Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: ⁶⁴Cu- and ²²⁵Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models

Journal of Nuclear Medicine, Journal Year: 2019, Volume and Issue: 61(4), P. 563 - 569

Published: Oct. 4, 2019

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because its low expression normal organs, FAP an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, 64Cu (half-life, 12.7 h) 225Ac 10 d), to label inhibitors (FAPIs) mice pancreatic cancer xenografts. Methods: Male nude (body weight, 22.5 ± 1.2 g) were subcutaneously injected cells (PANC-1, n = 12; MIA PaCa-2, 8). Tumor xenograft investigated after the intravenous injection 64Cu-FAPI-04 (7.21 0.46 MBq) by dynamic delayed PET scans (2.5 h injection). Static 1 68Ga-FAPI-04 (3.6 1.4 also acquired comparisons using same cohort (n Immunohistochemical staining was performed confirm xenografts FAP-α-antibody. For radioligand therapy, 225Ac-FAPI-04 (34 kBq) into PANC-1 6). size monitored compared that control Results: Dynamic imaging showed rapid clearance through kidneys slow washout from tumors. Delayed mild uptake tumors high liver intestine. Accumulation levels or organs significantly higher than 68Ga-FAPI-04, except heart, excretion urine 64Cu-FAPI-04. revealed abundant stroma significant suppression mice, without a change body weight. Conclusion: This proof-of-concept study could be theranostics treatment FAP-expressing cancer. α-therapy targeting effective will contribute development new strategy.

Language: Английский

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Comprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Aug. 8, 2019

Abstract Cancer cell lines are a cornerstone of cancer research but previous studies have shown that not all equal in their ability to model primary tumors. Here we present comprehensive pan-cancer analysis utilizing transcriptomic profiles from The Genome Atlas and the Cell Line Encyclopedia evaluate as models tumors across 22 tumor types. We perform correlation gene set enrichment understand differences between Additionally, classify into subtypes 9 our pancreatic results case study find commonly used line MIA PaCa-2 is transcriptionally unrepresentative adenocarcinomas. Lastly, propose new panel, TCGA-110-CL, for studies. This provides resource help researchers select more representative models.

Language: Английский

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3D approaches to model the tumor microenvironment of pancreatic cancer

Theranostics, Journal Year: 2020, Volume and Issue: 10(11), P. 5074 - 5089

Published: Jan. 1, 2020

In tumor engineering, 3D approaches are used to model components of the microenvironment and test new treatments.Pancreatic cancers a cancer substantial unmet need survival rates lower compared any other cancer.Bioengineering techniques increasingly applied understand unique biology pancreatic tumors design patient-specific models.Here we summarize how extracellular cellular elements their interactions have been studied in cell cultures.We review selected clinical trials, assess benefits therapies interfering with address limitations future perspectives.

Language: Английский

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Intratumoral Biosynthesis of Gold Nanoclusters by Pancreatic Cancer to Overcome Delivery Barriers to Radiosensitization

ACS Nano, Journal Year: 2024, Volume and Issue: 18(3), P. 1865 - 1881

Published: Jan. 11, 2024

Nanoparticle delivery to solid tumors is a prime challenge in nanomedicine. Here, we approach this through the lens of biogeochemistry, field that studies flow chemical elements within ecosystems as manipulated by living cellular organisms and their environments. We leverage biogeochemistry concepts related gold cycling against pancreatic cancer, considering mammalian drivers for nanoparticle biosynthesis. Sequestration nanoparticles has been demonstrated an effective strategy enhance radiotherapy; however, desmoplasia cancer impedes delivery. Our overcomes barrier applying atomic-scale agent, ionic gold, intratumoral comprehensive showed cancer-specific synthesis from externally delivered ions vitro murine model vivo; substantial colocalization (GNPs) with cell nuclei strong radiosensitization effect intracellularly synthesized GNPs; uniform distribution situ GNPs throughout tumor volume; nearly 40-day total suppression growth animal models treated combination radiation was also associated significantly higher median survival versus alone (235 vs 102 days, respectively).

Language: Английский

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Targeted Nanoparticle-Based Diagnostic and Treatment Options for Pancreatic Cancer

Cancers, Journal Year: 2024, Volume and Issue: 16(8), P. 1589 - 1589

Published: April 20, 2024

Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature lack early detection methods. A key obstacle PDAC is highly complex tumor environment characterized by dense stroma surrounding tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions these challenges, particularly creating novel delivery systems for existing anticancer drugs PDAC, such as gemcitabine paclitaxel. By using customization methods incorporating conjugated targeting ligands, tumor-penetrating peptides, therapeutic nucleic acids, nanoparticle-based enhance solubility, extend circulation time, improve targeting, control release, thereby minimizing side effects toxicity healthy tissues. Moreover, nanoparticles have also shown potential precise diagnostic PDAC. This literature review will delve into targeted mechanisms, pathways, approaches treating pancreatic cancer. Additional emphasis placed on study systems, with a brief mention those clinical trials. Overall, overview illustrates advances nanomedicine, underscoring role transcending constraints conventional therapies diagnostics.

Language: Английский

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Distinguishing mechanisms underlying EMT tristability

Cancer Convergence, Journal Year: 2017, Volume and Issue: 1(1)

Published: Oct. 18, 2017

The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer to acquire metastatic potential drug-resistance. Recent research has argued that epithelial (E) undergo either a partial attain hybrid epithelial/mesenchymal (E/M) phenotype typically displays collective migration, or complete adopt mesenchymal (M) shows individual migration. core regulatory network - miR-34/SNAIL/miR-200/ZEB1 been identified various studies, but how this regulates the transitions among E, E/M, M phenotypes remains controversial. Two major mathematical models ternary chimera switch (TCS) cascading bistable switches (CBS) both focus on network, have proposed elucidate dynamics, detailed analysis of well these two capture recent experimental observations about dynamics done.Here, via an integrated theoretical approach, we first show used understand two-step transition E→E/M→M, different responses SNAIL ZEB1 exogenous TGF-β irreversibility EMT. Next, present new results tend discriminate between models. We is at intermediate levels in E/M H1975 cells, HMLE overexpression not sufficient initiate absence FOXC2.These argue favor TCS model proposing miR-200/ZEB1 behaves as three-way decision-making enabling phenotypes.

Language: Английский

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Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery

Cancer Research, Journal Year: 2017, Volume and Issue: 78(2), P. 558 - 571

Published: Nov. 29, 2017

Abstract Physiologic barriers to drug delivery and selection for resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve the tumor microenvironment safely widen therapeutic window of nanoformulated cytotoxic drug. orthotopic xenograft models pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented relapse, reduced metastasis, increased both progression-free 1-year disease-free survival. enabled these durable improvements by targeting multiple compartments (i) increase intratumoral accumulation >10-fold, (ii) duration exposure above critical threshold, (iii) attenuate surges CD44 CXCR4 expression, which mediate chemoresistance often observed after multicycle chemotherapy. Overall, our results offer proof concept effectiveness minimize risks progression, extend patient Significance: A biophysical approach overcomes key treatment barriers, significantly reduces metastases, prolongs human cancer. Cancer Res; 78(2); 558–71. ©2017 AACR.

Language: Английский

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Gene Expression Comparison between the Lymph Node-Positive and -Negative Reveals a Peculiar Immune Microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study

Cancers, Journal Year: 2019, Volume and Issue: 11(7), P. 942 - 942

Published: July 4, 2019

Over the past several years there has been much debate with regards to prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) lymph nodes metastasis. The PDAC gene expression knowledge biologic alterations underlying node involvement convey a implication in dealing theranostic window. To this end, we provide an original bioinformatic dissection differences according nodal from large public available dataset. Comprehensive transcriptomic analysis 143 RNA-seq patient's derived samples indicated that WNT increased activation peculiar immune microenvironment identify subjects involvement. In frame thinking, validated pathway role increasing likelihood lymphatic dissemination vitro. Moreover, demonstrated for first time model potential therapeutic window XAV-939-a specific inhibitor-has re-educating tumor-permissive system. Finally, outline on bystander molecular drivers exerted by inhibition, providing picture proteomic oncogenic landscape changes elicited XAV-939 cells their implication. Our findings hold promise novel immune-based strategies targeting enhance cytotoxicity restore anti-PDAC immunity node-positive disease.

Language: Английский

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Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy

Cancer Science, Journal Year: 2019, Volume and Issue: 111(1), P. 266 - 278

Published: Nov. 20, 2019

Abstract According to cancer genome sequences, more than 90% of cases pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification rare We assessed the dynamics circulating tumor DNA (ct‐DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. G12/13 mutation was assayed by dPCR 47 paired tissue‐ ct‐DNA samples. The 21 were subjected quantitative monitoring at 4 8‐week intervals during chemotherapy. detected 45 those tissue DNA. In mutation‐negative cases, next‐generation sequencing revealed Q61K NRAS Q61R 23/45 (liver or lung metastasis, 18/19; allele frequency [MAF], 0.1%‐31.7%; peritoneal 3/9 [0.1%], locally advanced, 2/17 [0.1%‐0.2%]). monitoring, MAF value changed concordance disease state. 6 appeared concurrently liver metastasis. Among disappeared duration stable a partial response, reappeared time progressive disease. median progression‐free survival longer which after an initial course it continuously (248.5 vs 50 days, P < .001). Therefore, continuous assessment state could have prognostic utility

Language: Английский

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Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment

European Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 164, P. 92 - 105

Published: Dec. 21, 2018

Language: Английский

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