Late Intervention with anti-BRAFV600E Therapy Induces Tumor Regression in an Orthotopic Mouse Model of Human Anaplastic Thyroid Cancer

Abstract

Human anaplastic thyroid cancer (ATC) is a lethal disease with an advanced clinical presentation and median survival of 3 months. The BRAF(V600E) oncoprotein is a potent transforming factor that causes human thyroid cancer cell progression in vitro and in vivo; therefore, we sought to target this oncoprotein in a late intervention model of ATC in vivo. We used the human ATC cell line 8505c, which harbors the BRAF(V600E) and TP53(R248G) mutations. Immunocompromised mice were randomized to receive the selective anti-BRAF(V600E) inhibitor, PLX4720, or vehicle by oral gavage 28 d after tumor implantation, 1 wk before all animals typically die due to widespread metastatic lung disease and neck compressive symptoms in this model. Mice were euthanized weekly to evaluate tumor volume and metastases. Control mice showed progressive tumor growth and lung metastases by 35 d after tumor implantation. At that time, all control mice had large tumors, were cachectic, and were euthanized due to their tumor-related weight loss. PLX4720-treated mice, however, showed a significant decrease in tumor volume and lung metastases in addition to a reversal of tumor-related weight loss. Mouse survival was extended to 49 d in PLX4720-treated animals. PLX4720 treatment inhibited cell cycle progression from 28 d to 49 d in vivo. PLX4720 induces striking tumor regression and reversal of cachexia in an in vivo model of advanced thyroid cancer that harbors the BRAF(V600E) mutation.

p53 constrains progression to anaplastic thyroid carcinoma in a Braf -mutant mouse model of papillary thyroid cancer

“…Previous studies using MAPK pathway inhibitors in ATC had relied upon highly passaged human ATC cells in culture or transplanted into immunocompromised mice (16,31,32). Our results demonstrating an incomplete response of mATCs to PLX4720 are consistent with the reduced sensitivity of a variety of human thyroid carcinoma cell lines to MAPK pathway inhibition in cultured conditions.…”

PAX8 is expressed in anaplastic thyroid carcinoma diagnosed by fine-needle aspiration: a study of three cases with histological correlates

“…Fine-needle aspiration (FNA) is important in the management of ATCs for at least two reasons: first, patients often present with an advanced stage of disease, thereby precluding surgery as a first therapeutic choice (1), and second, the diagnosis of ATCs by FNA can help in the triaging of patients for BRAF mutational testing so that targeted therapy can be initiated in case of a positive result (3,4,5). However, in most cases, only undifferentiated cells are aspirated.…”

Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities

“…[66][67][68][69] In the recent past, a number of transgenic mice have been developed that mimic ATC in vivo [70][71][72][73] and serve as much more clinically relevant models for preclinical testing. These models have primarily been used to elucidate the hypothesis that ATCs arise as a progression from PTC or FTC due to hits to multiple signaling pathways and therefore provide the closest simulation environment reflective of direct in human testing.…”