Project Details
Projekt
The role and target potential of IGF2BP1 in ovarian cancer progression and immune evasion
Applicant
Dr. Nadine Bley
Subject Area
Hematology, Oncology
Cell Biology
Cell Biology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 468534282
High-grade serous ovarian carcinoma (HGSC) is the most common and deadliest cancer of the female reproductive tissue. Relapse rates are high and resistance to chemotherapy is frequently observed. Defects in the DNA damage response are crucial for the efficacy of the standard treatment with platinum reagents or recently approved PARP inhibitors. Although, immune therapy is considered for HGSC treatment, success rates of checkpoint inhibitors are less than for other cancer types, due to the lack of sufficient identification of responding patients. Transcriptome studies (TCGA, AOCS) identified four molecular HGSC-subtypes with distinct gene expression signatures and patient outcome. The C5 subtype is associated with poor prognosis and characterized by a mesenchymal trans-differentiation, enhanced DNA repair, elevated proliferation and immune evasion. Based on the RBP (RNA binding protein) census, we determined a set of eight oncofetal RBPs among the most up-regulated genes in the C5 subtype of HGSC in two independent datasets. Using a functional siRNA screen against these eight oncoRBPs, we identified IGF2BP1, as the most potent modulator of invasion, DNA damage and immune escape. IGF2BP1’s major role in cancer cells is to protect target transcripts from microRNA-mediated degradation. Thereby, the protein enhances the expression oncogenes like MYC/N, HMGA2, KRAS or E2F1 promoting tumor cell proliferation, invasion and metastasis. In preliminary studies, we observed that IGF2BP1 impairs MHCI presentation and at the same time enhances the synthesis of the T cell inhibitor PD-L1, promoting evasion from T cell directed tumor cell killing. In addition, preliminary studies strongly suggest that IGF2BP1 is a post-transcriptional modulator of the DNA Damage Response in HGSC tumor models. These roles of IGF2BP1 appear druggable by an IGF2BP1-directed small molecule inhibitor. Collectively, this indicates that IGF2BP1 is a versatile post-transcriptional enhancer of tumorigenic properties in the C5 subtype of HGSC and a bona fide therapeutic target in HGSC therapy. With the studies proposed, we will characterize the molecular mechanisms and effector pathways of IGF2BP1-directed immune evasion and DNA repair in C5-like tumor models. We aim at evaluating the direct inhibition of IGF2BP1 by small molecules as well as how such inhibition synergizes with standard treatments of HGSC. These efforts will initially focus on HGSC cell models and will be expanded to the pre-clinical testing of findings in murine and patient-derived organoids as well as HGSC mouse models. We expect to identify novel therapy concepts for an aggressive and hard to target subtype of HGSC.
DFG Programme
Research Units
