Animal Models and Their Role in Imaging-Assisted Co-Clinical Trials - PubMed (original) (raw)

Review

. 2023 Mar 16;9(2):657-680.

doi: 10.3390/tomography9020053.

Cristian T Badea 2, Thomas L Chenevert 3, Heike E Daldrup-Link 4, Li Ding 5, Lacey E Dobrolecki 6, A McGarry Houghton 7, Paul E Kinahan 8, John Kurhanewicz 1, Michael T Lewis 9, Shunqiang Li 5, Gary D Luker 3 10, Cynthia X Ma 5, H Charles Manning 11, Yvonne M Mowery 12 13, Peter J O'Dwyer 14, Robia G Pautler 15, Mark A Rosen 14 16, Raheleh Roudi 4, Brian D Ross 3 17, Kooresh I Shoghi 18, Renuka Sriram 1, Moshe Talpaz 19 20, Richard L Wahl 18, Rong Zhou 14 16

Affiliations

Review

Animal Models and Their Role in Imaging-Assisted Co-Clinical Trials

Donna M Peehl et al. Tomography. 2023.

Abstract

The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients' tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant optimization is quantitative imaging. The National Cancer Institute has organized a Co-Clinical Imaging Resource Program (CIRP) network to establish best practices for co-clinical imaging and to optimize translational quantitative imaging methodologies. This overview describes the ten co-clinical trials of investigators from eleven institutions who are currently supported by the CIRP initiative and are members of the Animal Models and Co-clinical Trials (AMCT) Working Group. Each team describes their corresponding clinical trial, type of cancer targeted, rationale for choice of animal models, therapy, and imaging modalities. The strengths and weaknesses of the co-clinical trial design and the challenges encountered are considered. The rich research resources generated by the members of the AMCT Working Group will benefit the broad research community and improve the quality and translational impact of imaging in co-clinical trials.

Keywords: animal models; breast cancer; co-clinical trials; colorectal cancer; imaging; lung cancer; myelofibrosis; osteosarcoma; pancreatic cancer; prostate cancer; sarcoma.

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Conflict of interest statement

The authors declare no conflict of interest. H.E.D.L. is a co-inventor on patents assigned to and managed by the University of California, Stanford University, and Bradford University and receives materials from MegaPro Biomedical Co. Ltd. (Zhubai City, Taiwan). L.E.D. is a compensated employee of StemMed Ltd. (Houston, TX, USA) and receives royalty income from StemMed Ltd. M.T.L. is a founder and limited partner in StemMed Ltd., a manager in StemMed Holdings, its general partner, and receives royalty income from StemMed Ltd. He is a founder and equity stakeholder in Tvardi Therapeutics, Inc. (Houston, TX, USA). S.L. has received license fees from Inotiv, Inc. (West Lafayette, IN, USA). G.L. has received research materials from Spexis. C.X.M. reports relationships with Agendia, AstraZeneca Pharm., Athenex, Bayer Healthcare Pharm., Eli Lilly and Comp. (Indianapolis, IN, USA), Guardant Health, Novartis Pharma AG, Olaris Inc. (Framingham, MA, USA), Pfizer Inc., Plus One Health GmbH, Sanofi-Genzyme, Seattle Genetics Inc. (Bothell, WA, USA), Tempus, and Wolters Kluwer. Y.M.M. has received research funding and pembrolizumab through institutional funding from Merck. R.LW. serves on the scientific advisory board of Clarity Pharmaceuticals, is a consultant, and receives stock options; is the clinical advisory board chair of Voximetry and receives stock options; and serves on scientific advisory boards and consults for BMS, Jubilant Draximage, Radiopharm, Siemens, Bayer, White Rabbit AI, and ITM.

Figures

Figure 1

Figure 1

The UCSF co-clinical project schema. The project focuses on assessing the response of SCNC to standard-of-care platinum-based chemotherapy using HP [1-13C]pyruvate MRI. The co-clinical project uses three established SCNC PDX that are propagated in the murine kidney, digested into single cells, and inoculated in the murine tibia and liver to match the metastatic SCNC patient population under study in the clinical trial. Upon reaching a volume of ~0.3 cc, assessed by MRI, tumors are characterized by baseline dynamic HP [1-13C]pyruvate MRI and mp-MRI. Following one cycle of treatment with carboplatin or placebo, tumors are again evaluated by combined dynamic HP [1-13C]pyruvate MRI and mp-MRI to investigate the reduction in the HP 13C MRI metric (apparent rate of conversion of [1-13C]pyruvate to [1-13C]lactate, kPL) as an early marker of response to chemotherapy. As a part of both clinical and pre-clinical protocols, kPL maps are overlaid on the corresponding T2 weighted anatomic images and correlated with changes in ADC images and tumor growth rate with treatment.

Figure 2

Figure 2

Examples of MRI and micro-CT images in the p53/MCA model and the schematics of the preclinical arm of the clinical trial.

Figure 3

Figure 3

Scheme of the co-clinical trial. Patients with WT KRAS CRC and immunocompromised nude mice bearing WT KRAS CRC PDX tissues receive the therapy with combined panitumumab and CB-839. Tumors are imaged pre- and post-treatment with 11C-glutamine/18F-glutamine and 18F-FSPG. Complementary to genomic approaches, a PET imaging-derived gene signature associated with treatment response is established.

Figure 4

Figure 4

The Stanford co-clinical trial design.

Figure 5

Figure 5

Co-clinical trial design for assessing MRI markers of tumor microenvironment changes in pancreatic cancer in response to a stroma-directed drug combined with chemo and immune checkpoint inhibitor.

Figure 6

Figure 6

ADC maps (upper row) and Ktrans maps (bottom row) of PDA tumor from a KPC mouse. Parametric maps are overlaid on T2W images and displayed in pseudo color using the color bars on the right. Suitable phantoms for DW- and DCE-MRI are scanned with the mouse for quality control.

Figure 7

Figure 7

Bone marrow transplant model for myelofibrosis in mice. Baseline spleen and bone marrow MRI data are obtained prior to transplantation. To generate mice with myelofibrosis (MF), normal donor hematopoietic stem and progenitor cells (HSCs) are transduced with a known driver mutation. Transduced HSCs are transplanted into recipient mice after myeloablative irradiation, using bone marrow MRI and spleen volume to quantify disease progression and response to therapy. The same MRI methods are used for clinical studies in patients with MF.

Figure 8

Figure 8

(A) Clinical imaging protocol and (B) preclinical imaging protocol to assess response to carboplatin/docetaxel therapy in TNBC.

Figure 9

Figure 9

Co-clinical study design. (A) Multicenter clinical imaging trial to predict response to ET using ΔFFNP-PET in patients with advanced ER+/HER- BCa. Tissue biopsies will be used for genopro-teomic discovery and to generate PDX. (B) The preclinical PDX imaging protocol to assess the efficacy ΔFFNP-PET and FES-PET in predicting response to Fulvestrant and Abemaciclib, alone and in combination, followed by pathology and genoproteomic discovery.

Figure 10

Figure 10

High-level schematic of co-clinical trial using PET imaging to develop image-based response criteria for preclinical studies of immune checkpoint inhibitor therapies in non-small cell lung cancer.

References

    1. Shoghi K.I., Badea C.T., Blocker S.J., Chenevert T.L., Laforest R., Lewis M.T., Luker G.D., Manning H.C., Marcus D.S., Mowery Y.M., et al. Co-Clinical Imaging Resource Program (CIRP): Bridging the Translational Divide to Advance Precision Medicine. Tomography. 2020;6:273–287. doi: 10.18383/j.tom.2020.00023. -DOI -PMC -PubMed
    1. Zhou J., Ding J., Qi J. Comparison of Typical Prostate Adenocarcinoma and Rare Histological Variant Prostate Cancer Showed Different Characteristics and Prognosis: A Surveillance, Epidemiology, and End Results Database Analysis. Eur. Urol. 2022;82:152–155. doi: 10.1016/j.eururo.2022.02.006. -DOI -PubMed
    1. Nguyen H.M., Vessella R.L., Morrissey C., Brown L.G., Coleman I.M., Higano C.S., Mostaghel E.A., Zhang X., True L.D., Lam H.-M., et al. LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease And Serve as Models for Evaluating Cancer Therapeutics. Prostate. 2017;77:654–671. doi: 10.1002/pros.23313. -DOI -PMC -PubMed
    1. Shi M., Wang Y., Lin D., Wang Y. Patient-Derived Xenograft Models of Neuroendocrine Prostate Cancer. Cancer Lett. 2022;525:160–169. doi: 10.1016/j.canlet.2021.11.004. -DOI -PubMed
    1. Gao B., Klumpen H.-J., Gurney H. Dose Calculation of Anticancer Drugs. Expert. Opin. Drug. Metab. Toxicol. 2008;4:1307–1319. doi: 10.1517/17425255.4.10.1307. -DOI -PubMed

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