Development of Novel Informative Preclinical Animal Models - CAPR Infrastructure

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

During past several months, CAPR researchers working under the guidance of the Center's Oversight Committee, composed of impactful CCR senior investigators and lead oncology specialists, embarked on novel initiatives aimed at developing additional clinically relevant cancer models, including PDX models for small cell lung carcinomas, Ewing sarcomas, neuroendocrine tumors of the gastrointestinal tract, high-grade brain malignancies, Kaposi sarcomas, etc. At the same time, new genetically engineered alleles have been established and validated for subsequent use in modelling pancreatic acinar cell carcinoma, papillary and anaplastic thyroid carcinomas, and plexiform neurofibromas. In addition, to respond to recommendations of the recent site visit review panel, CAPR launched efforts to convert in vivo several cancer-related murine alleles into ones expressing orthologous human molecules with a foresight of exploring such genetically "humanized" GEM tools in preclinical evaluation workflows aimed at assessment of anti-cancer biologicals or cell-based therapeutic formulations selectively interacting with human, but not mouse, target isoform. CAPR program continuously advances its mission of supporting the intramural CCR scientific community seeking access to informative cancer models and preclinical expertise in drug development. To date, six rounds of applications have been invited, reviewed and most promising projects selected by the CAPR Oversight Committee. About 10 of these projects have been in various stages of development or completing over the course of the last year. The key highlights of activities aimed at building and evaluating novel translational resources for preclinical experimentation with candidate cancer therapeutics include: 1. Development and characterization of a panel of surgical melanoma models suitable for tumor resection to examine biomaterial-assisted repair processes augmented by anti-PD1 immunooncology intervention. Such scaffold-implemented surgery procedures have been optimized, also in conjunction with the complementary study logistics, tissue biobanking, and histopathology-based biomarker evaluation. 2. Generation of n-Myc overexpressing xenograft animal models developing cancerous lesion sin the central nervous system. These models prove themselves instrumental in determining the synergistic signatures of several therapeutic formulations, including DRD2/3/4 antagonist ONC206 and S-adenosylhomocysteine hydrolase inhibitor DZNep-HCl. 3. Adopt and optimized for effective preclinical workflows GEMM mouse models expressing HrasG12S oncogene. Studies in these animals contributed to mechanistic understanding of RASopathy type of tumors, as well as assisted in analyses of organogenesis and behavioral phenotypes characteristic for patients with Costello syndrome. 4. Multiple biopsies, of both skin and GI tract origins, collected in patients with Kaposi sarcomas have been implanted in immunodeficient recipients to establish pdx models for this malignancy that is characterized by clear paucity of clinically relevant in vivo models. 5. Over 30 clinical small cell lung cancer (SCLC) biopsies have been implanted, expanded and banked to develop a rich collection of SCLC pdx models for ongoing and future development of therapeutic option for this highly clinically challenging malignancy type. 6. Constituent alleles have been established and extensively characterized to assemble a one-of-a-kind model for pancreatic acinar cell carcinoma (PACC). By combining conditional loss of Id3 and APC tumor suppressor genes with a transgenic allele expressing Cre recombinase in acinar cells, we seek to establish an unmet need model for pancreatic malignancy type that is frequently overlooked in drug development efforts to target pancreatic carcinogenesis.