Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models.

Autor:	Agarwal S; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Fang L; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., McGowen K; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Yin J; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Bowman J; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Ku AT; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Alilin AN; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Corey E; Department of Urology and., Roudier MP; Department of Urology and., True LD; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA., Dumpit R; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Coleman I; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Lee JK; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Nelson PS; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Capaldo BJ; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Mariani A; AstraZeneca, Gaithersburg, Maryland, USA., Hoover C; AstraZeneca, Gaithersburg, Maryland, USA., Senatorov IS; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Beshiri M; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Sowalsky AG; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Hurt EM; AstraZeneca, Gaithersburg, Maryland, USA., Kelly K; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2023 Nov 15; Vol. 133 (22). Date of Electronic Publication: 2023 Nov 15.
DOI:	10.1172/JCI162148
Abstrakt:	Antibody-drug conjugates (ADCs) are a promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 WT ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 nonexpressors governed response. Importantly, WT TP53 predicted nonresponsiveness (7 of 8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.
Databáze:	MEDLINE
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