A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches

Abstract

Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model–termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient’s parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a FGFR2 mutation and CCNE2 amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC.

The synergy of 177Lu-FAPI-46 with tyrosine kinase inhibitor in a sarcoma patient-derived xenograft mouse model

“…The protocol was derived from the method published by Lin et al. [ 9 ]. Details regarding the establishment of PDX are provided in the supplementary material.…”

Patient-derived xenograft models in cancer therapy: technologies and applications

“… 39 (84.8%) N/A N/A Chapuy et al 258 Diffuse large B-cell lymphoma (activated B-cell (ABC)-type tumors, germinal B-cell type tumors, and plasmablastic lymphoma) 9 (32%) N/A N/A Baschnagel et al 259 Small cell lung cancer brain metastases (Adenocarcinoma, sarcomatoid carcinoma) 9 (64%) N/A N/A Elst et al 260 Advanced penile cancer (Usual, warty-basaloid, sarcomatoid) 11 (61%) N/A N/A Lilja-Fischer et al 261 Oropharyngeal squamous cell carcinoma (N/A) 12 (35%) N/A N/A Zhang et al 262 B-cell lymphoma (Mantle cell lymphoma, Burkitt’s lymphoma, Follicular lymphoma, Marginal zone lymphoma, etc.) 16 (N/A) N/A N/A Chamberlain et al 263 Pancreatic neuroendocrine tumors (N/A) 1 (N/A) N/A N/A Lin et al 264 Dedifferentiated endometrial carcinoma (N/A) 1 (N/A) N/A N/A …”

Rare Subtype of Endometrial Cancer: Undifferentiated/Dedifferentiated Endometrial Carcinoma, from Genetic Aspects to Clinical Practice

“…The former was targeted with the FGFR inhibitor lenvatinib, while the latter was treated with the cell cycle inhibitor palbociclib in patient-derived xenograft (PDX) mice with UDEC. Compared with control mice, the tumor shrank significantly in the treatment arm [ 55 ]. The first approved FGFR2 inhibitor, pemigatinib, for treating cholangiocarcinoma [ 56 ] is now used in recurring FGFR -mutated solid tumors, including EC (NCT02393248, FIGHT-101).…”

“…( C , D ) Defects in MMR and the increased expression of PDL1 could be a target for immune checkpoint inhibitors [ 8 , 29 , 69 , 72 ]. ( E ) Mutations in FGFR2 and the amplification of CCNE2 could be a target for lenvatinib and Palbociclib [ 55 ]. ( F ) Mutation in TP53 could be a target for APE-246 and Wee1 kinase inhibitor [ 73 ].…”