In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 16_Supplement ( 2016-08-15), p. A06-A06
Abstract:
Introduction: Cutaneous T cell lymphomas (CTCL) represent a heterogeneous group of diseases. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes of CTCL. Discovery of new therapeutic targets in T cell lymphomas has been hampered by lack of appropriate discovery platforms. Few T cell lymphoma cell lines are available; and it is likely that they have departed significantly from the original disease through long-term in vitro cultivation. Objectives: To develop patient-derived T cell lymphoma mouse xenograft models (PDX) that recapitulate the clinical presentation of human diseases and to establish a drug discovery platform using these PDX models. Materials and Methods: To establish PDX models for MF and SS, we injected lymphocytes obtained from patients into an NSG mouse (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) either subcutaneously or intravenously. Next, we investigated whether tumor derived plasma cell-free DNA can serve as a surrogate for disease burden in PDX. We first established this method in xenografts bearing a subcutaneous tumor derived from a MF cell line. We measured tumor volume by manual caliper methods twice weekly and simultaneously, we collected plasma from these mice. We measured human-actin-specific cell-free DNA concentrations in the plasma by qPCR and examined whether they can correlate with the tumor volume measured by the caliber method. After validated this method in xenografts established with a MF cell line, we examined this method in PDX. To this end, we measured human-actin-specific cell-free DNA concentrations in PDX plasma at various time points post-inoculation and investigated whether they correlated with tumor progression in PDX. Results: Three weeks after inoculation of patient-derived malignant lymphocytes, the MF PDX mouse developed clinical syndrome of MF with erythematous, scaly skin lesions and alopecia. Necropsy revealed lymphocyte infiltration in the skin, spleen, liver and lungs, resembling the disease distribution of MF in humans. The erythematous skin lesions showed atypical lymphocyte infiltration in the epidermis, a diagnostic hallmark for MF. Additionally, immunohistochemistry staining reveled malignant cells in the epidermis expressed CD3 and CD4 without co-expression of CD7, which is identical to those of the donor patient's. Furthermore, we analyzed T cell receptor (TCR) clonality by PCR and demonstrated a clonal T-cell population in both patient and mouse specimens with similar amplified peaks, consistent with successful xenograft. Similarly, the PDX mouse for SS developed the clinical syndromes with skin rashes, alopecia and was found to have Sezary cells in the blood, a diagnostic hallmark for SS. Malignant cells isolated from the spleen of a SS PDX animal had the same immunophenotype and TCR clonality as that of the donor patients, indicating successful xenografts. Importantly, we were able to passage malignant cells from one generation of PDX to the next while maintaining the clinical presentation of the disease. Finally, we were able to demonstrate that in cell-line derived xenograft mice bearing subcutaneous tumors, human-actin-specific cell-free DNA concentrations in the plasma correlated with tumor volume assessed by manual caliber measurements. Next, we extended these results to MF/SS PDX, and were able to correlate human-actin cell-free DNA concentrations with tumor progression in in these mice. Conclusion: We established PDX models that recapitulate the clinic syndrome of MF and SS with characteristic skin, nodes and blood involvement by the malignant cells. Additionally, we demonstrated that tumor-specific cell-free DNA concentration can be used as a surrogate for tumor burden in PDX. Together, our results demonstrated that we can establish a drug discovery platform using clinically relevant PDX models for T cell lymphomas. Citation Format: Wei Ai, Yen-Chen Yang Yang, Shervin Afghani, Huaxin Gao, Laura Pincus Pincus, Linlin Wang Wang, Taha Rakhshandhroo, Ronald Balassanian, James Rubenstein, Ryan Gill, Frank McCormick. Development of a drug discovery platform using clinically relevant patient-derived xenograft models for cutaneous T cell lymphomas. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A06.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1557-3265.PDX16-A06
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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