Biology subjects

Wen, J. J.

Publications and source records attributed to Wen, J. J..

3 recordsLinked to original sources

bioRxiv2025

RSPO2-based peptibodies conjugated with pyrrolobenzodiazepine dimer or camptothecin analogs demonstrate potent anti-tumor activity by targeting the three receptors LGR4/5/6

Leucine-rich repeat containing, G protein-coupled receptor 4, 5, and 6 (LGR4/5/6) are three homologous receptors that are co-expressed or alternately expressed at high levels in tumor cells of colorectal cancer (CRC) and high-risk neuroblastoma (NB). Simultaneous targeting of all three receptors may provide increased efficacy or overcome drug resistance due to tumor heterogeneity and cancer cell plasticity. LGR4/5/6 all bind to R-spondins (RSPOs) with high affinity and potentiate Wnt/{beta}-catenin signaling in response. Previously, we showed that a peptibody based on a mutant RSPO4 furin domain that bound to LGR4/5/6 without potentiating Wnt/{beta}-catenin signaling was able to deliver cytotoxins into cancer cells that express any of the three receptors. We have now generated a mutant RSPO2 furin domain that retains high affinity binding to LGR4/5/6 without signaling activity. Peptibodies based on this RSPO2 furin mutant were conjugated with either pyrrolobenzodiazepine dimer (PBD) or camptothecin derivative (CPT2), and the resulting peptibody-drug conjugates (PDCs) showed potent and specific cytotoxic activity in NB and CRC cell lines expressing any of LGR4/5/6 in vitro and robust anti-tumor activity in vivo. The results support the potential of RSPO2-based PDCs for the treatment of CRC, high-risk NB, and other cancers that express any of LGR4/5/6.

pharmacology and toxicology↗

bioRxiv2024

Anti-tumor activity of camptothecin analog conjugate of a RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer.

Antibody-drug conjugates (ADCs) have emerged as a major modality of targeted cancer therapy, yet no ADC has been approved specifically for colorectal cancer (CRC). LGR4/5/6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related receptors that are expressed at high levels together or alternately in nearly all cases of CRC. ADCs targeting LGR5 have been shown to have robust anti-tumor potency, but not all CRC cells express LGR5 and LGR5-positive tumor cells may lose LGR5 expression due to cancer cell plasticity. R-spondin 4 (RSPO4) is a natural protein ligand of LGR4/5/6 with high affinity for all three receptors. We fused a mutant form of RSPO4 furin domain that retains high affinity binding to LGR4/5/6 to human IgG1 Fc to create a peptibody designated R462. Conjugation of R462 with a camptothecin analog designated CPT2 at eight drugs per peptibody led to the generation of R462-CPT2 that showed highly potent cytotoxic activity in vitro in CRC cell lines expressing any of LG4/5/6. In cell line xenograft and PDX models of CRC, R462-CPT2 demonstrated robust anti-tumor effect. Importantly, R462-CPT2 showed no major adverse effect at therapeutically effective dose levels. These results strongly support the use of RSPO ligand drug-conjugates that target LGR4/5/6 simultaneously for the treatment of CRC.

pharmacology and toxicology↗

bioRxiv2021

H2AFB1 is a cancer/testis gene involved in hyperactivation of ribosome biogenesis in Hodgkin Lymphoma

Testis-specific regulators of chromatin function are commonly ectopically expressed in human cancers, but their roles are poorly understood. Examination of 81 primary Hodgkin Lymphoma (HL) samples showed that the ectopic expression of the eutherian testis-specific histone variant H2A.B is an inherent feature of HL. In experiments using two HL-derived cell lines derived from different subtypes of HL, H2A.B knockdown inhibited cell proliferation. H2A.B was enriched in both the nucleoli of these HL cell lines and primary HL samples. We found that H2A.B enhanced ribosomal DNA (rDNA) transcription, was enriched at the rDNA promoter and transcribed regions, and interacted with RNA Pol I. Depletion of H2A.B caused the loss of RNA Pol I from rDNA chromatin. Remarkably, H2A.B was also required for high levels of ribosomal protein gene expression being located at the transcriptional start site and within the gene body. H2A.B knockdown reduced gene body chromatin accessibility of active RNA Pol II genes concurrent with a decrease in transcription. Taken together, our data show that in HL H2A.B has acquired a new function, the ability to increase ribosome biogenesis.

genomics↗