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57th Annual Meeting Abstracts


Presentation #2

Abstract Title

PLX4720 Reverses Cachexia And Induces Regression Of Anaplastic Thyroid Cancer

Author Block

Matthew A. Nehs, MD, Sushruta Nagarkatti, MD, Carmelo Nucera, MD, Peter M. Sadow, MD, Richard A. Hodin, MD, Sareh Parangi, MD 

Thyroid Cancer Research Laboratory, Division of Endocrine Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Abstract Body

Background: Anaplastic thyroid cancer (ATC) is almost uniformly fatal because of its aggressiveness and late stage at presentation. B-Raf(V600E) is a common mutation implicated in the progression of ATC. We hypothesized that the anti- B-Raf(V600E) compound, PLX4720, would induce regression of late-stage anaplastic thyroid cancer and extend survival in a mouse model.

Methods: We induced orthotopic anaplastic thyroid tumors in 48 SCID mice by injecting mouse thyroids with 8505c cells [B-Raf(V600E)+/+] engineered to express GFP. Mice were randomized to receive either PLX4720 orally or vehicle after 28 days of tumor growth. Six mice were sacrificed weekly; each week, tumor volume, lung metastases, and mouse weight were measured. Histological analysis was performed on all samples.

Results: In control mice, tumor volume and number of lung metastases demonstrated exponential growth until the tumor burden was fatal by 35 days. At that time, all control mice had large tumors (115 mm3 +/- 14 mm3), were cachectic, and were sacrificed due to their tumor-related weight loss (average: 31% decrease from baseline). However, PLX4720-treated mice showed a progressive decrease in tumor volume (down to 9 mm3 +/- 2 mm3 by 49 days) and lung metastases in addition to a reversal of tumor-related weight loss (average: 12% increase in weight). Mouse survival was extended by 40% in PLX4720-treated animals.

Conclusion: PLX4720, as a selective anti-B-Raf(V600E) compound, induces striking tumor regression and reversal of cachexia in an orthotopic mouse model of anaplastic thyroid cancer and may be the first effective treatment for these advanced-stage cancers that harbor this mutation.

 

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