Abstract A9: Bioluminescent orthotopic PDX models of primary pancreatic cancer and residual/metastatic breast cancer predict efficacy of standard of care and experimental treatments
Authors: Cuiffo Benjamin G. , Deas Olivier , Lyng Gregory D. , Cairo Stephano , Le Ven Enora , Judde Jean-Gabriel , Sonis Stephen T. 
Published: May 2016

Background: Only 5% of investigational anti-cancer agents are ultimately clinically successful. This may be attributed in part to the historical preclinical use of human cell lines that poorly recapitulate tumor heterogeneity in imperfect xenograft models. To model critical influences of tissue environment on tumor behavior and therapeutic response, heterogeneous patient-derived xenografts (PDX) can be assayed following implantation at orthotopic sites in rodents. Challenges to this approach include inaccessibility of certain organs or inability to track residual or metastatic disease. To address these problems, we utilized pancreatic (PANx-005) or metastatic breast (HBCx-14) PDXs transduced with stable bioluminescent reporters in efficacy studies of standard of care (SOC) and experimental treatments in clinically recapitulative models.

Methods: Freshly excised PDXs were transduced with lentiviral vectors stably expressing luciferase, and implanted orthotopically into NOD scid gamma (NSG) mice. For our primary pancreatic cancer model, the pancreas was surgically exposed, and ∼2.5 × 106 PANx-005-Luc cells were inoculated directly. Post-op, tumor growth was monitored in-life (Xenogen IVIS® Lumina Series III instrument (IVIS)). Mice were randomized into treatment groups when mean tumor radiance (TR) reached 3.0 × 106 photons/sec. Control animals received no treatment; SOC groups received either focused fractionated radiation (12 Gy as 3×4 Gy fractions, Q5D (SRT)) or gemcitabine (75 mg/kg, 2QWx4, i.p.), and the experimental group received (+)-JQ-1 BET bromodomain inhibitor (50 mg/kg, QD, i.p.). For the residual/metastatic breast cancer model, ∼1.5 × 106 HBCx-14-Luc were injected directly into the 4th inguinal mammary fat pad. Tumor growth and response were monitored throughout the study by IVIS. When individual TR reached 7.5 × 109 photons/sec, the primary tumor was resected and the animal enrolled into a treatment group to be treated for residual/metastatic disease. Control animals received no treatment; SOC groups received either SRT, capacetabine (540 mg/kg QDx5/ 1week rest, p.o.) or docetaxel (20 mg/kg, Q3Wx2, i.p.); while experimental animals received (+)-JQ-1 (50 mg/kg, QD, i.p.).

Results: Tumor seeding approached 100% in both models. Growth kinetics resembled clinical indications, including rapid growth and lung metastases for the HBCx-14 tumors, and slower growth of PANCx-005 tumors. Efficacies of individual treatments recapitulated clinical responses: HBCx-14 tumors were high responders to capecitabine and (+)-JQ-1, and low-responders to docetaxel, while PANx-005 tumors displayed high response to (+)-JQ-1 and lower response to gemcitabine.

Conclusions: The translational predictivity of preclinical cancer models is enhanced by the use of human PDXs that preserve tumor heterogeneity, are assayed at orthotopic sites, and are utilized in models that recapitulate clinical situations (e.g. treatment of residual disease vs primary tumor). The use of stable bioluminescent reporters in such assays greatly enhances precision in monitoring tumor growth and treatment response. Currently available preclinical oncology models are more recapitulative, precise and predictive than ever before, and appear poised to engender improved translational success.

Citation Format: Benjamin G. Cuiffo, Olivier Deas, Gregory D. Lyng, Stephano Cairo, Enora Le Ven, Jean-Gabriel Judde, Stephen T. Sonis. Bioluminescent orthotopic PDX models of primary pancreatic cancer and residual/metastatic breast cancer predict efficacy of standard of care and experimental treatments. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A9.