The natural sulfoglycolipid derivative SQAP improves the therapeutic efficacy of tissue factor-targeted radioimmunotherapy in the stroma-rich pancreatic cancer model BxPC-3.
Ontology highlight
ABSTRACT:
SUBMITTER: Takakusagi Y
PROVIDER: S-EPMC8628266 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Pancreatic cancer remains one of medicine's largest areas of unmet need. With five-year survival rates of < 8%, little improvement has been made in the last 50 years. Typically presenting with advance stage disease, treatment options are limited. To date, surgery remains the only potentially curative option, however, with such late disease presentation, the majority of patients are unresectable. Thus, new therapeutic options and a greater understanding of the complex stromal interactions within the tumour microenvironment are sorely needed to revise the dismal outlook for pancreatic cancer patients. Natural killer (NK) cells are crucial effector units in cancer immunosurveillance. Often used as a prognostic biomarker in a range of malignancies, NK cells have received much attention as an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. Despite this interest, the role of NK cells in pancreatic cancer remains poorly defined. Nevertheless, increasing evidence of the importance of NK cells in this dismal prognosis disease is beginning to come to light. Here, we review the role of NK cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of NK cells as therapy.
| S-EPMC8240050 | biostudies-literature
Project description:Pancreatic adenocarcinoma (PA) is among the most aggressive human tumors with an overall 5-year survival rate of <5% and available treatments are only minimal effective. WNT/β-catenin signaling has been identified as one of 12 core signaling pathways that are commonly mutated in PA. To obtain more insight into the role of WNT/β-catenin signaling in PA we established human PA cell lines that are deficient of the central canonical WNT signaling protein β-catenin by using zinc-finger nuclease (ZFN) mediated targeted genomic disruption in the β-catenin gene (CTNNB1). Five individual CTNNB1 gene disrupted clones (BxPC3ΔCTNNB1) were established from a BxPC-3 founder cell line. Despite the complete absence of β-catenin, all clones displayed normal cell cycle distribution profiles, overall normal morphology and no elevated levels of apoptosis although increased doubling times were observed in three of the five BxPC3ΔCTNNB1 clones. This confirms that WNT/β-catenin signaling is not mandatory for long term cell growth and survival in BxPC-3 cells. Despite a normal morphology of the β-catenin deficient cell lines, quantitative proteomic analysis combined with pathway analysis showed a significant down regulation of proteins implied in cell adhesion combined with an up-regulation of plakoglobin. Treatment of BxPC3ΔCTNNB1 cell lines with siRNA for plakoglobin induced morphological changes compatible with a deficiency in the formation of functional cell to cell contacts. In addition, a re-localization of E-cadherin from membranous in untreated to accumulation in cytoplasmatic puncta in plakoglobin siRNA treated BxPC3ΔCTNNB1 cells was observed. In conclusion we describe in β-catenin deficient BxPC-3 cells a rescue function for plakoglobin on cell to cell contacts and maintaining the localization of E-cadherin at the cellular surface, but not on canonical WNT signaling as measured by TFC/LEF mediated transcription.
| S-EPMC4275244 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2'-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5-mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAF), along with increased amounts of 5-hydroxymethyl-cytosine (5-HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early-treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the CAFs. Expression profiling and immunohistochemistry highlighted DAC induction of STAT1 in the tumors, and DAC plus IFN-? produced an additive antiproliferative effect on PDAC cells. DAC induced strong expression of the testis antigen deleted in azoospermia-like (DAZL) in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
| S-EPMC3548986 | biostudies-literature
Project description: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.
| S-EPMC3942829 | biostudies-literature
Project description:Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high-risk metastatic neuroblastoma. Building on this experience, novel combinations of antibodies, cytokines, cells, and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In this review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions.
| S-EPMC4254523 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by high expression of extracellular matrix in tumor tissue, which contributes to chemoresistance and poor prognosis. Here, we developed 3D pancreatic cancer spheroids, based on pancreatic cancer cells and fibroblast co-culture, which demonstrate innate desmoplastic properties and stay poorly permeable for model nanoparticles. Our study revealed that establishment of tumors by transplantation of spheroids significantly improved subcutaneous xenograft model of PDAC, which stays the most widely used animal model for testing of new drugs and drug delivery approaches. Spheroid based tumors abundantly produced different extracellular matrix (ECM) components including collagen I, fibronectin, laminin and hyaluronic acid. These tumors were highly reproducible with excellent uniformity in terms of ECM architecture recapitulating clinical PDAC tumors, whereas in more common cell based xenografts a significant intertumor heterogeneity in extracellular matrix production was found. Moreover, spheroid based xenografts demonstrated higher expression of pro-fibrotic and pro-survival PDAC hallmarks in opposite to cell based counterparts. We believe that future development of this model will provide an effective instrument for testing of anti-cancer drugs with improved predictive value.
| S-EPMC6295361 | biostudies-literature
Project description:Cancer stem cells (CSCs) subpopulation within the tumour is responsible for metastasis and cancer relapse. Here we investigate in vitro and in vivo the effects of a pancreatic (pro)enzyme mixture composed of Chymotrypsinogen and Trypsinogen (PRP) on CSCs derived from a human pancreatic cell line, BxPC3. Exposure of pancreatic CSCs spheres to PRP resulted in a significant decrease of ALDEFLUOR and specific pancreatic CSC markers (CD 326, CD 44 and CxCR4) signal tested by flow cytometry, further CSCs markers expression was also analyzed by western and immunofluorescence assays. PRP also inhibits primary and secondary sphere formation. Three RT2 Profiler PCR Arrays were used to study gene expression regulation after PRP treatment and resulted in, (i) epithelial-mesenchymal transition (EMT) inhibition; (ii) CSCs related genes suppression; (iii) enhanced expression of tumour suppressor genes; (iv) downregulation of migration and metastasis genes and (v) regulation of MAP Kinase Signalling Pathway. Finally, in vivo anti-tumor xenograft studies demonstrated high anti-tumour efficacy of PRP against tumours induced by BxPC3 human pancreatic CSCs. PRP impaired engrafting of pancreatic CSC's tumours in nude mice and displayed an antigrowth effect toward initiated xenografts. We concluded that (pro)enzymes treatment is a valuable strategy to suppress the CSC population in solid pancreatic tumours.
| S-EPMC6684636 | biostudies-literature
Project description:Rationale: Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass. Type I collagen is the major component of the extracellular matrix (ECM), which acts as a barrier to impede the delivery of drugs into the tumor microenvironment. While the strategy to deplete PDAC stroma has failed in clinical trials, normalization of the stroma to allow chemotherapy to kill the tumor cells in the "nest" could be a promising strategy for PDAC therapy. We hypothesize that silencing the poly(rC)-binding protein 2 (αCP2, encoded by the PCBP2 gene) leads to the destabilization and normalization of type I collagen in the PDAC stroma. Methods: We develop a micro-flow mixing method to fabricate a peptide-based core-stabilized PCBP2 siRNA nanocomplex to reverse the accumulation of type I collagen in PDAC tumor stroma. Various in vitro studies were performed to evaluate the silencing activity, cellular uptake, serum stability, and tumor penetration of the PCBP2 siRNA nanocomplex. We also investigated the penetration of small molecules in stroma-rich pancreatic cancer spheroids after the treatment with the PCBP2 siRNA nanocomplex. The anti-tumor activity of the PCBP2 siRNA nanocomplex and its combination with gemcitabine was evaluated in an orthotopic stroma-rich pancreatic cancer mouse model. Results: Silencing the PCBP2 gene using siRNA reverses the accumulation of type I collagen in human pancreatic stellate cells (PSCs) and mouse NIH 3T3 fibroblast cells. The siRNA nanocomplex significantly reduces ECM production and enhances drug penetration through desmoplastic tumor stroma. The combination of gemcitabine with the PCBP2 siRNA nanocomplex markedly suppresses the tumor progression in a desmoplastic PDAC orthotopic mouse model. Conclusion: This approach provides a new therapeutic avenue to improve the antitumor efficacy of PDAC therapies by normalizing tumor stroma using the PCBP2 siRNA nanocomplex.
| S-EPMC7797682 | biostudies-literature
Project description:BackgroundTargeted Radioimmunotherapy (RIT) is an attractive approach to selectively localize therapeutic radionuclides to malignant cells within primary and metastatic tumors while sparing normal tissues from the effects of radiation. Many human malignancies express B7-H3 on the tumor cell surface, while expression on the majority of normal tissues is limited, presenting B7-H3 as a candidate target for RIT. This review provides an overview of the general principles of targeted RIT and discusses publications that have used radiolabeled B7-H3-targeted antibodies for RIT of cancer in preclinical or clinical studies.MethodsDatabases including PubMed, Scopus, and Google Scholar were searched for publications through June 2018 using a combination of terms including "B7-H3", "radioimmunotherapy", "targeted", "radiotherapy", and "cancer". After screening search results for relevancy, ten publications were included for discussion.ResultsB7-H3-targeted RIT studies to date range from antibody development and assessment of novel Radioimmunoconjugates (RICs) in animal models of human cancer to phase II/III trials in humans. The majority of clinical studies have used B7-H3-targeted RICs for intra- compartment RIT of central nervous system malignancies. The results of these studies have indicated high tolerability and favorable efficacy outcomes, supporting further assessment of B7-H3-targeted RIT in larger trials. Preclinical B7-H3-targeted RIT studies have also shown encouraging therapeutic outcomes in a variety of solid malignancies.ConclusionB7-H3-targeted RIT studies over the last 15 years have demonstrated feasibility for clinical development and support future assessment in a broader array of human malignancies. Future directions worthy of exploration include strategies that combine B7-H3- targeted RIT with chemotherapy or immunotherapy.
| S-EPMC8668195 | biostudies-literature
Project description:Chemoimmunotherapy with antibody-drug conjugates (ADC) is emerging as a promising therapy for solid tumors, whereas radioimmunotherapy (RAIT) of solid tumors has been relatively ineffective because of their resistance to radiation. We developed antibody-SN-38 conjugates that have significant antitumor activity in xenograft models at nontoxic doses. The goal of this study was to determine if an ADC could be combined with RAIT to enhance efficacy without a commensurate increase in host toxicity. Nude mice bearing human pancreatic cancer xenografts (Capan-1 and BxPC-3) were treated with a single dose of 90Y-labeled antimucin antibody (hPAM4; clivatuzumab tetraxetan) alone or in combination with an anti-Trop-2-SN-38 conjugate, typically administered twice weekly over 4 weeks. The combination, even at RAIT's maximum tolerated dose, controlled tumor progression and cured established xenografts significantly better than the individual treatments without appreciable toxicity. The ADC could be started 1 week after or up to 2 weeks before RAIT with similar enhanced responses, but delaying RAIT for 2 weeks after the ADC was less effective. A nonspecific ADC provided additional benefit over using free drug (irinotecan), but the response was enhanced with the specific ADC. When targeting Capan-1 with ample mucin, hPAM4 could be used as the RAIT and the ADC agent without losing effectiveness, but in BxPC-3 with less mucin, targeting of different antigens was preferred. These studies show the feasibility of combining ADC and RAIT for improved efficacy without increased toxicity.
| S-EPMC5654622 | biostudies-literature