B7-H3 as a Therapeutic Target in Advanced Prostate Cancer

Guo, Christina; Figueiredo, Ines; Gürel, Bora; Neeb, Antje; Seed, George; Carreira, Suzanne; Rekowski, Jan; Buroni, Lorenzo; Welti, Jon; Bogdan, Denisa; Gallagher, Lewis; Sharp, Adam; Maza, Maria D. Fenor de la; Rescigno, Pasquale; Westaby, Daniel; Chandran, Khobe; Riisnaes, Ruth; Ferreira, Ana; Miranda, Susana; Calì, Bianca; Alimonti, Andrea; Bressan, Silvia; Nguyen, Alana H.T.; Shen, Michael M.; Hawley, Jessica E.; Obradovic, Aleksandar Z.; Drake, Charles G.; Bertan, Claudia; Baker, Chloe; Tunariu, Nina; Yuan, Wei; Bono, Johann S. de

doi:10.1016/j.eururo.2022.09.004

Cited by 27 publications

(27 citation statements)

References 69 publications

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“…6A). B7-H3 is a cell surface protein and emerging therapeutic target in CRPC ( 32 ). Although B7-H3 is expressed in nearly all prostate cancers, there is a wide range of expression across CRPC and some suggestion that NEPC tumors may have lower B7-H3 expression compared with prostate adenocarcinoma ( 32 ).…”

Section: Resultsmentioning

confidence: 99%

Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer

Yamada,

Venkadakrishnan,

Mizuno

et al. 2023

Sci. Transl. Med.

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Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMTs) are highly expressed, and global DNA methylation is dysregulated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and substantially reduced NEPC tumor development and metastasis in vivo. Decitabine, a pan-DNMT inhibitor, attenuated tumor growth in NEPC patient–derived xenograft models, as well as retinoblastoma gene ( RB1 )–deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1 -proficient CRPC. We further found that DNMT inhibition increased expression of B7 homolog 3 (B7-H3), an emerging druggable target, via demethylation of B7-H3. We tested DS-7300a (i-DXd), an antibody-drug conjugate targeting B7-H3, alone and in combination with decitabine in models of advanced prostate cancer. There was potent single-agent antitumor activity of DS-7300a in both CRPC and NEPC bearing high expression of B7-H3. In B7-H3–low models, combination therapy of decitabine plus DS-7300a resulted in enhanced response. DNMT inhibition may therefore be a promising therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3–low prostate cancer to DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis, and the development of biomarker-driven therapeutic strategies for these populations may ultimately help improve patient outcomes.

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Section: Resultsmentioning

confidence: 99%

Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer

Yamada,

Venkadakrishnan,

Mizuno

et al. 2023

Sci. Transl. Med.

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“…The efficacies of dual blockade of B7-H3/PD-L1 or B7-H3/CTLA-4, in the absence of an AR inhibitor, have yet to be tested in our preclinical models. Given the importance of AR signaling in prostate cancer, efforts have been made to study the associations between B7-H3 and AR (26,(34)(35)(36). The potential regulatory role of AR signaling on B7-H3 and whether B7-H3 mediated immunosuppression contributes to castration resistance have yet to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…However, the roles of B7-H3 in cancer development and the tumor immune microenvironment remain unclear, partially because of the lack of tissue-specific deletion models. Although prior studies reported that AR signaling might be associated with B7-H3 expression ( 26 , 34 – 36 ), we still have a limited understanding of genetic alterations and oncogenic pathways that contribute to B7-H3 dysregulation. These gaps in knowledge hinder the application of immunotherapy targeting B7-H3 in malignancies.…”

Section: Introductionmentioning

confidence: 99%

Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies

et al. 2023

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Checkpoint immunotherapy has yielded meaningful responses across many cancers but has shown modest efficacy in advanced prostate cancer. B7 homolog 3 protein (B7-H3/ CD276 ) is an immune checkpoint molecule and has emerged as a promising therapeutic target. However, much remains to be understood regarding B7-H3’s role in cancer progression, predictive biomarkers for B7-H3–targeted therapy, and combinatorial strategies. Our multi-omics analyses identified B7-H3 as one of the most abundant immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Here, we sought in vivo genetic evidence for, and mechanistic understanding of, the role of B7-H3 in PTEN/TP53- deficient prostate cancer. We found that loss of PTEN and TP53 induced B7-H3 expression by activating transcriptional factor Sp1. Prostate-specific deletion of Cd276 resulted in delayed tumor progression and reversed the suppression of tumor-infiltrating T cells and NK cells in Pten/Trp53 genetically engineered mouse models. Furthermore, we tested the efficacy of the B7-H3 inhibitor in preclinical models of castration-resistant prostate cancer (CRPC). We demonstrated that enriched regulatory T cells and elevated programmed cell death ligand 1 (PD-L1) in myeloid cells hinder the therapeutic efficacy of B7-H3 inhibition in prostate tumors. Last, we showed that B7-H3 inhibition combined with blockade of PD-L1 or cytotoxic T lymphocyte–associated protein 4 (CTLA-4) achieved durable antitumor effects and had curative potential in a PTEN/TP53 -deficient CRPC model. Given that B7-H3–targeted therapies have been evaluated in early clinical trials, our studies provide insights into the potential of biomarker-driven combinatorial immunotherapy targeting B7-H3 in prostate cancer, among other malignancies.

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“…To further address this treatment gap, ongoing work is focused on better understanding the individual immune landscapes of subtypes of CRPCs, with the goal of defining specific targets that are likely to respond to existing immunotherapies or targeted therapies. As a recent example, research efforts have identified B7H3, a checkpoint molecule, to be highly expressed in CRPC (Brady et al 2021a), and although expression is less in NEPC when compared to adenocarcinoma (Guo et al 2022), it has demonstrated targeted therapeutic potential for this patient population. Given the diverse nature of this disease subtype, personalized, combination therapeutic strategies that target the multifaceted tumor burden, in addition to harnessing the advancements made in other neuroendocrine subtypes such as small-cell lung cancer, may drive improved outcomes for patients with NEPC.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity and the tumor microenvironment in neuroendocrine prostate cancer

Brady

Nelson

2022

Journal of Endocrinology

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Neuroendocrine prostate cancer, generally arising late in the disease trajectory, is a heterogenous subtype that infers a worse prognosis and limited treatment options for patients. Characterization of the complex landscape of this disease subtype and scrutiny of the relationship between tumor cells and cells of the surrounding tumor microenvironment have aided in elucidating some of the mechanisms of neuroendocrine disease biology and have uncovered a multitude of signaling pathways involved in disease transdifferentiation under therapeutic selection. In this review, we discuss current efforts to better understand the heterogenous landscape of neuroendocrine prostate cancer and summarize research efforts to define the interplay between tumor cells and the microenvironment, with an emphasis on the immune component. Research efforts have uncovered several potential therapeutic approaches that may improve disease outcomes for patients diagnosed with neuroendocrine prostate cancer, including the potential for combination immunotherapies. However, additional research is required to fully address and exploit the contribution of tumor cell and microenvironment heterogeneity in developing effective treatment strategies.

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B7-H3 as a Therapeutic Target in Advanced Prostate Cancer

Cited by 27 publications

References 69 publications

Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer

Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer

Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies

Heterogeneity and the tumor microenvironment in neuroendocrine prostate cancer

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