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Abstract

Purpose: 

Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.

Experimental Design:

We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.

Results: 

AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.

Conclusions:

These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy.

Author information

Prabakaran PJ1, Javaid AM1, Swick AD1, Werner LR1, Nickel KP1, Sampene E2,3, Hu R3,4, Ong IM2,3, Bruce JY3,5, Hartig GK3,6, Wieland AM3,6, Canon J7, Harari PM1,3, Kimple RJ8,3.

1 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health Madison, Madison, Wisconsin.

2 Department of Biostatistics, University of Wisconsin School of Medicine and Public Health Madison, Madison, Wisconsin.

3 University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health Madison, Madison, Wisconsin.

4 Department of Pathology, University of Wisconsin School of Medicine and Public Health Madison, Madison, Wisconsin.

5 Department of Medicine, University of Wisconsin School of Medicine and Public Health Madison, Madison, Wisconsin.

6 Department of Surgery, University of Wisconsin School of Medicine and Public Health Madison, Madison, Wisconsin.

7 Oncology Research, Amgen, Inc., Thousand Oaks, California.

8 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health Madison, Madison, Wisconsin. rkimple@humonc.wisc.edu.