bims-necame 2025-08-24 papers

Issue of 2025–08–24
three papers selected by
Grigor Varuzhanyan, UCLA

bioRxiv. 2025 Aug 11. pii: 2025.08.07.669104. [Epub ahead of print]

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype.
Graphical abstract:
Significance Statement: EZH2 plays a key role in driving cell state transitions in neuroendocrine prostate cancer (NEPC), guiding cancer cells towards a more aggressive, therapy-resistant cell type. This transformation creates a specific vulnerability, as NEPC cells become highly reliant on both EZH2 and PI3K/mTORC1-translation signaling. Targeting this dependency, we demonstrate that combining EZH2 with PI3K/mTORC1 inhibition provides effective suppression of NEPC cell growth, offering a promising therapeutic strategy for treating this challenging and aggressive prostate cancer subtype.

DOI: https://doi.org/10.1101/2025.08.07.669104

J Transl Med. 2025 Aug 19. 23(1): 940

SC134-deruxtecan, a fucosyl-GM1 targeting ADC for small cell lung cancer therapy.

Bryony Heath, Bubacarr G Kaira, Dhruma Thakker, Omar J Mohammed, Ruhul Choudhury, Foram Dave, Poonam Vaghela, Elena Dubinina, Tina Parsons, Lindy Durrant, Mireille Vankemmelbeke.

BACKGROUND: Small cell lung cancer (SCLC) remains a difficult disease to treat with poor long-term survival rates. New therapies offer modest overall survival benefit beyond that of chemotherapy alone, necessitating the development of improved therapies. Fucosyl-GM1 (FucGM1) is a glycolipid highly expressed on SCLC cells, but virtually absent in normal tissues, suggesting strong potential for targeted therapy. We have developed SC134-deruxtecan, an antibody drug conjugate (ADC) targeting FucGM1 in SCLC, and characterized its preclinical activity.
METHODS: SC134 binding specificity and affinity were tested through enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry against several SCLC cell lines, and immunohistochemistry (IHC) of clinical samples and animal tissues. In silico modelling supplemented the FucGM1 binding specificity. Internalization kinetics and colocalization of SC134 with the lysosomes were investigated through imaging flow cytometry. Direct cytotoxicity as well as bystander killing and antibody dependent cell cytotoxicity (ADCC) by SC134-deruxtecan were determined using in vitro cell cytotoxicity assays. SC134-deruxtecan's efficacy was evaluated in vivo using a DMS79 xenograft model.
RESULTS: SC134 specifically targets FucGM1, without GM1 cross-reactivity, with nanomolar affinity. In silico modelling of the SC134 FucGM1 binding site revealed a relatively narrow binding pocket, occupied by the terminal three glycans with multiple Fucose-engaging interactions. Robust FucGM1 expression in frozen SCLC patient tissues was evident, whilst tissue cross-reactivity analysis indicated non-human primates as well as mice as suitable tox models. FucGM1 binding by SC134 led to effective internalization, with a 6.9-h half-life, lysosomal colocalization, culminating in sub-nanomolar drug delivery efficiency, across a range of payloads. Covalent deruxtecan conjugation of SC134 with a DAR 8 and a cleavable linker showed effective (nanomolar) in vitro killing of SCLC cell lines such as DMS79 and DMS153, with concentration-dependent bystander killing of FucGM1-negative AGS cells. SCLC cell killing was further augmented through ADCC. Potent in vivo DMS79 xenograft killing was seen at 3mg/kg SC134-deruxtecan, which was well tolerated.
CONCLUSION: The tumour-specific nature of FucGM1, combined with the potent SCLC killing by SC134-deruxtecan underscore the development potential of SC134 for use as an ADC therapy against SCLC.

Keywords: ADC; Fucosyl-GM1; Glycolipid; Internalization; Small cell lung cancer

DOI: https://doi.org/10.1186/s12967-025-06940-2

Clin Nucl Med. 2025 Aug 20.

Diffusely Increased Bone Marrow Uptake on DOTATATE PET/CT Due to PRRT-related Myelodysplasia Syndrome.

Chenxi Wu, Ekaterina Menshikova, Amol M Takalkar.

We report an unusual imaging finding on DOTATATE PET/CT in a patient with prior 177Lu-DOTATATE treatment for metastatic small bowel neuroendocrine tumor. Five years post-treatment follow-up DOTATATE PET/CT for fatigue and back pain showed new diffusely increased bone marrow uptake in addition to focal uptake corresponding to known metastases. Faint/mild bone marrow uptake of DOTATATE can be seen due to the presence of SST-2 receptor on CD-34 hematopoietic progenitor cells in the marrow, but diffusely increased marrow uptake, as in this case, was not deemed physiologic and was concerning for marrow pathology. Subsequent bone marrow biopsy confirmed therapy-related myelodysplastic syndrome (t-MDS).

Keywords: DOTATATE; MDS; PET/CT; bone marrow uptake; myelodysplastic syndrome

DOI: https://doi.org/10.1097/RLU.0000000000006095