Therapeutic and immunomodulatory potential of pazopanib in malignant phyllodes tumor.

Autor: Ng DYX; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.; Duke-NUS Medical School, Singapore, Singapore., Li Z; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore., Lee E; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.; Division of Medical Oncology, National Cancer Centre, Singapore, Singapore., Kok JST; Cancer Discovery Hub, National Cancer Centre, Singapore, Singapore., Lee JY; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore., Koh J; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.; Institute of Molecular and Cellular Biology, Singapore, Singapore., Ng CC; Cancer Discovery Hub, National Cancer Centre, Singapore, Singapore., Lim AH; Cancer Discovery Hub, National Cancer Centre, Singapore, Singapore., Liu W; Cancer Discovery Hub, National Cancer Centre, Singapore, Singapore., Ng SR; Institute of Molecular and Cellular Biology, Singapore, Singapore., Lim KS; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore., Huang XX; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore., Hong JH; Duke-NUS Medical School, Singapore, Singapore.; Institute of Molecular and Cellular Biology, Singapore, Singapore., Guan P; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.; Laboratory of Biodiversity Genomics, Genome Institute of Singapore, Singapore, Singapore., Sim Y; Department of Breast Surgery, Division of Surgical Oncology, National Cancer Centre, Singapore, Singapore.; Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.; SingHealth Duke-NUS Breast Centre, Singapore, Singapore., Thike AA; Division of Pathology, Singapore General Hospital, Singapore, Singapore., Nasir NDM; Division of Pathology, Singapore General Hospital, Singapore, Singapore., Li S; Duke-NUS Medical School, Singapore, Singapore., Tan PH; Duke-NUS Medical School, Singapore, Singapore. tan.puay.hoon@singhealth.com.sg.; Division of Pathology, Singapore General Hospital, Singapore, Singapore. tan.puay.hoon@singhealth.com.sg., Teh BT; Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore. teh.bin.tean@singhealth.com.sg.; Duke-NUS Medical School, Singapore, Singapore. teh.bin.tean@singhealth.com.sg.; Institute of Molecular and Cellular Biology, Singapore, Singapore. teh.bin.tean@singhealth.com.sg.; Laboratory of Biodiversity Genomics, Genome Institute of Singapore, Singapore, Singapore. teh.bin.tean@singhealth.com.sg., Chan JY; Duke-NUS Medical School, Singapore, Singapore. jason.chan.y.s@nccs.com.sg.; Division of Medical Oncology, National Cancer Centre, Singapore, Singapore. jason.chan.y.s@nccs.com.sg.; Cancer Discovery Hub, National Cancer Centre, Singapore, Singapore. jason.chan.y.s@nccs.com.sg.
Jazyk: angličtina
Zdroj: NPJ breast cancer [NPJ Breast Cancer] 2022 Apr 01; Vol. 8 (1), pp. 44. Date of Electronic Publication: 2022 Apr 01.
DOI: 10.1038/s41523-022-00413-1
Abstrakt: Malignant phyllodes tumors (PT) are rare aggressive fibroepithelial neoplasms with high metastatic potential and lack effective therapy. We established a patient-derived xenograft (PDX) and cell line model (designated MPT-S1) of malignant PT which demonstrated clinical response to pazopanib. Whole exome sequencing identified somatic mutations in TP53, RB1, MED12, and KMT2D. Immunohistochemistry and genomic profiles of the tumor, PDX and cell line were concordant. In keeping with clinical observation, pazopanib reduced cell viability in a dose-dependent manner and evoked apoptosis, and led to significant abrogation of in vivo tumor growth. Whole transcriptomic analysis revealed that pazopanib decreased expression of genes involved in oncogenic and apoptosis signaling. We also observed decreased expression of ENPP1, with known roles in cancer invasion and metastasis, as well as STING pathway upregulation. Accordingly, pazopanib induced micronuclei formation, and evoked phospho-TBK1 and PD-L1 expression. In an additional cohort of malignant PT (n = 14), six (42.9%) showed comparable or higher levels of ENPP1 relative to MPT-S1, highlighting its potential role as a therapeutic target. In conclusion, we established MPT-S1, a new PDX and cell line model, and provided evidence for the clinical efficacy of pazopanib in malignant PT.
(© 2022. The Author(s).)
Databáze: MEDLINE
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