Biology subjects

Rahmy, S.

Publications and source records attributed to Rahmy, S..

3 recordsLinked to original sources

bioRxiv2025

CDH3 as a Novel Therapeutic Target in Basal-like Double-Negative Prostate Cancer

PurposeBasal-like (also known as double-negative) prostate cancers are aggressive tumors that lack effective targeted therapies. We aimed to delineate the role of CDH3 (P-cadherin) in basal-like prostate cancer and evaluate CDH3-directed therapeutic strategies. MethodsWe integrated genetically engineered mouse models (GEMMs) of prostate cancer, bulk and single-cell transcriptomic analyses, and a suite of in vitro and in vivo experiments. CDH3 expression and associated signaling pathways were examined in Pten/Apc double-knockout mouse prostates and human datasets. Functional studies included antibody-drug conjugate (ADC) cytotoxicity assays and the development of chimeric antigen receptor (CAR) T cells targeting CDH3, tested in prostate cancer cell lines and xenograft models. ResultsPten/Apc double deletion in prostate GEMMs led to highly aggressive tumors with markedly elevated CDH3 expression and enrichment of non-canonical WNT signaling components. Transcriptomic analyses of patient-derived prostate tumors confirmed that CDH3 is significantly upregulated in basal-like prostate cancer subtypes relative to luminal subtypes. Single-cell RNA sequencing revealed CDH3 expression predominantly in basal epithelial cells. Mechanistically, we found that active YAP1 signaling and a WNT5A-ROR2 non-canonical WNT axis drive CDH3 expression. Targeting CDH3 with a CDH3-specific ADC induced potent, antigen-dependent killing of CDH3 prostate cancer cells in vitro and significantly suppressed tumor growth in in vivo metastatic prostate cancer models. Likewise, CDH3-targeted CAR T cells specifically recognized and lysed CDH3-expressing prostate tumor cells while sparing CDH3-negative cells, leading to tumor regression and improved survival in mouse models, especially when combined with PD-1 checkpoint blockade. ConclusionsCDH3 is a key marker and functional driver of basal-like prostate cancer. Therapeutic strategies leveraging CDH3, including ADCs and CAR T cells, demonstrate strong preclinical efficacy, supporting the development of CDH3-targeted treatments to overcome resistance in aggressive prostate cancer.

cancer biology↗

bioRxiv2023

Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides

Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that PD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to PD-1, as decreasing Acod1 levels in PD-1 resistant cancer cells can sensitize tumors to PD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naive CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on secretion of ITA, but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.

cancer biology↗

bioRxiv2023

Overcome Prostate Cancer Resistance to Immune Checkpoint Therapy with Ketogenic Diet-Induced Epigenetic Reprogramming

Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we developed a syngeneic murine PCa model with acquired ICB resistance. Using this model, synergistic efficacy was achieved by combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or supplementation of ketone body {beta}-hydroxybutyrate (BHB, endogenous HDACi) via 1,3-butanediol-admixed food. CKD and BHB supplementation delayed PCa tumors as monotherapy, and both BHB and adaptive immunity are required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that the HDACi and ketogenesis-enhanced ICB therapy involves cancer-cell-intrinsic (upregulated MHC class I molecules) and extrinsic mechanisms (CD8+ T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophils). Overall, these findings underscore the potential of using HDACi and optimized KD to enhance ICB therapy for PCa.

cancer biology↗