Correction to: Longitudinal PET Imaging to Monitor Treatment Efficacy by Liposomal Irinotecan in Orthotopic Patient-Derived Pancreatic Tumor Models of High and Low Hypoxia

Abstract Purpose Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer. Procedures Mice were randomized into nal-IRI treated and untreated controls. Magnetic resonance imaging was used for monitoring treatment efficacy, positron emission tomography (PET) imaging with F-18-labelled fluoroazomycinarabinoside ([18F]FAZA) for tumor hypoxia quantification, and F-18-labelled fluorothymidine ([18F]FLT) for tumor cell proliferation. Results The highly hypoxic OCIP51 tumors showed significant response following nal-IRI treatment compared with the less hypoxic OCIP19 tumors. [18F]FAZA-PET detected significant hypoxia reduction in treated OCIP51 tumors, 8 days before significant changes in tumor volume. OCIP19 tumors also responded to therapy, although tumor volume control was not accompanied by any reduction in [18F]FAZA uptake. In both models, no differences were observable in [18F]FLT uptake in treated tumors compared with control mice. Conclusions Hypoxia modulation may play a role in nal-IRI’s mechanism of action. Nal-IRI demonstrated greater anti-tumor activity in the more aggressive and hypoxic tumor model. Furthermore, hypoxia imaging provided early prediction of treatment response.

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Deposition characteristics and resulting DNA damage patterns of liposomal irinotecan (nal-IRI) in pancreatic cancer xenografts.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.335 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 335-335

Author(s):

Shannon C. Leonard ◽

Nancy Paz ◽

Stephan G Klinz ◽

Daniel Gaddy ◽

Helen Lee ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Tumor Cells ◽

Stromal Cells ◽

Pancreatic Tumor ◽

Tumor Models ◽

Deposition Area ◽

The Us ◽

Liposomal Irinotecan ◽

Repeated Dosing

335 Background: Liposomal irinotecan (nal-IRI, ONIVYDE) is approved in the US, EU and other countries in combination with 5-fluorouracil/leucovorin for treatment of patients with metastatic pancreatic cancer after disease progression following gemcitabine-based therapy. We report pharmacokinetic and extended pharmacodynamic effects of nal-IRI in pancreatic tumor models compared to non-liposomal irinotecan HCl. Methods: AsPC-1, BxPC-3 and CFPAC-1 tumors were grown in NOD-SCID mice. For efficacy animals were dosed q7d with 25-50 mg/kg irinotecan HCl or at 5x lower doses of nal-IRI. For PK-PD studies doses of 10-50 mg/kg of fluorescently-labeled nal-IRI were used; samples were collected up to 72 hr for irinotecan HCl and up to 168 hr for nal-IRI. Tumor samples were evaluated for liposome localization, macrophage and tumor markers, vessels, DNA damage and apoptosis. Results: nal-IRI yields sustained circulation and delivery of its payload to tumors compared to irinotecan HCl. This results in improved control of growth rates across a range of pancreatic tumor models even at 5x lower doses. DNA damage in BxPC-3 tumors has a comparable extent with both formulations, but is maximal at 6 hr after irinotecan HCl (50 mg/kg) and at 72 hr after nal-IRI (10 mg/kg). Liposomes deposit in tumors heterogeneously around functional vessels. Accumulation peaks at 6 - 24 hr with similar deposition patterns in cell- or patient-derived xenografts. Liposomes are predominantly taken up by macrophages and to a lesser extent by tumor or other stromal cells. DNA damage is mostly confined to tumor cells, a majority of which have not internalized liposomes. DNA damage and apoptosis are seen only minimally in non-tumor cells even when displaying high liposome uptake. Conclusions: nal-IRI improves tumoral deposition of its payload in pancreatic tumor models. Deposition is heterogeneous and restricted to perivascular areas. DNA damage predominantly in tumor cells outside of the liposomal deposition area suggests sufficient intratumoral levels of the SN-38 active metabolite, possibly after payload release by stromal macrophages and concomitant conversion. Effects of repeated dosing cycles should be explored.

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Abstract 1970: Preclinical candidate TQB3824, a small molecule inhibitor of CDC7, shows strong antitumor efficacy in colorectal and pancreatic tumor models

10.1158/1538-7445.am2021-1970 ◽

2021 ◽

Author(s):

Gang Li ◽

Xiquan Zhang ◽

Ling Yang ◽

Xin Tian ◽

Zhong xiong ◽

...

Keyword(s):

Small Molecule ◽

Pancreatic Tumor ◽

Small Molecule Inhibitor ◽

Antitumor Efficacy ◽

Tumor Models ◽

Molecule Inhibitor

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In vivo bioluminescence tomography-guided radiation research platform for pancreatic cancer: an initial study using subcutaneous and orthotopic pancreatic tumor models

Optics and Ionizing Radiation ◽

10.1117/12.2546503 ◽

2020 ◽

Author(s):

Zijian Deng ◽

Xiangkun Xu ◽

Hamid Dehghani ◽

Juvenal Reyes ◽

Lei Zheng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Tumor ◽

Initial Study ◽

Tumor Models ◽

Bioluminescence Tomography ◽

Research Platform ◽

Radiation Research

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Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach

PLoS ONE ◽

10.1371/journal.pone.0260186 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0260186

Author(s):

Marta Braga ◽

Chee Hau Leow ◽

Javier Hernandez Gil ◽

Jin H. Teh ◽

Laurence Carroll ◽

...

Keyword(s):

Pet Imaging ◽

Microvessel Density ◽

Ex Vivo ◽

Cost Effective ◽

Cxcr4 Expression ◽

Attractive Alternative ◽

Tumor Models ◽

Chemokine Receptor 4 ◽

And Control ◽

Vascular Compartment

The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40–60 min post-injection between the two tumor models (p<0.05). Ex vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature.

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