bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B027: Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer
Authors: Martinez-Conde Antonia , Ene Hila , Ben-Meir Kerem , Frechtel-Gerzi Roni , Dor-On Eyal , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: January 2024

Abstract
Purpose: Ovarian cancer is the leading cause of death among cancers of the female reproductive system. Surgery and platinum-based adjuvant chemotherapy followed by PARP inhibitor (PARPi) maintenance therapy is standard treatment for most patients diagnosed with ovarian cancer. The mechanism of action of PARPi and platinum-based therapy involves the induction of DNA damage, which requires the Fanconi Anemia (FA)- BRCA pathway for repair, making these agents most beneficial in cancers with BRCA mutations. However, 75% of patients with ovarian cancer have BRCA wild type tumors and therefore their benefit from PARPi is limited. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cancer cell death. Recent research demonstrated TTFields induce a state of BRCAness in multiple cancer types, as well as anticancer effects in ovarian cancer preclinical models. This study investigated the impact of TTFields concomitant with carboplatin or PARPi in ovarian cancer cell lines. Methods: A2780 (BRCA wild type), OVCAR3 (BRCA mutated), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or concomitant with application of carboplatin or a PARPi (olaparib or niraparib). Efficacy assessments included cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying the effects on cell count and colony formation. Results: TTFields treatment reduced cell count, increased overall effect, and elevated apoptosis. Carboplatin, olaparib, and niraparib exhibited dose-dependent effects in all cell lines. When TTFields were applied together with these drugs, a synergistic interaction was observed in the BRCA wild-type A2780 cells and platinum-resistant A2780cis cells, while an additive effect was noted in the BRCA mutant OVCAR-3 cells. Conclusions: This data implies potential advantages for TTFields concomitant with platinum-based chemotherapy and PARPi in ovarian cancer, even without underlying BRCA mutations. This aligns with the BRCAness state induced by TTFields and suggests a benefit in platinum resistant cancer. Overall, TTFields may augment the efficacy of ovarian cancer treatment in both adjuvant and maintenance settings.
Citation Format: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B027.
Abstract B028: Preclinical effects of Tumor Treating Fields (TTFields) applied with cisplatin for treatment of cervical cancer
Authors: Frechtel-Gerzi Roni , Gerasimova Daria , Zeevi Einav , Monin Roni , Fishman Hila , Schlachet-Drukerman Inbar , Mumblat Helena , Martinez-Conde Antonia , Dor-On Eyal , Tzchori Itai , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram , Palmer Greg , Secord Angeles A. 
Published: January 2024

Abstract
Introduction: Though largely preventable, cervical cancer remains a significant health issue. Treatment of early-stage disease usually involves surgery; while systemic therapy is often required for advanced, recurrent, or metastatic cases. Most patients with advanced disease receive cisplatin-containing chemotherapy combinations in the first-line setting. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Concomitant treatment with TTFields and cisplatin has shown benefit in other tumor types. This in vitro study assessed the effects of TTFields in cervical cancer cells and explored their efficacy together with cisplatin. Methods: Cervical cancer cell lines were exposed to TTFields (0.5 V/cm for Ca Ski cells, 1 V/cm RMS for HeLa and SiHa cells; 72 h) at varying frequencies (100-400 kHz) followed by cell count assays. TTFields (200 kHz) were then applied with a range of cisplatin doses, and cell count, colony formation, and apoptosis were evaluated. Overall effect was calculated as the product of the relative reductions in cell count and colony formation. TTFields-treated cells were also examined for formation of γH2AX (a DNA damage marker) using fluorescent microscopy and for the expression of Fanconi Anemia (FA)-BRCA pathway proteins involved in repairing cisplatin-induced DNA damage via Western blot. Results: TTFields treatment reduced cell count in all cervical cancer cell lines tested. A frequency of 200 kHz was determined effective and used for all experiments. Cisplatin exhibited dose-response effects, which were augmented when TTFields were co-applied. TTFields also induced DNA damage in the cells and downregulated the expression of FA-BRCA pathway proteins. Conclusions: These preclinical findings suggest that TTFields should be explored as a potential treatment for cervical cancer. TTFields-induced downregulation of the FA-BRCA pathway creates a conditional vulnerability that may account for the enhanced efficacy seen when TTFields are applied together with cisplatin, providing mechanistic insight.
Citation Format: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Roni Monin, Hila Fishman, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg Palmer, Angeles A. Secord. Preclinical effects of Tumor Treating Fields (TTFields) applied with cisplatin for treatment of cervical cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B028.
Abstract IA007: Targeting the hypoxia-induced DDR to improve radiotherapy response
Authors: Hammond Ester 
Published: January 2024

Abstract
Regions of hypoxia (insufficient oxygen) occur to some extent in most if not all solid tumors. Within hypoxic regions the levels of oxygen are heterogeneous and can reach near anoxic levels, often referred to as radiobiological hypoxia. Cells experiencing radiobiological hypoxia are significantly more resistant to radiation-induced DNA damage and negatively impact radiotherapy response. A number of clinical studies have demonstrated that hypoxia is a significant indicator of poor patient response. Radiobiological hypoxia, unlike milder hypoxic conditions, leads to a robust DNA damage response although interestingly, this occurs in the absence of detectable DNA damage. Instead, the hypoxia-induced DDR has been attributed to the accumulation of replication stress. Previously, we demonstrated that hypoxia-induced replication stress originated from reduced nucleotide availability due to the oxygen-dependency of ribonucleotide reductase. More, recently we have implicated the accumulation of R-loops in contributing to not only the hypoxia-induced DDR but also transcriptional stress. Numerous factors play key roles in maintaining R-loops and preventing the accumulation of DNA damage including the DNA/RNA helicase SETX. Using SETX has an exemplar, we have demonstrated that targeting R-loop factors leads to increased DNA damage in hypoxic conditions. Currently, we are testing the hypothesis that hypoxia specific R-loop factors are potential therapeutic targets which offer the possibility of increasing the radiosensitivity of hypoxic cells.
Citation Format: Ester Hammond. Targeting the hypoxia-induced DDR to improve radiotherapy response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA007.
Abstract IA009: Scars of faulty DNA repair in cancer whole genomes
Authors: Setton Jeremy , Powell Simon , Imielinski Marcin 
Published: January 2024

Abstract
Cancer genomes provide a record of the genetic alterations acquired from DNA damage and DNA repair defects during normal cell development and carcinogenesis. Genome-wide somatic alteration patterns in BRCA1-deficient (BRCA1d) and BRCA2-deficient (BRCA2d) cancers are attributed to a deficiency in homologous recombination (HR), a major pathway for the repair of double-strand breaks (DSBs) in human cells. Some of these mutational patterns may reflect specific error-prone repair mechanisms of DSB repair that cells use in the absence of HR. Such mutational patterns can provide biomarkers of HR-deficiency and help identify clinically relevant therapeutic vulnerabilities. HRD is has been associated with specific DNA rearrangements and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements specifically associated with HR-deficient (HRD) cancers only minimally impact chromosomal structure. Addressing this, we combined a genome graph analysis of short-read whole genome sequencing (WGS) profiles across thousands of tumors with deep linked-read (LR) WGS of 46 BRCA1- or BRCA2-mutant breast cancers to discover a distinct class of HR deficiency-enriched rearrangements called reciprocal pairs. LR WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long molecule data. While one (cis) outcome corresponded to the copy and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10kb) duplications at each junction. We propose an HR-independent replication restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. LR WGS additionally identified single-strand annealing (SSA) as a BRCA2-deficiency specific repair pathway in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- vs. BRCA2-deficient genomes. In conclusion, our data reveal classes of BRCA1- and BRCA2-deficiency specific rearrangements as a source of cytogenetic aberrations in HRD cells.
Citation Format: Jeremy Setton, Simon Powell, Marcin Imielinski. Scars of faulty DNA repair in cancer whole genomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA009.
Abstract IA015: Using systems approaches to interrogate DNA double strand break signaling and repair for optimal tumor cell killing
Authors: Kruswick Alex , Kooij Bert van de , Emmons Tiffany R. , Sriram Ganapathy , Martin Emma D. , Arvind Anjali , van Attikum Haico , Yaffe Michael B. 
Published: January 2024

Abstract
Repair of DNA double strand breaks (DSBs) occurs through multiple distinct repair pathways including canonical and microhomology-mediated/Pol Q-dependent end joining (c-NHEJ and alt-NHEJ), homologous recombination (HR), and single strand annealing (SSA). Exactly how a particular DSB dictates which pathway is selected for repair, and the extent to which different DSB repair pathways cross-talk with each other is incompletely understood, but appears to be influenced by the specific type of DNA ends, the extent of DNA resection, the cell state and stage of the cell cycle, and the chromatin context around the break. To simultaneously interrogate multiple DNA DSB repair pathways in a systems-based manner at the single cell level, we built upon the pioneering DSB repair reporter systems created by the Jasin, Stark, Scharenberg and Certo labs to create several new CRISPR-based DNA DSB reporter systems that readout the repair of a single genomic DNA DSB by error-free c-NHEJ, mutagenic c- and alt-NHEJ, HR or SSA using multi-color fluorescence-based imaging and flow cytometry approaches. Using these DSB reporter systems we show that competition between short-range and long-range end resection influences the choice between repair by HR versus SSA, demonstrate accepted and novel functions for a variety of DNA damage sensors and repair proteins in NHEJ and HR, and illustrate the feasibility of using this system to interrogate the effects of patient-specific mutations in DNA repair proteins on DNA DSB repair pathway choice. Finally, we show that DNA DSBs created by topoisomerase inhibitor treatment in live but DNA-damaged tumor cells are capable of activating anti-tumor immune responses by signaling through both canonical and non-canonical DNA break sensing and response pathways.
Citation Format: Alex Kruswick, Bert van de Kooij, Tiffany R. Emmons, Ganapathy Sriram, Emma D. Martin, Anjali Arvind, Haico van Attikum, Michael B. Yaffe. Using systems approaches to interrogate DNA double strand break signaling and repair for optimal tumor cell killing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA015.
Abstract IA023: The role of RTF2 in replication and replication stress response
Authors: Smogorzewska Agata , Broton Cayla , Blobel Nicolas J. , Conti Brooke 
Published: January 2024

Abstract
The replisome faithfully coordinates the essential process of genome duplication despite genomic sequences or lesions that slow or stall replication fork progression, collectively termed replication stress. Such lesions threaten the accurate transmission of the genome; as such, cells have evolved many mechanisms of replication fork protection and repair to ensure that the genome is fully replicated within the confines of S phase. Our group has previously characterized the essential protein Replication Termination Factor 2 (RTF2) as one such facilitator of replication control during both unperturbed and stalled conditions. During unperturbed replication, RTF2 localizes the Ribonuclease H2 heterotrimer (RNase H2) to replication forks, where RNase H2 facilitates the removal of ribonucleotides aberrantly incorporated into the genome to ensure replication fork speeds and promote the completion of genome duplication. When the replisome encounters fork-stalling lesions, however, RTF2-RNase H2 are removed from the replisome through the action of proteasome shuttle proteins DNA Damage Inducible 1 and 2 (DDI1/2) to promote replication restart dependent upon PRIM1, the primase subunit of DNA polymerase α. Further, we find that cells depleted of RTF2 accumulate mitotic markers, including phosphorylated FOXM1 and cyclin B1, during S phase and exhibit abnormal nuclear structures. Together, these findings suggest that RTF2-deficient cells bypass the S/G2 checkpoint, in which ATR functions to suppress CDK1 activity and mitotic progression while replication is ongoing and implicate RTF2 as a mediator of replication checkpoint control.
Citation Format: Agata Smogorzewska, Cayla Broton, Nicolas J. Blobel, Brooke Conti. The role of RTF2 in replication and replication stress response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA023.
Abstract IA024: Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses
Authors: Adolph Madison , Balakrishnan Swati , Chazin Walter , Cortez David 
Published: January 2024

Abstract
RAD51 nucleoprotein filaments are central to maintaining genome stability, governing crucial processes like homology-directed double-strand break repair, replication fork reversal, and shielding replication forks from nucleases. The precise regulation of RAD51 filament formation and stability is critical for these functions, which suppress tumorigenesis and determine cellular responses to common cancer therapies. RADX is a pivotal regulator of RAD51 in the context of DNA replication, impacting replication fork reversal and fork stabilization. After identifying RADX as an RPA-related RAD51 regulator, we have worked to understand how it acts, thereby elucidating its role in genome stability and its influence on cancer cell responses to PARP inhibitors and chemotherapies. Genetically, RADX exhibits a dual role, capable of either inhibiting or promoting replication fork reversal based on the levels of replication stress. Biochemical studies show that RADX has inhibitory effects on RAD51 strand exchange and D-loop formation activities, achieved through direct binding to single-strand DNA and RAD51, along with the stimulation of RAD51 ATP hydrolysis. These activities collectively destabilize RAD51 nucleofilaments, opposing the stabilizing effects of BRCA2. Cells lacking RADX regulatory functions exhibit replication defects, DNA damage accumulation, reduced growth, and heightened sensitivity to DNA damage and replication stress. Structural analyses, including cryo-electron microscopy and mass photometry, revealed how RADX binds ssDNA and show it exists in multiple oligomeric states with a preference for trimers when bound to single-stranded DNA. Negative stain electron microscopy imaging supports a model wherein RADX functions by capping and restricting the growing ends of RAD51 filaments. In summary, our findings provide a comprehensive understanding of the regulatory mechanisms governing RAD51 nucleofilament dynamics by RADX, emphasizing its crucial role in coordinating replication fork stability and genome integrity. This knowledge not only contributes to the fundamental understanding of cellular processes but also offers insights into potential therapeutic interventions targeting RAD51-controlled pathways.
Citation Format: Madison Adolph, Swati Balakrishnan, Walter Chazin, David Cortez. Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA024.
Abstract PR011: Novel role of glycogen synthase kinase-3β in determining cancer cell response to PARPi through regulation of 53BP1 function
Authors: Xia Fen , Allam Heba , Acklin Scarlett , Patra Mousumi , West Kirk , Leung Justin 
Published: January 2024

Abstract
Glycogen synthase kinase-3β (GSK3β) is a multifunctional serine/threonine kinase involved in various cellular processes and signaling pathways. Accumulating evidence suggests GSK3β plays a role in cancer treatment with effects on tumorigenesis and treatment response. We have previously shown that inhibition of GSK3β protects neurons from ionizing radiation-induced apoptosis through regulation of the repair of double strand breaks (DSBs). Here, we investigate the molecular mechanism underlying GSK3β regulation of DSB repair. We illustrate that GSK3β directly interacts with 53BP1 and phosphorylates 53BP1 at threonine 334 amino acid (T334) within a region heavily phosphorylated by several stress kinases. Phosphorylation at T334 inhibits 53BP1’s function in recruitment to and retention at DSB sites as well as canonical NHEJ. In contrast, phosphorylation at Thr334 of 53BP1 enhances single strand DNA resection and promotes homologous recombination (HR) repair. Most importantly, genetic and pharmacologic inhibition of GSK3β-53BP1 signaling axis dramatically enhances the PARPi cytotoxic response of BRCA1 proficient cancer cells. The assessment of the effect of GSK3β-53BP1 axis on tumor cell response to radiation treatment is underway. In conclusion, this study establishes the connection between GSK3β kinase and DSB repair through its phosphorylation and regulation of 53BP1 property. Moreover, it demonstrates that GSK3β kinase activity uniquely results in inhibition of 53BP1 as opposed to other kinases that enhance 53BP1 function. Importantly, this novel signaling axis provides a strategy for targeting BRCA1-proficinet cancer cell resistance to PARPi.
Citation Format: Fen Xia, Heba Allam, Scarlett Acklin, Mousumi Patra, Kirk West, Justin Leung. Novel role of glycogen synthase kinase-3β in determining cancer cell response to PARPi through regulation of 53BP1 function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR011.
The Oncolytic Activity of Zika Viral Therapy in Human Neuroblastoma In Vivo Models Confers a Major Survival Advantage in a CD24-dependent Manner
Authors: Mazar Joseph , Brooks Jeanne K. , Peloquin Matthew , Rosario Rosa , Sutton Emma , Longo Matthew , Drehner Dennis , Westmoreland Tamarah J. 
Published: January 2024

Abstract

Neuroblastoma is the most common extracranial tumor, accounting for 15% of all childhood cancer-related deaths. The long-term survival of patients with high-risk tumors is less than 40%, and MYCN amplification is one of the most common indicators of poor outcomes. Zika virus (ZIKV) is a mosquito-borne flavivirus associated with mild constitutional symptoms outside the fetal period. Our published data showed that high-risk and recurrent neuroblastoma cells are permissive to ZIKV infection, resulting in cell type–specific lysis. In this study, we assessed the efficacy of ZIKV as an oncolytic treatment for high-risk neuroblastoma using in vivo tumor models. Utilizing both MYCN-amplified and non-amplified models, we demonstrated that the application of ZIKV had a rapid tumoricidal effect. This led to a nearly total loss of the tumor mass without evidence of recurrence, offering a robust survival advantage to the host. Detection of the viral NS1 protein within the tumors confirmed that a permissive infection preceded tissue necrosis. Despite robust titers within the tumor, viral shedding to the host was poor and diminished rapidly, correlating with no detectable side effects to the murine host. Assessments from both primary pretreatment and recurrent posttreatment isolates confirmed that permissive sensitivity to ZIKV killing was dependent on the expression of CD24, which was highly expressed in neuroblastomas and conferred a proliferative advantage to tumor growth. Exploiting this viral sensitivity to CD24 offers the possibility of its use as a prognostic target for a broad population of expressing cancers, many of which have shown resistance to current clinical therapies.

Significance:
Sensitivity to the tumoricidal effect of ZIKV on high-risk neuroblastoma tumors is dependent on CD24 expression, offering a prognostic marker for this oncolytic therapy in an extensive array of CD24-expressing cancers.