Predicting HCC Response to Multikinase Inhibitors With In Vivo Cirrhotic Mouse Model for Personalized Therapy

Abstract

Background & Aims Hepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of multikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy. Methods Cirrhosis was induced in NOD Scid gamma mice with 4 months of thioacetamide administration. Patient derived xenografts (PDXs) were created by transplant of human HCC subcutaneously into non-cirrhotic mice and intra-hepatically into both cirrhotic and non-cirrhotic mice. The applicability of cirrhotic PDXs for drug testing was tested with 16 days of either sorafenib or lenvatinib. Treatment response was evaluated by MRI. Results 8 out of 19 (42%) human HCC engrafted in the cirrhotic model compared with only 3 out of 19 (16%) that engrafted in the subcutaneous non-cirrhotic model. Tumor vasculature was preserved in the cirrhotic model but was diminished in the non-cirrhotic models. Metastasis developed in 3 cirrhotic PDX lines and was associated with early HCC recurrence in all 3 corresponding patients (100%), compared with only 5 out of 16 (31%) of the other PDX lines, P = .027. The cirrhotic model was able to predict response and non-response to lenvatinib and sorafenib respectively in the corresponding patients. Response to lenvatinib in the cirrhotic PDX was associated with reduction in CD34, VEGFR2 and CLEC4G immunofluorescence area and intensity (all P ≤ .03). Conclusions A clinically relevant cirrhotic PDX model preserves tumor angiogenesis and allows prediction of response to multikinase inhibitors for personalized therapy.

In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling

“…The use of syngeneic and xenographic models has been widely used in studies of the combination of drugs used in HCC therapy, such as sorafenib, and drugs that enhance its effects by reducing tumor resistance to treatment [ 272 , 385 , 386 , 387 ], in immunotherapeutic studies [ 273 , 388 , 389 , 390 ] and new drug trials [ 391 , 392 ]. In the context of the combination of drugs with known potentialities, chemical induction of HCC by DEN in Fisher and Wistar rats (50 mg/kg, once a week, for 12–14 weeks) was used respectively to evaluate the effects of treatment with sorafenib + ARQ (AKT inhibitor) and sorafenib + fluvastatin (cholesterol-lowering), showing that the combination of drugs increased apoptosis, reducing cell proliferation, angiogenesis and activation of HSC [ 393 , 394 ].…”

“…On the other hand, studies also associate the carcinogenic action of DEN with the fibro-cirrhotic capacity of CCl 4 in the chemo [ 397 ] and immunotherapeutic tests [ 398 ]. TAA has also been used in preclinical tests in mice (200 mg/Kg ip or 200 mg/L in drinking water) associated or not with syngeneic and xenographic models, enabling the evaluation of drugs with known or promising potential, chemo or immunotherapy [ 386 , 388 , 399 ].…”

“…Genetic engineering enabled the creation of transgenic animals with structural and metabolic alterations totally directed to the specificity of the questions formulated for the object of study. In the preclinical researches of HCC, these animals can be inserted in different models, directing the results to a specific signaling pathway both in the testing of new drugs [ 386 , 388 , 396 , 397 ] and in new therapies [ 388 , 389 , 390 , 398 ].…”

“…The results not only proved the efficient destruction of CPC3 positive cells but also proved that CPC3 is not present in normal cells and can be an HCC-specific antigen and, therefore, an excellent therapeutic target [ 390 ]. Currently, preclinical studies combine numerous tools such as liver cell lines, syngeneic and xenographic models, chemical induction and transgenic animals [ 386 , 388 , 393 , 396 , 397 , 399 ] in search of treatment alternatives for HCC.…”

Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria: a meta-analysis of 18,421 patients

“…Liver transplantation (LT) and liver resection (LR) are first line options for curative treatment of HCC (4)(5)(6). LT treats both the tumour and the surrounding cirrhotic microenvironment (7,8). It is associated with excellent long-term survival outcomes (9)(10)(11).…”