Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models
Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly
Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly
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Research Article Cell biology

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

Abstract

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.

Authors

Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly

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Figure 4

Contributing biomarker subclasses of B7H3-PBD-ADC sensitivity.

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Contributing biomarker subclasses of B7H3-PBD-ADC sensitivity. (A) Heatm...
(A) Heatmap of the pathways contributing to the RepStress signature score. Organoid models are ranked from left to right based on increasing B7H3-PBD nAUC (bottom panel). Top panel showing RepStress and RB signature scores. (B) Comparison of z-transformed RepStress score in AD nonresponders (ARPC-NR), ARPC responders (ARPC-R), and non-ARPC responders (NonARPC-R). Color indicates RB1 genotype. (C) Univariate correlation analyses between nAUC and MsigDB gene signatures, including refined IFN signature score for prostate cancer labeled as PCa_IFN_Score. Spearman correlation coefficient is shown for top significant gene sets. FDR ≤ 0.05, Benjamini and Hochberg method for multiple hypothesis test correction. (D) Volcano plot for differentially expressed genes between B7H3-PBD-ADC–responsive ARPC models versus nonresponsive ARPC models. Dotted lines are shown for log2 fold change of –2 and 2 at FDR ≤ 0.01. (E) Comparison of IFN score with SLFN11 expression. (F) B7H3-PBD-ADC response categorized by SLFN11 expression. Red line indicates median nAUC for each group. NR, nonresponder; R, responder; +/- indicates SLFN11 expression. P<0.05; significant, Wilcoxon test. (G) Distribution of ARPC models based on TP53 genomic status and SLFN11 expression. (H) Schematic of proposed biomarker based therapeutic decisions for B7H3-PBD-ADC treatment of patients with mPC. For multiple group comparisons in panel B and F, P values were determined by Wilcoxon test and adjusted using the Holm method.