Abstract B48: Animal models in use by the NCI PREVENT Cancer Preclinical Drug Development Program

Abstract

Abstract The Chemopreventive Agent Development Research Group in the Division of Cancer Prevention at the National Cancer Institute administers the PREVENT Program to facilitate the development of cancer preventive interventions, including chemical and immunologic agents, and biomarkers for potential use in clinical trials (https://prevention.cancer.gov/major-programs/prevent-cancer-preclinical). Recent technologic advances have enabled generation of newer preclinical animal models, which recapitulate the tumorigenic process of human cancers and have become the mainstay for translational research, as these models may be more likely to provide clinically translatable observations. Several carcinogen-induced rat and mouse models, along with genetically engineered mouse (GEM) and other transgenic animal models, are at the forefront of evaluating cancer-preventive efficacy of drugs and vaccines in various organ sites. A wide array of organ-specific animal cancer models is in use for agent efficacy and toxicity evaluations through the PREVENT program. Key characteristics of these animal models adopted by PREVENT studies include relevance to human cancers such as organ site pathology, involvement of genetic or carcinogenic drivers, and transformation of precursor lesions, as well as a consistent tumor burden within a well-defined time period. Examples of organ site–specific animal models employed by the PREVENT studies include GEM/transgenic models: BRCA1ex11, TgMMTV-neu, TgN(C3-1-TAg)cJeg, MMTV-PPARδ BRCA1co/co, MMTVCre+/+, p53 (breast); APCMin/+, B6-Msh2loxP/loxP,Tg(Vil-Cre), AKRMin/+, ApcMin/FCCC, PIRC (Rat) (colon); AJp53wt/A135V, Trp53F2-10/F2-10, Rb1F19/F19, Adeno-Cre, A/J-ULp53, FVB-CCSPKrasG12D, B6-CCSP-EGFRL858R (lung); Asc−/−, Nf2+/−,Cdkn2a+/− (mesothelioma); LSL-KrasG12D/+ , p48Cre/+, Pdx1Cre, Ptf1Cre, SMAD4-/-, Trp53R172H, Ptf1aCreERTM, hMuc1, LSL-KrasG12V, ROSA_rtTA, p53L/+, iKRasG12D/+ (pancreas); TRAMP, PtenKO, Ptenflox/flox.R26ERG(CreERT2) (prostate); Dicer-/-, Pten-/-, Amhr2+/-, Ad-mCherry-Cre (ovarian); and the carcinogen induced cancer models: MNU, DMBA (breast); OH-BBN (bladder); AOM (colon); NNK, B[a]p, NTCU (lung); asbestos (mesothelioma), MNU (prostate); and 4NQO (head and neck). Agents/drugs that have been or are being evaluated for cancer-preventive efficacy using these models include chemoprevention agents: A438079, AR-509, AZ10606120, Aspirin, Atorvastatin, Bazedoxifene, Bexarotene, Brevail, Budesonide, Ciclesonide, ED-71, ERB-041, Erlotinib, Gefitinib, GLG-302, Gugglesterone, GW274150, INT-747, JNJ-26070109, Lapatinib, Licofelone, LFA9, LY500307, Metformin, Naproxen, Omeprazole, Onc-201, Pioglitazone, PX-102, Rapamycin, SC144, SD-6010, ShetA2, Selumitenib, SR-3029, Sulindac, YS-121, XL-147 and YF476; and immuno-prevention vaccines (DNA, peptide, protein): Plac1, α-enolase, Neu, IGF-1R, IGFBP-2, anti-Fusobacterium nucleatum vaccine, TERT, multivalent-peptide, DLK1, KRAS, EGFR, Muc1, α-enolase, and mesothelin vaccines. Results from these studies will provide important data that will inform “go/no go” decisions in terms of advancing agents towards clinical trials targeting high-risk populations at the early stages of cancer development. Through the PREVENT program, different strategies including alternative dosing, lower dose drug combinations, and drug/vaccine combinations are being developed with the goal to minimize toxicity and improve efficacy. Importantly, the next generation of organ-site-specific inducible GEM models may allow for agent intervention at different stages of cancer development in adult animals representing human pathologies. We will present selected efficacy and mechanistic data for various chemopreventive agents/vaccines tested using these preclinical animal models. Acknowledgments: These studies have been conducted by academic/industrial contract Principal Investigators as part of the NCI PREVENT Program. Citation Format: Altaf Mohammed, Mark Steven Miller, Elizabeth Glaze, Romaine I. Fernando, Jennifer Fox, Ronald A. Lubet, Shizuko Sei, Robert H. Shoemaker. Animal models in use by the NCI PREVENT Cancer Preclinical Drug Development Program [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B48.