bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA07: Genetic determinants of tumor development, therapy response and resistance in mouse models of BRCA-deficient breast cancer
Authors: Jonkers Jos 
Published: April 2017

Abstract
Heterozygous germline mutations in BRCA1 or BRCA2 strongly predispose to development of breast and ovarian cancer (as well as other cancer types) via loss of the remaining wildtype allele. BRCA1/2-deficient cancers are defective in DNA double-strand break (DSB) repair via homologous recombination (HR) and therefore hypersensitive to DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors. However, these treatments do not result in tumor eradication and eventually resistance develops. To maximize therapeutic efficacy of these drugs and achieve durable remissions, it is important to unravel the mechanisms by which these tumors acquire resistance to platinum drugs and PARP inhibitors, in order to develop combination therapies that prevent development of resistance or re-sensitize resistant tumors.
To study therapy response and resistance in a realistic in vivo setting, we have established several genetically engineered mouse models (GEMMs) and patient-derived tumor xenograft (PDX) models for BRCA-deficient breast cancer. These mice develop mammary tumors that are characterized by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Using cross-species oncogenomics and reverse genetics, we have identified several cancer genes including p53, MYC and RB as critical drivers in BRCA1-associated breast cancer. In addition, we have used these mammary tumor models for preclinical evaluation of therapy response and elucidation of mechanisms of acquired drug resistance. Using functional genetic screens, reverse genetics and genomic analysis of therapy-resistant tumors, we found that therapy response and resistance of BRCA1-deficient mammary tumors to cisplatin and the clinical PARP inhibitor olaparib is affected by several factors, including drug efflux transporter activity, type of BRCA1 founder mutation and restoration of HR repair via loss of 53BP1 or REV7. Also BRCA1 re-activation via genetic or epigenetic mechanisms contributes to therapy resistance in PDX models of BRCA1-deficient breast cancer. Importantly, pharmacokinetic or HR-related mechanisms underlie olaparib-resistance in only a fraction of BRCA1/2-deficient mammary tumors, indicating the existence of additional, unknown mechanisms.
Citation Format: Jos Jonkers. Genetic determinants of tumor development, therapy response and resistance in mouse models of BRCA-deficient breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA07.
Abstract IA10: DNA repair mutations in ovarian carcinoma and relationship to therapeutic response
Authors: Swisher Elizabeth M. 
Published: April 2017

Abstract
Ovarian carcinomas with germline or somatic mutations in BRCA1 and BRCA2 are sensitive to platinum chemotherapy and to PARP inhibitors. The therapeutic role of damaging mutations in other homologous recombination genes is less certain. We will review various measures of homologous recombination deficiency in ovarian cancer and their correlation with efficacy of PARP inhibitor therapy in the relapsed setting.
Citation Format: Elizabeth M. Swisher. DNA repair mutations in ovarian carcinoma and relationship to therapeutic response [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA10.
Abstract IA12: Poisoning cancer with oxidized nucleotides by targeting MTH1
Authors: Helleday Thomas 
Published: April 2017

Abstract
DNA damaging agents, i.e., radio- and chemotherapy, constitute the backbone for treatment of a wide variety of cancers and may result in complete cure from the disease. Here, I will give an overview on how DNA repair can be targeted using completely novel inhibitors and more specifically how cancer cells may require a specific DNA repair pathway to mediate survival to the high load of endogenous DNA damage. Cancers have deregulated levels of reactive oxygen species (ROS), damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools, converting 8-oxo-dGTP to 8-oxo-dGMP, to prevent incorporation of damaged bases during DNA replication. MTH1 overexpression reverses the mutator phenotype caused by mismatch repair defects and prevents Ras-induced senescence by suppressing the overall level of DNA damage. These data suggest that a majority of damage in cancer cells occur on the free dNTP pool and that this need sanitation for cancer cell survival. Here we show that cancer cells are dependent on MTH1 activity for survival, due to the effects of MTH1 in preventing incorporation of oxidized dNTPs into DNA to avoid ATM and p53 mediated apoptosis. As MTH1-/- mice are viable and MTH1 is not required for survival of non-transformed cells, targeting MTH1 may selectively cause DNA damage to cancer cells. We validate MTH1 as an anti-cancer target in vivo and describe small molecules, TH287 and TH588 that potently and selectively inhibit MTH1. Protein co-crystal structures demonstrate that the compounds bind as inhibitors in the enzymatic pocket of MTH1. These first-in-class inhibitors of the Nudix hydrolase family cause increased incorporation of oxidized dNTPs in cells subject to high ROS levels, causing DNA damage and cytotoxicity to cancer cells. This study exemplifies a new general therapeutic approach to convert oxidative stress to cytotoxic DNA damage and cancer cell death. Here, I will present the progression of MTH1 inhibitors from pre-clinical development into early clinical trials.
References:
Gad et al 2014 Nature. 508(7495):215-21.
Citation Format: Thomas Helleday. Poisoning cancer with oxidized nucleotides by targeting MTH1 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA12.
Abstract IA13: Replication stress in cancer pathogenesis: Mechanisms and treatment opportunities
Authors: Bartek Jiri , Bartkova Jirina 
Published: April 2017

Abstract
Replication stress (RS) induced by activated oncogenes and loss of some tumor suppressors is emerging as one of the hallmarks of cancer. The RS-induced DNA damage and the ensuing activation of cell cycle checkpoints commonly induce cellular senescence or cell death of the nascent tumor cells, providing an inducible intrinsic barrier to cancer progression. On the other hand, this scenario creates an environment that favors outgrowth of tumor cell clones featuring p53 mutations and other checkpoint defects such as those in ATM or Chk2 kinases, events that allow tumor growth at the expense of enhanced genomic instability. The ongoing enhanced RS, on the other hand, unmasks higher dependence of tumor cells on RS-support pathways such as those provided by the ATR-Chk1 axis and replication fork protective mechanisms, a vulnerability that can be targeted by inhibitors of ATR, Chk1, MK2 and Wee1 kinases, for example.
The lecture will briefly outline this concept and then focus on our new data relevant for three of the open questions in this field:
i) How are the molecular obstacles such as RNA-DNA hybrids and aberrant intermediates resulting from RS-causing collisions between replication and transcription resolved in cells?;
ii) What is the impact of RS and the ensuing ATR signaling on the mutation spectra (mutation signatures) in major types of human solid tumors such as breast carcinomas?; and
iii) How do human aggressive cancers such as glioblastomas cope with the excessive endogenous RS, how do such mechanisms promote tumor cell survival and how could this knowledge help in designing innovative treatment strategies.
Citation Format: Jiri Bartek, Jirina Bartkova. Replication stress in cancer pathogenesis: Mechanisms and treatment opportunities [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA13.
Abstract IA19: PARP trapping and Schlafen 11
Authors: Pommier Yves , Murai Junko 
Published: April 2017

Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARP inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs.
Citation Format: Yves Pommier, Junko Murai. PARP trapping and Schlafen 11 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA19.
Abstract IA26: Dual functions of PARP1 in prostate cancer: mechanisms and implications for therapeutic intervention
Authors: Knudsen Karen E. 
Published: April 2017

Abstract
Prostatic adenocarcinoma (PCa) is the 2nd leading cause of cancer death in US men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct AR antagonists, as PCa is exquisitely dependent on androgen receptor (AR) activity for survival. Furthermore, recent studies identified AR as a major effector of DNA repair, manifest through the ability of the receptor to regulate DNAPK expression and activity. While AR directed therapeutics effectively suppress the pro-proliferative, pro-survival, and pro-DNA repair functions of AR and result in tumor remission, relapse is common. Recurrent disease arises largely due to resurgent AR activity with 2-3 years, and there is no cure for this castration-resistant phase (CRPC, castration-resistant PCa). Thus, there is a significant need to develop new means for targeting recurrent AR activity or develop adjuvant therapies in advanced PCa.
The function of PARP1 in DNA repair has been cultivated as a therapeutic target for tumors incurring alterations of specific DNA repair pathways. However, it is now clear that factors beyond DNA repair alterations play a role in the response to PARP1 inhibitors-- as noted in the TO-PARP trial, not all patients with DNA repair alterations responded to PARP1 inhibitors as single agents; conversely, a significant number tumors lacking BRCA1/2 or other DNA repair alterations show objective responses to PARP1 inhibitors in PCa and other cancers. PARP1 is known to harbor a second major cellular function on chromatin as a transcriptional co-regulator, capable of modulating chromatin structure and selected transcription factor activity. Notably, previous studies demonstrated that PARP1 regulates AR residence on chromatin, and downstream AR-dependent tumor progression. Recent unpublished studies to be discussed demonstrate that PARP1 activity is significantly enriched in lethal disease, and that a newly identified gene signature of PARP1-regulated networks is associated with poor outcome. Further, mechanistic investigation revealed new insight into the means by which PARP1 inhibitors likely act function as single agents in advanced prostate cancer, manifest through both DNA repair and transcriptional regulatory functions.
Citation Format: Karen E. Knudsen. Dual functions of PARP1 in prostate cancer: mechanisms and implications for therapeutic intervention [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA26.
Abstract IA27: Exploiting the inhibition of cullin-RING-ligases in DSB repair as a therapeutic strategy
Authors: Morgan Meredith 
Published: April 2017

Abstract
While single component E3 ubiquitin ligases have established roles in DNA double-strand break (DSB) repair, the function of multicomponent cullin-RING-ligases (CRL) in DSB repair is only beginning to emerge. FBXW7 is a substrate recognition component of Skp1-Cullin1-F-box E3 ubiquitin ligases previously known only to regulate the proteasomal degradation of substrates such as Cyclin E and MCL1. Given that FBXW7 loss promotes genomic instability, we hypothesized that FBXW7 may have a direct function in DSB repair. To establish the functions of FBXW7 in DSB repair, we first demonstrated the rapid localization of FBXW7 to DSB sites in an ATM-dependent manner. Subsequently, we found that FBXW7 depletion impaired nonhomologous end-joining (NHEJ), but not homologous recombination (HR) repair, resulting in persistent radiation-induced DSBs. Investigation of the molecular mechanisms of FBXW7 in NHEJ revealed that FBXW7 interacts with and promotes K63-linked ubiquitination of XRCC4. This ubiquitination of XRCC4 promotes interaction between the XRCC4/XLF/LIG4 and DNAPK/KU70/KU80 complexes to facilitate NHEJ. To begin to therapeutically leverage this mechanism, strategies to both pharmacologically inhibit FBXW7-CRLs and to exploit FBXW7 mutations occurring in human cancers are being developed. To address the former, pevonedistat (MLN4924), an agent which inhibits CRLs via inhibition of cullin-neddylation, inhibits FBXW7-mediated XRCC4 ubiquitination and NHEJ. This activity leads to increased sensitivity of tumor cells to chemotherapy and radiation and represents a strategy that may be particularly effective in cancers with other DSB repair defects. As another strategy to leverage the mechanisms of FBXW7 in NHEJ, loss-of-function mutations in the WD domain of FBXW7 which occur frequently in human cancers are being explored. These mutations render cells defective in NHEJ and more sensitive to DNA damage. Thus, we hypothesize that inhibition of other DSB repair pathways (e.g. alternative-end-joining) may be an effective therapeutic strategy for FBXW7 mutant cancers. These novel mechanisms of NHEJ regulation as well as their implications in the treatment of human cancers with an emphasis on pancreatic and colorectal cancers will be discussed.
This work was supported by NIH grants R01CA163895, P50CA130810, R01CA118762, R01CA156744, and R01CA171277.
Citation Format: Meredith Morgan. Exploiting the inhibition of cullin-RING-ligases in DSB repair as a therapeutic strategy [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA27.
Abstract PR04: Mechanism for PARPi resistance: Homologous recombination without BRCA1
Authors: He Yizhou Joseph , Meghani Khyati , Chowdhury Dipanjan 
Published: April 2017

Abstract
Approximately 15-20% of all epithelial ovarian cancers harbor germline or somatic mutations in BRCA1/2. Despite PARP inhibitor induce synthetic lethality in non-cancerous mouse embryo fibroblast cells that harbor BRCA1/2 mutations, a substantial fraction of BRCA1/2-mutated tumors patients do not respond to PARPi treatment, and a large fraction of BRCA1/2-mutated tumors patients eventually develop resistance to PARPi suggest significant frequency of acquired mutation lead to PARPi resistance preventing complete cure.
We use CRISPR based library screen identified ATMIN/DYNLL1 loss as strong candidate for PARPi and cisplatin resistance mechanism. Targeted mutation on ATMIN or its transcription target DYNLL1 lead to increase of Cisplatin IC50 up to 200% and Olaparib IC50 up to 400%. More interestingly, ATMIN/DYNLL1 loss lead to restoration of Homologous recombination in BRCA1 mutant cells. ATMIN is under-expressed in about 30% ovarian cancer patient and low ATMIN expression correlate with shorter survival. Since ATMIN is important for DNA base damage repair but not Double Strand Break repair, we hypothesis ATMIN play important role in DNA damage repair pathway choice to suppress DSB repair while promote DNA base damage repair. Cells with mutant BRCA1 and loss ATMIN/DYNLL1 may result in abnormal DSB repair activity and lead to resistance to DNA damage agent such as Olaparib and Cisplatin.
This abstract is also being presented as Poster A18.
Citation Format: Yizhou Joseph He, Khyati Meghani, Dipanjan Chowdhury. Mechanism for PARPi resistance: Homologous recombination without BRCA1 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR04.
Abstract PR17: The transcriptional repressor Slug promotes the DNA damage response
Authors: Zhou Wenhui , Ouyang Jian , Huber Kathryn , Kuperwasser Charlotte 
Published: April 2017

Abstract
The transcriptional repressor Slug/SNAI2 orchestrates epigenetic programs indispensable for tissue self-renewal and tumorigenesis. Although Slug-deficient animals are highly sensitive to lethal irradiation, the direct biological relationship between Slug and the DNA damage response remains largely unexplored. Here we report that Slug interacts with DNA repair proteins, including FANCI, BCCIP and PARP1, in a mass spectrometry screen for Slug binding partners. In response to double-strand breaks (DSBs) induced by irradiation, Slug-deficient cells exhibited a marked delay in the resolution of γH2ax foci. Furthermore, we showed that Slug inhibition significantly impaired DSBs repair that is mediated by homologous recombination. Accordingly, Slug-deficient mouse tissue accumulates DNA damage markers and showed altered nuclear morphology. Mechanistically, Slug interacts with and is stabilized by ATM upon DNA damage. Finally, we demonstrated that Slug depletion sensitizes aggressive triple-negative breast cancer cells to irradiation and chemotherapy. These findings suggest that Slug may be an important regulator of the DNA damage response and an attractive therapeutic target for aggressive cancer types.
This abstract is also being presented as Poster B16.
Citation Format: Wenhui Zhou, Jian Ouyang, Kathryn Huber, Charlotte Kuperwasser. The transcriptional repressor Slug promotes the DNA damage response [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR17.
Abstract PR20: A 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms
Authors: Cuella-Martin Raquel , Oliveira Catarina , Lockstone Helen E. , Snellenberg Suzanne , Grolmusova Natalia , Chapman J Ross 
Published: April 2017

Abstract
The tumor suppressor protein 53BP1 was first identified as a p53-interacting protein over two decades ago, however its direct contribution to p53-dependent cellular activities has remained enigmatic. Having reinvestigated the link between 53BP1 and p53, we now show 53BP1 plays an important role in directly stimulating genome-wide p53-dependent gene transactivation and repression events in response to ionizing radiation (IR) and synthetic p53 activation. We have also fine-mapped the domains in 53BP1 that modulate p53 activity and reveal it requires both auto-oligomerization and its tandem-BRCT domain-mediated bivalent interactions with p53 and the ubiquitin-specific protease USP28. Loss of 53BP1 or USP28 catalytic activities results in inefficient p53-dependent cell-cycle checkpoint and exit responses. Mechanistically, we show 53BP1-USP28 cooperation to be essential for stimulating normal p53-promoter element interactions and downstream gene transactivation-associated events, yet dispensable for 53BP1-dependent DSB repair regulation. Collectively, our data indicate a upstream role for 53BP1-USP28 complexes in priming p53's transcriptional potential, providing a mechanistic explanation for 53BP1-p53 cooperation in controlling anti-tumorigenic cell-fate decisions. Moreover, we reveal these activities to be distinct and separable from 53BP1's regulation of DNA double-strand break repair pathway choice, and establish the prime function for the 53BP1 BRCT domain and its interaction partner USP28. Our study therefore defines important and novel functions for 53BP1 in enforcing a vital tumor suppressor pathway that are likely to contribute to tumor suppression. In the meeting we will describe these findings and update on recent progress.
This abstract is also being presented as Poster B04.
Citation Format: Raquel Cuella-Martin, Catarina Oliveira, Helen E. Lockstone, Suzanne Snellenberg, Natalia Grolmusova, J Ross Chapman. A 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR20.