scholarly journals The HROC-Xenobank—A High Quality Assured PDX Biobank of >100 Individual Colorectal Cancer Models

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5882
Author(s):  
Stephanie Matschos ◽  
Florian Bürtin ◽  
Said Kdimati ◽  
Mandy Radefeldt ◽  
Susann Krake ◽  
...  
Keyword(s):  
Gene Expression Analysis ◽  
Tumor Tissue ◽  
Hot Spot ◽  
In Vivo Studies ◽  
Cooperative Research ◽  
High Quality ◽  
Current Time ◽  
Cancer Models ◽  
Low Passage

Based on our research group’s large biobank of colorectal cancers (CRC), we here describe the ongoing activity of establishing a high quality assured PDX biobank for more than 100 individual CRC cases. This includes sufficient numbers of vitally frozen (n > 30 aliquots) and snap frozen (n > 5) backups, “ready to use”. Additionally, PDX tumor pieces were paraffin embedded. At the current time, we have completed 125 cases. This resource allows histopathological examinations, molecular characterizations, and gene expression analysis. Due to its size, different issues of interest can be addressed. Most importantly, the application of low-passage, cryopreserved, and well-characterized PDX for in vivo studies guarantees the reliability of results due to the largely preserved tumor microenvironment. All cases described were molecularly subtyped and genetic identity, in comparison to the original tumor tissue, was confirmed by fingerprint analysis. The latter excludes ambiguity errors between the PDX and the original patient tumor. A cancer hot spot mutation analysis was performed for n = 113 of the 125 cases entities. All relevant CRC molecular subtypes identified so far are represented in the Hansestadt Rostock CRC (HROC)-Xenobank. Notably, all models are available for cooperative research approaches.

scholarly journals Confocal Laser Endomicroscopy Assessment of Pituitary Tumor Microstructure: A Feasibility Study

2020 ◽  
Vol 9 (10) ◽  
pp. 3146 ◽  
Author(s):  
Evgenii Belykh ◽  
Brandon Ngo ◽  
Dara S. Farhadi ◽  
Xiaochun Zhao ◽  
Michael A. Mooney ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Tumor ◽  
Tumor Tissue ◽  
Ex Vivo ◽  
In Vivo Studies ◽  
Confocal Laser Endomicroscopy ◽  
Confocal Laser ◽  
Frozen Sections ◽  
Tuberculum Sellae

This is the first study to assess confocal laser endomicroscopy (CLE) use within the transsphenoidal approach and show the feasibility of obtaining digital diagnostic biopsies of pituitary tumor tissue after intravenous fluorescein injection. We confirmed that the CLE probe reaches the tuberculum sellae through the transnasal transsphenoidal corridor in cadaveric heads. Next, we confirmed that CLE provides images with identifiable histological features of pituitary adenoma. Biopsies from nine patients who underwent pituitary adenoma surgery were imaged ex vivo at various times after fluorescein injection and were assessed by a blinded board-certified neuropathologist. With frozen sections used as the standard, pituitary adenoma was diagnosed as “definitively” for 13 and as “favoring” in 3 of 16 specimens. CLE digital biopsies were diagnostic for pituitary adenoma in 10 of 16 specimens. The reasons for nondiagnostic CLE images were biopsy acquisition <1 min or >10 min after fluorescein injection (n = 5) and blood artifacts (n = 1). In conclusion, fluorescein provided sufficient contrast for CLE at a dose of 2 mg/kg, optimally 1–10 min after injection. These results provide a basis for further in vivo studies using CLE in transsphenoidal surgery.

scholarly journals 922 A novel autotaxin inhibitor, IOA-289, modulates tumor, immune and stromal cell function and has monotherapy activity in fibrotic cancer models

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A967-A967
Author(s):  
Marcel Deken ◽  
Karolina Niewola ◽  
Elisa Matas-Rico ◽  
Ragini Medhi ◽  
Alan Carruthers ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Response To Therapy ◽  
In Vivo Studies ◽  
Human Dose ◽  
Cancer Models ◽  
Claude Bernard ◽  
Collagen Iii

BackgroundAutotaxin (ATX) is a secreted glycoprotein that hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). The expression of both ATX and LPA is elevated in most solid tumors and plasma. LPA signaling directly modulates tumor cell function and contributes to the development of the fibrotic tumor microenvironment, a mechanism by which tumors evade host immunity and impairs response to therapy. IOA-289 is a potent, orally available autotaxin inhibitor which is being developed as a novel treatment of solid tumours burdened with a high degree of fibrosis.MethodsInhibition of ATX activity in human plasma was determined by measuring reduction in LPA species as quantified by LC-MS/MS. In vitro activity on biomarkers of fibrosis was assessed using the BioMAP screen and fibroblast cell cultures. T cell migration was measured using 48-well chemotaxis chambers. PK/PD studies were performed following a single oral dose of IOA-289 in mice, and plasma LPA was used as a PD biomarker. In vivo efficacy was studied in two models of breast cancer, 4T1 and E0771. Bioinformatics used TCGA and GTEX publicly available datasets.ResultsIOA-289 inhibits plasma LPA18:2 with an IC50 of 36nM, with similar results for other LPA species. IOA-289 inhibited fibrosis relevant factors in the BioMAP phenotypic screen, including sIL-6, MCP-1, αSMA, collagen-III, and sVEGF. In further studies, IOA-289 inhibited the secretion of PAI-1 and IL-6 by stimulated fibroblasts. LPA and cancer cell conditioned media inhibited T cell chemotaxis in vitro and the effect was overcome in the presence of IOA-289. The efficacious human dose of IOA-289 was determined following PK/PD studies using plasma LPA as a biomarker of response to ATX inhibition. In vivo studies showed that IOA-289 inhibited metastasis of 4T1 cells, enhanced the infiltration of T cells into 4T1 s.c. implanted tumors and prevented the growth of primary, orthotopically implanted E0771 tumors. Bioinformatics analysis demonstrated elevated ATX expression in pancreatic cancer (PDAC), and PDAC patient plasma showed a correlation of ATX levels with CA-19-9.ConclusionsThe ATX/LPA pathway represents a novel target for anti-cancer therapy with actions on the tumor, immune cell and stromal environment. IOA-289 is a highly potent and selective inhibitor of ATX with demonstrated monotherapy activity in cancer models. Based on the mechanism of action we are investigating combinations of IOA-289 with chemotherapy, immunotherapy and novel agents in ongoing preclinical studies. An acceptable safety and PK profile support the clinical development of IOA-289 which is currently in a phase I clinical trial.Ethics ApprovalThe 4T1 study was approved by The University Claude Bernard Lyon 1 Ethics Board; approval number DR2014-38 (vM). The E0771 study was reviewed and approved by the Institutional Animal Care and Use Committee of the contract research organization (Covance, Ann Arbor, MI, USA), an AAALAC International accredited program.

scholarly journals Parthanatos-inducing zinc agent C010DS-Zn elicits anti-tumor immune responses involving T cells and macrophages in vivo

2021 ◽  
Author(s):  
Jinhyuk F Chung ◽  
Zhisheng Her ◽  
Wai Mun Kong ◽  
Qingfeng Chen
Keyword(s):  
T Cells ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Solid Cancer ◽  
Dna Damages ◽  
Complex Agent ◽  
Cancer Models ◽  
Low Passage

Immune checkpoint inhibitors opened a new horizon in cancer therapy by enabling durable and complete responses in patients, but their wider application against general solid cancers has been hampered by the lack of a broadly acting anti-cancer immune response initiating agents. Parthanatos is a previously unexplored immunogenic programmed necrosis mechanism that is triggered by the hyperactivation of PARP DNA repair and executed by an efficient DNA-fragmentation mechanism. We developed a proprietary macromolecular zinc complex agent C010DS-Zn that efficiently induced parthanatos against 4T1 murine cancer cells in vitro, which was characterized as PARP-mediated necrotic death with massive DNA damages. Ex vivo screening of its cytotoxicity against a panel of 53 low-passage human solid cancer PDX tumor fragments demonstrated its consistent delivery of characteristically DNA-damaging cell death that was unseen in the corresponding apoptosis positive controls. Further characterization of its in vivo treatment effects versus the immunosuppressive 4T1-Balb/c and immunogenic CT26-Balb/c syngeneic cancer models showed that sufficiently high intravenous C010DS-Zn treatments led to robust initiation of the tumor-suppressed antitumor immune compartments such as T cells and macrophages. At lower non-anticancer doses, C010DS-Zn treatment still led to significantly reduced macrophage content and inflammation in the 4T1 tumor, suggesting its potential utility against macrophage-mediated inflammations such as those seen in MAS or COVID19. Given the observation of its low serum bioavailability in a rat pharmacokinetic study, these results suggest potential development opportunities for C010DS-Zn to become a widely applicable immune initiation agent with chemo-like broad applicability upon its pharmacokinetic improvements.

scholarly journals A 3D View of Colorectal Cancer Models in Predicting Therapeutic Responses and Resistance

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 227
Author(s):  
Eileen Reidy ◽  
Niamh A. Leonard ◽  
Oliver Treacy ◽  
Aideen E. Ryan
Keyword(s):  
Colorectal Cancer ◽  
3D Model ◽  
Treatment Options ◽  
3D Models ◽  
In Vivo Studies ◽  
The Past ◽  
Monolayer Cultures ◽  
Cancer Models

Although there have been many advances in recent years for the treatment of colorectal cancer (CRC), it still remains the third most common cause of cancer-related deaths worldwide. Many patients with late stage CRC display resistance to multiple different therapeutics. An important aspect in developing effective therapeutics for CRC patients is understanding the interactions that take place in the tumor microenvironment (TME), as it has been shown to contribute to drug resistance in vivo. Much research over the past 100 years has focused on 2D monolayer cultures or in vivo studies, however, the efficacy in translating these to the clinic is very low. More recent studies are turning towards developing an effective 3D model of CRC that is clinically relevant, that can recapitulate the TME in vitro and bridge the gap between 2D cultures and in vivo studies, with the aim of reducing the use of animal models in the future. This review summarises the advantages and limitations of different 3D CRC models. It emphasizes how different 3D models may be optimised to study cellular and extracellular interactions that take place in the TME of CRC in an effort to allow the development of more translatable effective treatment options for patients.

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 603-613 ◽  
Author(s):  
Christian Wichmann ◽  
Yvonne Becker ◽  
Linping Chen-Wichmann ◽  
Vitali Vogel ◽  
Anna Vojtkova ◽  
...  
Keyword(s):  
Amino Acids ◽  
Hot Spot ◽  
Chromosomal Translocation ◽  
Structural Motif ◽  
In Vivo Studies ◽  
Tetramerization Domain ◽  
The Stability ◽  
Transplantation Model

Abstract RUNX1/ETO, the fusion protein resulting from the chromosomal translocation t(8;21), is one of the most frequent translocation products in acute myeloid leukemia. Several in vitro and in vivo studies have shown that the homo-tetramerization domain of ETO, the nervy homology region 2 (NHR2), is essential for RUNX1/ETO oncogenic activity. We analyzed the energetic contribution of individual amino acids within the NHR2 to RUNX1/ETO dimer-tetramer transition and found a clustered area of 5 distinct amino acids with strong contribution to the stability of tetramers. Substitution of these amino acids abolishes tetramer formation without affecting dimer formation. Similar to RUNX1/ETO monomers, dimers failed to bind efficiently to DNA and to alter expression of RUNX1-dependent genes. RUNX1/ETO dimers do not block myeloid differentiation, are unable to enhance the self-renewal capacity of hematopoietic progenitors, and fail to induce leukemia in a murine transplantation model. Our data reveal the existence of an essential structural motif (hot spot) at the NHR2 dimer-tetramer interface, suitable for a molecular intervention in t(8;21) leukemias.

scholarly journals IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shao-Wei Lu ◽  
Hong-Chin Pan ◽  
Yu-Hsiang Hsu ◽  
Kung-Chao Chang ◽  
Li-Wha Wu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Proinflammatory Cytokine ◽  
Tumor Tissue ◽  
Transgenic Mouse Model ◽  
Ductal Adenocarcinoma ◽  
Murine Models ◽  
Model Combination ◽  
Poor Overall Survival ◽  
Cancer Models

Abstract Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.

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