RESULTS: The results showed that the FAP was expressed in both stromal fibroblast cells (98/134, 73.1%) and carcinoma cells (102/134, 76.1%). All 4 pancreatic cancer cell lines expressed FAP protein at different levels. Protein bands corresponding to the proteolytically active 170-kDa seprase dimer and its88-kDa seprase subunit were identif ied. Higher FAP expression in carcinoma cells was associated with tumor size (P < 0.001), fi brotic focus (P = 0.003), perineural invasion (P = 0.009) and worse clinical outcome (P = 0.0085). CONCLUSION: FAP is highly expressed in carcinoma cells and f ibroblasts in PDAC tissues, and its expression is associated with desmoplasia and worse prognosis.
基金Key Scientific Research Program for Young Scholars in Fujian,Grant/Award Number:2021ZQNZD016Fujian Natural Science Foundation for Distinguished Young Scholars,Grant/Award Number:2022D005+3 种基金Medical and Health Guidance Projects of Xiamen,Grant/Award Numbers:3502Z20209269,3502Z20224ZD1001National Natural Science Foundation of China,Grant/Award Numbers:82071961,82102094Fujian Natural Science Foundation for Youth Innovation,Grant/Award Number:2022J05314Fujian Research and Training Grants for Young and Middle-Aged Leaders in Healthcare。
文摘Quinoline-based fibroblast activation protein(FAP)inhibitor(FAPI)-based positron emission tomography(PET)imaging and radioligand therapy(RLT)are being investigated for use in a wide variety of diseases,and recent results have been promising.This review summarizes the current status of FAPI radiopharmaceuticals in PET imaging of malignant tumors and benign conditions and compares their diagnostic efficacy with ^(18)F-fluorodeoxyglucose.In addition,we summarize the previously published FAP-targeted RLT data and discuss its current clinical use and future potential.Our qualitative summary can inform future research directions,medical guidelines,and optimal clinical decision-making.
基金supported by the National Natural Science Foundation of China(W2411008,823B2043,22122504,and 22235006)the Cancer Research and Translational Platform Project of Zhongnan Hospital of Wuhan University(ZLYNXM202004).
文摘Hepatectomy is a critical treatment for liver cancer,but achieving complete tumor removal remains challenging.The development of tumor-targeting probes capable of accurately identifying tumor locations and providing real-time intraoperative navigation is of significant clinical importance.We synthesize a tumor-targeted probe by conjugating a fibroblast activation protein inhibitor(FAPI)with near-infrared organic room temperature phosphorescence(RTP)material.We then analyze its surgical navigation performance in the liver cancer model and its imaging performance in fresh patient-derived samples.In vivo validation reveals that the probe exhibits optimal phosphorescence intensity within 48 h(8.53×10^(5)p s^(−1)cm^(−2)sr^(−1))and an average signal-to-noise ratio of 16.The probe could effectively identify FAP-positive samples from liver cancer patients.The successful application of phosphorescence-guided surgery suggests that the near-infrared RTP probe holds significant clinical translational value and could serve as an auxiliary tool for the surgical treatment of liver cancer.
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04)+6 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2024-12M-ZH-009,2023-I2M-2-006,2023-I2M-QJ010,2021-I2M-1-026,and 2021-I2M-3-001,China)the Beijing Nova Program and Beijing Nova Program Interdisciplinary Cooperation Project to Ksupported by the Beijing Natural Science Foundation(Nos.L234044,L248087,L246051 and 7252206,China)the Fundamental Research Funds for the Central Universities(Nos.3332023044,3332023151,China)the China Postdoctoral Science Foundation(No.2025M773592)the China National Nuclear Corporation Young Talent Program,the special project of“Technological Innovation”project of CNNC Medical Industry Co.Ltd(ZHYLYB2021005)Medical+X Innovation Team of the Discipline Construction Enhancement Project,the Second Affiliated Hospital of Soochow University(XKTJ-TD202410).
文摘The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.
基金funded by the Beijing Municipal Natural Science Foundation(Grant No.Z200018)the National Natural Science Foundation of China(Grant No.22225603)the Ministry of Science and Technology of the People's Republic of China(Grant Nos.2021YFA1601400).
文摘Targeted alpha therapy(TAT)is an innovative approach in cancer treatment that aims to selectively deliver high-energy radiation to cancer cells while minimizing damage to healthy tissues.^(225)Ac,an alpha radionuclide with a half-life of 10 days and emitting 4 alpha particles and 2 beta particles in its decay chain,has shown promise for TAT.Fibroblast activation protein(FAP)has emerged as a valuable target for the development of radiopharmaceuticals in the context of TAT,given its expression in various cancers.However,a challenge arises when using FAPtargeting agents such as FAP inhibitors(FAPIs)in combination with^(225)Ac due to their rapid clearance from the tumor.To address this challenge,the FAP-targeting antibody PKU525 was developed as a TAT drug.The conjugation ratios of the chelator and the labeling procedure were systematically investigated,resulting in an efficient and stable radiolabeling method.Biodistribution studies were conducted using[^(225)Ac]Ac-DOTA-PKU525 with average drug-to-antibody ratios(DARs)of 1.85,3.87,and 7.72.A single dose of 11.1 kBq of[^(225)Ac]Ac-DOTA-PKU525 with DAR 3.87 demonstrated significant inhibition of 4T1-hFAP tumor growth.No significant weight changes were observed throughout the treatment period,and histological examination of the major organs revealed no adverse side effects.In conclusion,[^(225)Ac]Ac-DOTA-PKU525 exhibited both safety and efficacy in 4T1-hFAP tumor-bearing mice,indicating its potential for clinical translation in FAP-targeted alpha therapy.Further development and evaluation of this TAT approach hold promise for improving cancer treatment outcomes.
文摘BACKGROUND This report describes a rare case of a small gastric cancer lesion with widespread bone metastases and markedly elevated alkaline phosphatase levels that was initially misdiagnosed as rheumatoid arthritis,as the patient’s sole clinical manifestation was chronic bone pain persisting for 1 year.CASE SUMMARY An 83-year-old man was admitted due to worsening generalized joint pain over 1 year.Serum alkaline phosphatase levels were markedly elevated,and technetium-99m methylene diphosphonate single-photon emission computed tomography(CT)and fluorine-18 sodium fluoride positron emission tomography(PET)/CT images showed symmetrical diffuse uptake of the radiotracers throughout the skeleton.Initially,Paget’s disease was suspected,but abnormal hematologic tumor markers and bone biopsy confirmed metastatic adenocarcinoma.Fluorine-18-fluorodeoxyglucose PET/CT did not reveal a primary tumor.The patient had a history of colon polypectomy and tubulovillous adenoma with atypical hy-perplasia on pathological examination 10 years prior.Further investigation using gallium-68-labeled fibroblast-activation protein inhibitor PET/CT images showed increased punctate uptake in the gastric antrum.Gastroscopy demonstrated a 1.0 cm ulcerated mass in the prepyloric region,and histopathological evaluation of the biopsy specimen revealed poorly differentiated adenocarcinoma.The incidence of bone metastases from gastric cancer is very low,especially with such extensive involvement.CONCLUSION Occult gastric carcinomas with bone metastases necessitate proactive high-risk surveillance and multidisciplinary integration to improve diagnostic accuracy and clinical outcomes.
基金performed at the expense of the subsidy allocated to Kazan Federal University for the fulfillment of the stated task in the field of scientific activity,No.FZSM-2023-0011.
文摘Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy approaches,these methods rely on direct destruction of tumor cells with minimal impact on the aggregate of nearby non-tumor cells,the extracellular matrix,and blood vessels that form the tumor microenvironment(TME).The TME is known to be heterogeneous and dynamic,exerting both antitumor and pro-tumor effects depending on the specific features and stage of carcinogenesis.TME has been shown in several studies to promote malignancy,angiogenesis,and metastasis in tumors in general and melanoma in particular.Consequently,a significant number of studies in thefield of melanoma therapy have been redirected to investigate the effects of individual TME constituents,their prognostic significance for patients,and the potential of therapeutic intervention to improve overall patient survival.This review highlights novel therapeutic approaches targeting two key resident cell types in the melanoma microenvironment:tumor-associated macrophages(TAMs)and cancer-associatedfibroblasts(CAFs).The review discusses their role in disease progression and summarizes the results of preclinical and clinical trials of targeted therapies against these cell types in the melanoma TME.
基金Supported by NIH R01 CA169702-01A1(to Zheng L)NIH K23 CA148964-01(to Zheng L)+6 种基金Johns Hopkins School of Medicine Clinical Scientist Award(to Zheng L)Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins(to Zheng L)The National Pancreas Foundation(to Zheng L)Lefkofsky Family Foundation(to Zheng L)the NCI SPORE in Gastrointestinal Cancers P50 CA062924(to Zheng L)Lustgarten Foundation(to Zheng L)the Sol Goldman Pancreatic Cancer Center grants(to Zheng L)
文摘Pancreatic ductal adenocarcinoma(PDA)is among the deadliest cancers in the United States and in the world.Late diagnosis,early metastasis and lack of effective therapy are among the reasons why only 6%of patients diagnosed with PDA survive past 5 years.Despite development of targeted therapy against other cancers,little progression has been made in the treatment of PDA.Therefore,there is an urgent need for the development of new treatments.However,in order to proceed with treatments,the complicated biology of PDA needs to be understood first.Interestingly,majority of the tumor volume is not made of malignant epithelial cells but of stroma.In recent years,it has become evident that there is an important interaction between the stromal compartment and the less prevalent malignant cells,leading to cancer progression.The stroma not only serves as a growth promoting source of signals but it is also a physical barrier to drug delivery.Understanding the tumor-stroma signaling leading to development of desmoplastic reaction and tumor progression can lead to the development of therapies to decrease stromal activity and improve drug delivery.In this review,we focus on how the current understanding of biology of the pancreatic tumor microenvironment can be translated into the development of targeted therapy.
基金This work was supported by the National Natural Science Foundation of China(No.82171986).
文摘Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accurate controls,making the results less specific and less confirmative.This study aimed to establish a pair of cell lines,in which one highly expresses FAP(HT1080-hFAP)and the other has no detectable FAP(HT1080-vec)as control,to accurately evaluate the specificity of the FAP-targeted theranostics in vitro and in vivo.Methods The cell lines of the experimental group(HT1080-hFAP)and no-load group(HT1080-vec)were obtained by molecular construction of the recombinant plasmid pIRES-hFAP.The expression of hFAP in HT1080 cells was detected by PCR,Western blotting and flow cytometry.CCK-8,Matrigel transwell invasion assay,scratch test,flow cytometry and immunofluorescence were used to verify the physiological function of FAP.The activities of human dipeptidyl peptidase(DPP)and human endopeptidase(EP)were detected by ELISA in HT1080-hFAP cells.PET imaging was performed in bilateral tumor-bearing nude mice models to evaluate the specificity of FAP.Results RT-PCR and Western blotting demonstrated the mRNA and protein expression of hFAP in HT1080-hFAP cells but not in HT1080-vec cells.Flow cytometry confirmed that nearly 95%of the HT1080-hFAP cells were FAP positive.The engineered hFAP on HT1080 cells had its ability to retain enzymatic activities and a variety of biological functions,including internalization,proliferation-,migration-,and invasion-promoting activities.The HT1080-hFAP xenografted tumors in nude mice bound and took up^(68)GA-FAPI-04 with superior selectivity.High image contrast and tumor-organ ratio were obtained by PET imaging.The HT1080-hFAP tumor retained the radiotracer for at least 60 min.Conclusion This pair of HT1080 cell lines was successfully established,making it feasible for accurate evaluation and visualization of therapeutic and diagnostic agents targeting the hFAP.
基金supported by the National Natural Science Foundation of China(81701729,91949121)Guangdong Basic and Applied Basic Research Foundation(2021A1515011099,China)+1 种基金Outstanding Youths Development Scheme of Nanfang Hospital,Southern Medical University(2017J010,China)Nanfang Hospital Talent Introduction Foundation of Southern Medical University(123456,China)。
文摘In recent years,fibroblast activation protein(FAP)has emerged as an attractive target for the diagnosis and radiotherapy of cancers using FAP-specific radioligands.Herein,we aimed to design a novel^(18)Flabeled FAP tracer([^(18)F]Al F-P-FAPI)for FAP imaging and evaluated its potential for clinical application.The[^(18)F]Al F-P-FAPI novel tracer was prepared in an automated manner within 42 min with a non-decay corrected radiochemical yield of 32±6%(n=8).Among A549-FAP cells,[^(18)F]Al F-P-FAPI demonstrated specific uptake,rapid internalization,and low cellular efflux.Compared to the patent tracer[^(18)F]FAPI-42,[^(18)F]Al F-P-FAPI exhibited lower levels of cellular efflux in the A549-FAP cells and higher stability in vivo.Micro-PET imaging in the A549-FAP tumor model indicated higher specific tumor uptake of[^(18)F]Al F-P-FAPI(7.0±1.0%ID/g)compared to patent tracers[^(18)F]FAPI-42(3.2±0.6%ID/g)and[68 Ga]Ga-FAPI-04(2.7±0.5%ID/g).Furthermore,in an initial diagnostic application in a patient with nasopharyngeal cancer,[^(18)F]Al F-P-FAPI and[^(18)F]FDG PET/CT showed comparable results for both primary tumors and lymph node metastases.These results suggest that[^(18)F]Al F-P-FAPI can be conveniently prepared,with promising characteristics in the preclinical evaluation.The feasibility of FAP imaging was demonstrated using PET studies.
基金funded by the Ministry of Science and Technology of the People’s Republic of China(2021YFA1601400)the National Natural Science Foundation of China(22225603 and 22441051)the New Cornerstone Science Foundation(The XPLORER PRIZE)and Changping Laboratory to Z.L.,and the National Nature Science Foundation of China(22306005)to B.-S.M.
文摘Late-stage functionalization is an attractive strategy that allows chemists to bypass lengthy synthetic processes,facilitating the rapid generation of drug analogs with potentially enhanced pharmacokinetic and pharmacological properties.This study describes a novel approach for cross-dehydrogenative oxyalkylation,leveraging a unique g-ray-enabled photoredox process to generate oxyalkyl radicals,followed by a Minisci-type addition in an aqueous solution.The metal-and oxidant-free aqueous conditions,coupled with excellent functional group compatibility,establish this method as a versatile protocol for the late-stage oxyalkylation of unprotected,structurally complex drug molecules.Notably,this method demonstrated improved pharmacokinetics in hydroxymethylated fibroblast activation protein inhibitor(FAPI)molecules,highlighting its potential to accelerate drug discovery efforts.
文摘Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant anticancer properties,particularly through immune modulation.In this study,we explored the therapeutic potential of Ginsenoside Rg3 hydrogel in the treatment of gastric cancer,focusing on its ability to target fibroblast activation protein(FAP),a key mediator of tumor progression.Using reverse molecular docking and gene expression analysis,we identified FAP as a primary molecular target of Rg3.Preclinical evaluations revealed that Rg3 hydrogel effectively inhibited the proliferation and invasion of gastric cancer cells in vitro.Furthermore,the hydrogel promoted immunogenic cell death,resulting in a robust immune response against the tumor.Our findings suggest that Ginsenoside Rg3 hydrogel holds promise as a novel immune-based therapeutic strategy for gastric cancer,offering a potential pathway to improved clinical outcomes and treatment strategies.
基金This work was in part supported by the National Natural Science Foundation of China(No.82071967)CAMS Innovation Fund for Medical Science(No.CIFMS-2021-I2M-1-025)+2 种基金National Key Research and Development Program of China(No.2016YFC0901500)CAMS Fund for Rare Diseases Research(No.2016ZX310174-4)Tsinghua university and PUMCH Joint Fund(No.PTQH201906006).
文摘Pancreatic cancer is one of the most lethal malignancies in the world.Cancer-associated fibroblasts are one of the main components of tumor microenvironment in pancreatic cancer and play an essential role in tumor progression.Fibroblast activation protein that is expressed in specific subtypes of cancer-associated fibroblasts promotes tumor growth and is related to poor survival.Recent researches have preliminarily demonstrated a promising potential of radiopharmaceuticals targeting fibroblast activation protein in diagnosis and therapy of pancreatic cancer.This article comprehensively reviews the current development and clinical translation of fibroblast activation protein inhibitor-targeting radiopharmaceuticals in pancreatic cancer and provides significant perspectives for future investigations.
基金supported by National Natural Science Foundation of China(grant numbers:82003796,81803566,81973340 and 81630095)Local Innovative and Research Teams Project of the Guangdong Pearl River Talents Program(grant number:2017BT01Y036,China)+5 种基金National High-level Personnel of the Special Support Program(DM Zhang,China)National Science and Technology Major Project(grant number:2018ZX09711001008-008,China)Key-Area Research and Development Program of Guangdong Province(grant number:2020B1111110004,China)Natural Science Foundation of Guangdong Province(grant number:2019A1515010144,China)Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy(grant number:2020B1212060076,China)Special Funds for the Cultivation of Guangdong College Students’Scientific and Technological Innovation(grant number:pdjh2021a0052,China)。
文摘Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently,there are no molecular targeted drugs approved for osteosarcoma treatment,particularly effective drugs for osteosarcoma with pulmonary metastases.It has been reported that fibroblast activation protein alpha(FAPa)is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis,demonstrating that FAPa-targeted agents might be a promising therapeutic strategy for osteosarcoma.In the present study,we reported that the FAPa-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPa-positive osteosarcoma cells in vitro and in vivo.Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells.Importantly,it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition(EMT)of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo.Mechanistically,Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway,leading to inhibition of the growth and metastatic spread of osteosarcoma cells.These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPa-positive osteosarcoma,particularly osteosarcoma with pulmonary metastases.
