Development and Preclinical Applications of Pancreatic Adenocarcinoma Models

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

CAPR recent progress in pursuing its internal development initiatives in pancreatic disease modelling includes generation and full characterization of three relevant Cre-inducible missense p53 GEM strains in which the non-recombined allele expresses wild type p53 prior to a Cre-driven conversion to a mutant isoform expressing one. The p53aa172 inducible mutant strain has been bred with PDX-Cre and KRASG12D-lsl mice to generate animals that are similar to the KPC model, with the exception that they harbor no null allele prior to expression of p53-172. Development of pancreatic malignancies in these mice (KPwt-172C) is similar to that of KPC mice, except that the ectopic tumors do not develop and PDAC develops with a somewhat shortened latency. Furthermore, orthotopic KPC-PDA GDA models have been established from several KPC-derived primary tumors and demonstrated to develop PDA with characteristics of the parental malignancy. As an intriguing observation, the metastatic rate in such KPC-GDA models has increased to about 70 %, thus potentially enabling studies on mechanisms and treatment of metastatic disease. This high metastatic rate makes this model ideal for evaluating therapies for metastatic disease. As one of the most visible preclinical resource for intramural CCR investigators, CAPR pancreatic program is involved in multiple collaborative initiatives with CCR PI labs. For example, the pancreatic team has recently finalized a large, multi-modular collaborative project with Dr. Udo Rudloff's lab pursuing a comprehensive IND-enabling characterization of metarrestin compound employing both de novo and syngeneic orthotopic transplant models of pancreatic adenocarcinoma (PDAC). Multiple integrated preclinical assessment studies interrogating bioavalability, in vivo toxicity, a spectrum of molecular responses to treatment, as well as efficacy as monotherapy and in combination with gemcitabine standard of care, have been completed and have been used to support the IND submission for metarrestin that has been recently successfully approved paving the way to launch clinical evaluation of metarrestin formulations in first-in-human trials interrogating metarrestin tolerability and anti-cancer efficacy. The results of this joint effort have been published as two collaborative publications co-authored by CAPR scientists. Expanding collaborative relations with Dr. Rudloff's section of the Rare Tumor initiative, CAPR also made significant progress with the second, CAPR Oversight Committee-approved PI initiated study to evaluate another molecule - a biosimilar peptide compound RP-182 - which has shown promise as a potential microenvironment re-modelling factor in PDAC. CAPR has conducted several pilot multi-organ PK studies to explore bioavailability in pancreatic tumors, other PDAC-affected tissues (e.g. lung and liver) and circulation. CAPR has also conducted preclinical efficacy evaluation experiments to assess the anti-tumor potency of RP-182 peptide in KPC model, as well as in orthotopic pancreatic cancer models established using wild-type and CD206-deficient syngeneic recipient animals to confirm the hypothesis of CD206 receptor being a specific target molecule for RP-182 peptide. The position paper reporting on this novel approach in targeting the tumor infiltrating macrophage population polarized by M2 type has been published earlier this year in Science Translational Medicine journal. CAPR pancreatic program has also completed the first part of a collaborative project with Dr. George Pavlakis' laboratory aimed at investigation of immunologic signatures in pancreatic tumors treated with recombinant hetIL-15 cytokine. Pancreatic tumor bearing animals have been subject to dosing with control vehicle compound or with IL-15 and gemcitabine as single drug regimens, or IL-15/Gemcitabine combination therapy. CAPR is currently evaluating the data from this study. Continuing to deliver on its extensive collaborative work with Dr. Christine Alewine, CAPR researchers established a broad allelic series of genetically modified mouse models expressing either chimeric mouse/human mesothelin (MSLN) protein under the transcriptional control of the endogenous mMSLN locus, or a fully human MSLN ortholog in a narrow expression domain in the thyroid gland. Upon extensive molecular characterization, these validated new tools offer immunocompetent models in which recipient animals are either immunologically 'tolerized' against orthologous human MSLN protein or lack MSLN expression in either a constitutive or a conditional manner. These models are currently used for syngeneic allografting studies with PDAC cells expressing humanized MSLN protein to prepare cohorts of tumor bearing animals to assess the efficacy of recombinant immunotoxins designed to recognize human MSLN protein by antibody binding to human MSLN-specific epitopes. To summarize the activities of CAPR pancreatic program, seven collaborative manuscripts have been published in 2019-2021, including two high-profile paper on metarrestin drug development and RP-182 peptide discovery and evaluation as potential therapeutic compound, both appearing in Science Translational Medicine. One of investigational compounds (metarrestin) is currently undergoing clinical testing in Phase I-II study conducted at the CCR Clinical Center. Another drug formulation (a small molecule candidate compound NCGC072) has been characterized in several single- and multi-dose administration pharmacokinetics experiments and is in preparation for the IND application filing.