Angiocrine Bioscience (United States)

Abstract Background: HER2 (Human Epidermal Growth Factor Receptor 2) amplification is a key molecular alteration defining multiple cancer types. The recent HER2-targeted antibody-drug conjugate (ADC), DS8201 (Enhertu), representing a groundbreaking advancement, demonstrated remarkable and practice-changing efficacy across diverse clinical settings. Despite DS8201 achieving significant clinical benefit in multiple HER2-positive tumor types, the existence of non-responders and acquired resistance remains a recognized challenge requiring further investigation. In this study, we established an Enhertu-pretreated patient-derived xenograft (PDX) model, LU9681, derived from a patient's progressive lesion biopsy after multiple treatments, including Enhertu. Method: The NSCLC PDX model LU9681, was established by subcutaneously engrafted in immunodeficient mice. HER2 expression level in the tumor tissue was detected by IHC and FISH. Treatment of DS8201 (2mg/kg, 5mpk and 10mpk, i.v. Q3W) in LU9681 was started when the average tumor volume reached around 150-180mm3. The progressive disease of the treatment group was defined according the RECIST guideline (version 1.1) as follow: At least a 20% increase in the TV, taking as reference the smallest TV on study, calculated as ΔVm-f %=100% × ((Vfinal – Vminimum) / Vminimum). Result: In this study, we established a NSCLC PDX model, LU9681, derived from metastatic pleural effusion of a patient who had undergone multiple treatments including 5 cycles Enhertu, (400mg once every 3 weeks via infusion). During this treatment, patient’s pleural effusion resolved temporarily and had stable disease before relapse. In preclinical studies, amplification and expression of HER2 was detected in the tumor tissue of LU9681. The in vivo efficacy studies demonstrated tumor progression in the 2 mpk and 5 mpk DS8201 treatment groups. In the 10 mpk DS8201 treatment groups, initial tumor regression was observed at the beginning of each treatment cycle, followed by tumor progression at later stages, which is similar to patient response in clinical settings. With long-term continuous treatment of 10 mpk DS8201, some tumors showed persistent progression without regression. HER2 IHC analysis of the relapsed tumors revealed decreased HER2 protein expression on the cytomembrane, and translocation of HER2 to cytoplasm and nucleus compared to untreated LU9681 tumors. Conclusion: The Enhertu-pretreated PDX model, LU9681, validated in this study, provides robust and clinically relevant platform for the investigating mechanisms of resistantce to DS8201 and assists in the exploration and development of novel therapeutic strategies. Citation Format: Jinxi Wang, Ling Chen, Leilei Chen, Likun Zhang, Wubin Qian, Mingxuan Du, Ludovic Bourre, Jessie Jingjing. Wang. Characterization of DS8201 (Enhertu) in a Clinically Pretreated NSCLC Patient-Derived Xenograft (PDX) Model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A044.

Abstract Screening patient peripheral blood using our proposed non-invasive method can boost the accuracy in selecting proper candidates for immune checkpoint therapy in the clinical setting, thereby leading to higher success in treatment. The immune system is regulated by a sophisticated network of modulatory molecules. In chronic infections and cancers, T cell exhaustion can arise when clearance of antigens is incomplete due to sustained expression of co-inhibitory molecules. T cell exhaustion has been exploited by some cancers, and also described in chronic infections with latency. Such exhausted T cells may be reversed with the right immune checkpoint blockade, thereby restoring effector T cell function. We have optimized a T cell Exhaustion Recall Antigen Assay, demonstrating T cell exhaustion may be reversed by immune checkpoint blockades in certain hosts. We hypothesize that understanding of the capacity and expressions of co-inhibitory molecules assist in predicting responders for specific immune checkpoint therapies. We have used a flow cytometry-based approach to examine changes in an array of immune checkpoint molecules on activated T cells and antigen presenting cells. We first tested the effect of anti-PD1 on tumor antigen-specific activated T cells using splenocytes from PMEL T cell receptor (TCR) transgenic mouse, which expresses mouse homologue of human premelanosome protein, or gp100. Activated CD3+CD8+ gp100-specific T cell population and IFNγ production were measured by flow cytometry. Secondly, we evaluated the expression levels of various immune checkpoint molecules post anti-CD3 stimulation of human peripheral blood mononuclear cells (PBMC) from characterized healthy hosts. Surprisingly, we found high expressions of co-inhibitory and co-stimulatory molecules including CTLA-4, PD1, PDL-1/PDL2, TIGIT, LAG3, TIM3, GITR, are associated with poor response to immune checkpoint blockades. Levels of activated T cells and cytokine production in donors with high checkpoint receptors showed lower T cell activations and cytokine production. Screening patient peripheral blood using our proposed non-invasive method can boost the accuracy in selecting proper candidates for immune checkpoint therapy in the clinical setting, thereby leading to higher success in treatment. Citation Format: Pirouz M. Daftarian, Marybeth George, Eden Kleiman, Wushouer Ouerkaxi, Amy Yamamura, Zhongliang Li, Mingfa Zang, Derron Yu, Eunmi Hwang, Annie X. An, Ann E. Lin, Henry Li. Expressions of co-inhibitory / co-stimulatory molecules may impact immune checkpoint therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4124.

Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets.Experimental Design: We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC.Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs.Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. Clin Cancer Res; 24(2); 360-9. ©2017 AACR.

Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors. The induction phase (days 0-8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8-20), RUNX1+ FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20-28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGFβ and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.