Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Jo, Ukhyun; Murai, Yasuhisa; Takebe, Naoko; Thomas, Anish; Pommier, ﻿Yves

doi:10.3390/cancers13184601

Cited by 29 publications

(27 citation statements)

References 156 publications

(283 reference statements)

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“…Within these samples ∼10% demonstrated homozygous RB1 alterations ( 22, 23 ). The influence of SLFN11 upon drug sensitivity has been associated qualitatively with presence of the RNA and protein ( 9, 18, 19 ). From the SU2C RNAseq data, we estimated that about 40% of RB1 intact samples expressed SLFN11 (see methods) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Dotted line on the bar plot indicates 3 rd quantile. Patient samples are categorized based upon ARPC and SCNPC phenotypes defined by Nyquist et al (9). (C) Analysis of SU2C data to predict likely responders based on RB1 and SLFN11 status, and IFN score.…”

Section: Resultsmentioning

confidence: 99%

“…It should be noted that LuCaP 96 expressed WT TP53 , and previous analyses of BRCA1/2 deficient breast cancer PDXs have suggested approximately 25% are non-responsive to PBD, a phenotype that may be associated with a less compromised HRD resulting from minimal mutations to additional DNA repair proteins, including TP53 ( 28, 29 ). Finally, it has previously been shown that inhibition of ATR, a cell cycle checkpoint protein that is crucial for allowing replication fork repair prior to entry into M phase, is a synthetic lethal for in vitro selected SLFN11 NEG tumors ( 9, 19 ). We characterized a naturally occurring, PBD-responsive, SLFN11 NEG ATR loss of function model, NCI-PC155, consistent with these previous findings from experimentally-selected models ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…SLFN11 is a DNA/RNA helicase that is actively recruited to sites of DNA damage and appears to irreversibly block stressed replication forks, leading to the hypothesis that SLFN11 is a dominant inhibitor of stressed replication fork repair. SLFN11 is a biomarker for response to a variety of other therapeutics, including topoisomerase and PARP inhibitors as well as platinum chemotherapeutics ( 9, 18 ). It is worth noting that SLFN11 protein levels are not quantitatively correlated with IFN scores ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…PBD dimers bind in a sequence specific manner to form inter-strand crosslinks (ICLs) leading to double strand DNA breaks due to replication fork arrest ( 8 ). Previous studies have shown that tumors with enhanced replication stress are more sensitive to deleterious replication fork blocks caused by topoisomerase inhibitors, PARP inhibitors, and platinum DNA cross-linking agents ( 9, 10 ). Characterizing the utility of PBD dimers for the treatment of cancers exhibiting replication stress is a question of interest.…”

Section: Introductionmentioning

confidence: 99%

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Tumor-derived biomarkers beyond antigen expression enhance efficacy of CD276/B7H3 antibody-drug conjugate in metastatic prostate cancer

Agarwal

Fang

McGowen

et al. 2022

Preprint

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B7H3, a cell surface protein often associated with higher grade solid tumors of various origins, is an attractive therapeutic target due to its frequent upregulated expression relative to normal tissue. In a large cohort of treatment-resistant, metastatic castrate resistant prostate cancer (mPC) patient derived xenografts and organoids, we present a comprehensive therapeutic and biomarker analysis. The 26 models tested encompass the heterogeneous genomic and histological categories of clinical mPC. In vitro and in vivo treatment with an anti-B7H3 targeted antibody conjugated to a pyrrolobenzodiazepine (PBD) cytotoxic agent were efficacious in 70% of models. All models expressed some B7H3 protein, the levels of which did not correlate with responses. Underlying susceptibilities to B7H3-PBD-ADC exposure were observed as multiple imperfectly overlapping classes of biomarkers, unrelated to androgen receptor dependence and substantially expanded beyond current homologous repair deficiencies. RB1 deficiency and/or replication stress, particularly prominent in small cell neuroendocrine prostate cancer (SCNPC), predicted responsiveness. The presence of SLFN11 in SCNPC and adenocarcinoma models correlated perfectly with vulnerability, although an absence of SLFN11 was not predictive. Of particular interest, an elevated interferon signature in adenocarcinomas, associated with alteration of wild type TP53, was quantitatively correlated with responsiveness. Finally, we also observed that susceptible models uniquely associated with the loss of select downstream DNA repair proteins. The above biomarkers are expressed in toto in about 70% of mPC clinical samples, suggesting broad potential for mechanistically complementary treatment of tumors escaping current regimens.One Sentence SummaryB7H3-PBD-ADC sensitivity in metastatic prostate cancer is associated with replication stress, SLFN11 expression related to interferon signaling, and alterations in specific DNA repair factors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor-derived biomarkers beyond antigen expression enhance efficacy of CD276/B7H3 antibody-drug conjugate in metastatic prostate cancer

Agarwal

Fang

McGowen

et al. 2022

Preprint

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Targeting ATR in Cancer Medicine

Salguero,

Valladolid,

Robinson

et al. 2023

Cancer Treatment and Research

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Advances in molecular targeted therapies to increase efficacy of (chemo)radiation therapy

et al. 2023

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Recent advances in understanding the tumor’s biology in line with a constantly growing number of innovative technologies have prompted characterization of patients’ individual malignancies and may display a prerequisite to treat cancer at its patient individual tumor vulnerability. In recent decades, radiation- induced signaling and tumor promoting local events for radiation sensitization were explored in detail, resulting the development of novel molecular targets. A multitude of pharmacological, genetic, and immunological principles, including small molecule- and antibody-based targeted strategies, have been developed that are suitable for combined concepts with radiation (RT) or chemoradiation therapy (CRT). Despite a plethora of promising experimental and preclinical findings, however, so far, only a very limited number of clinical trials have demonstrated a better outcome and/or patient benefit when RT or CRT are combined with targeted agents. The current review aims to summarize recent progress in molecular therapies targeting oncogenic drivers, DNA damage and cell cycle response, apoptosis signaling pathways, cell adhesion molecules, hypoxia, and the tumor microenvironment to impact therapy refractoriness and to boost radiation response. In addition, we will discuss recent advances in nanotechnology, e.g., RNA technologies and protein-degrading proteolysis-targeting chimeras (PROTACs) that may open new and innovative ways to benefit from molecular-targeted therapy approaches with improved efficacy.

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Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Cited by 29 publications

References 156 publications

Tumor-derived biomarkers beyond antigen expression enhance efficacy of CD276/B7H3 antibody-drug conjugate in metastatic prostate cancer

Tumor-derived biomarkers beyond antigen expression enhance efficacy of CD276/B7H3 antibody-drug conjugate in metastatic prostate cancer

Targeting ATR in Cancer Medicine

Advances in molecular targeted therapies to increase efficacy of (chemo)radiation therapy

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