bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B056: Modulation of the DNA replication stress response and chemo-response by the mono-ADP-ribosyltransferase PARP14
Authors: Dhoonmoon Ashna , Nicolae Claudia M , Moldovan George-Lucian 
Published: December 2023

Abstract
Genomic instability is a major hallmark of cancer and one of the most common causes is DNA replication stress. Mutations in genes involved in the DNA replication stress response are closely linked to cancer predisposition and progression but this has been exploited clinically. In the advent of personalized medicine, it has become clear that a better understanding of underlying mechanisms is important to advance cancer therapy, especially to address chemoresistance. Here, we identified novel roles for PARP14, a lesser studied member of the PARP family, in regulation of the replication stress response, and subsequently genomic stability and chemo-response. PARP14 is an ADP-ribosyltransferase with multiple roles in transcription, signaling, and DNA repair. To understand the biological functions of PARP14, we first catalogued the genetic components that impact cellular viability upon loss of PARP14 by performing an unbiased, comprehensive, genome-wide CRISPR knockout genetic screen in PARP14-deficient cells. We uncovered the ATR-CHK1 pathway as essential for viability of PARP14-deficient cells and identified regulation of DNA replication dynamics as an important mechanistic contributor to the synthetic lethality observed. Furthermore, we showed that PARP14 plays a central role in stabilization of stalled replication forks which arise due to high replication stress level in BRCA1/2 deficient cells. Mechanistically, we showed that PARP14 mediates stalled replication fork degradation via its interaction with the nuclease MRE11. Moreover, we also identified KU as an essential component of a multi-step mechanism by which the KU-PARP14 axis differentially promotes degradation by the nucleases MRE11 and EXO1. This mechanism restores genomic stability in BRCA-deficient cells and subsequently promotes chemoresistance. Overall, our work provides insights into novel mechanisms by which PARP14 affects the replication stress response and demonstrates that PARP14 can be used as a biomarker for chemo-response.
Citation Format: Ashna Dhoonmoon, Claudia M Nicolae, George-Lucian Moldovan. Modulation of the DNA replication stress response and chemo-response by the mono-ADP-ribosyltransferase PARP14 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B056.
Abstract B064: Single-cell RNA sequencing reveals tumorigenic trajectories of mismatch repair deficient cells
Authors: Vitor Alexandra , Benfatto Salvatore , Zenke Frank , Waszak Sebastian , Mardin Balca 
Published: December 2023

Abstract
Mismatch repair (MMR) deficiency is commonly found in tumors with high mutational burden. Although the mutational signatures of these deficiencies are determined, the initial trajectories these cells follow to reach a tumorigenic state with high mutational load have not been studied due to lack of isogenic model systems. For this reason, we generated three isogenic MMR deficient cell lines from a normally untransformed cell line with few genomic abnormalities and low mutational burden. After continued culturing of these MMR-deficient cell lines for several months, we profiled them by single cell RNA sequencing using the 10X Chromium platform. Next, we identified different clusters of cells in MMR deficient cell lines that acquire tumorigenic properties. In these clusters, we identified gene expression signatures that are responsible from the tumorigenic properties of these clusters of cells. After isolation of the single clones that bear these gene expression signatures, we characterized how MMR deficiency can give rise to tumors with particular gene expression trajectories. In addition, we performed CRISPR/Cas9-based genome-wide screens to understand the vulnerabilities of these clusters of cells. Altogether, our results shed light on the early steps of tumorigenesis in MMR deficiency.
Citation Format: Alexandra Vitor, Salvatore Benfatto, Frank Zenke, Sebastian Waszak, Balca Mardin. Single-cell RNA sequencing reveals tumorigenic trajectories of mismatch repair deficient cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B064.
Abstract B069: Targeting vulnerabilities in double strand break repair in cancer with polymerase theta inhibitors
Authors: Noronha Katelyn , Liu Samantha , Lucas Karlie , Bindra Ranjit S. 
Published: December 2023

Abstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in approximately 80% of secondary glioblastomas and low-grade gliomas and to a lesser extent in AML, cholangiocarcinoma, colorectal cancer, and chondrosarcomas. Mutations in IDH1/2 lead to the overproduction of 2-hydroxyglutarate (2HG), which has been named an “oncometabolite” and is implicated in cancer progression. Work by our group has shown that 2HG induced hypermethylation suppresses homologous recombination repair. As a result, cells with mutations in IDH1/2 accumulate double strand breaks (DSBs) that must be addressed by other modes of DSB repair, such as canonical NHEJ or polymerase theta mediated end joining (TMEJ). Furthermore, TMEJ is understudied in IDH1/2-mutant cancers but has been studied extensively in other HR-deficient cancer contexts, such as BRCA-mutant cancers. Conflicting reports remain on whether TMEJ promotes genomic stability or instability in these contexts, due to its error prone repair. To better understand how IDH1/2-mutant cells utilize TMEJ and polymerase theta’s impact on genomic stability, we studied the effects of polymerase theta inhibitors on isogenic cell line models of the IDH1R132H mutation. We find that mRNA levels of polymerase theta are increased in IDH1-mutant cell lines. Using a polymerase theta inhibitor, ART558, we also observed reduced viability in IDH1-mutant cells compared to parental cells. This loss of viability in IDH1-mutant cells is likely a result of the observed increase of gamma H2AX subnuclear foci in IDH1-mutant cells treated with ART558, which is a marker of unresolved DNA damage. Preliminary data suggests that this unrepaired damage is contributing to an overall increase in micronuclei formation in IDH1-mutant cells treated with ART558 as well. Taken together, these results suggest that IDH1-mutant cells upregulate polymerase theta expression to promote genomic stability through repair of persistent DSBs. This study on TMEJ in IDH1/2 mutant cancers has identified a therapeutic vulnerability in these HR-deficient cancers that can be targeted with polymerase theta inhibitors.
Citation Format: Katelyn Noronha, Samantha Liu, Karlie Lucas, Ranjit S. Bindra. Targeting vulnerabilities in double strand break repair in cancer with polymerase theta inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B069.
Abstract B070: Antitumor effect of AZD5305, a selective PARP1 inhibitor, in breast and gastric cancer cells
Authors: Ham Sujin , Kim So Hyeon , Hwang Hae Min , Lee Minyoung , Noh Youlim , Lee Changyun , Kim Yu-Jin , Kim Jinyong , Lee Dae-Won , Lee Kyung-Hun , Im Seock-Ah 
Published: December 2023

Abstract
Background: Poly (ADP-ribose) polymerase (PARP) 1 has multiple cellular functions including its crucial role in DNA damage response. PARP inhibitor (PARPi) blocks the synthesis of PAR polymers and traps PARP1 on the damage sites. Currently approved PARPis target both PARP1 and PARP2, but the inhibition of PARP2 can cause undesirable hematological toxicity. AZD5305 is a novel selective PARP1 inhibitor that can reduce the hematological toxicity by off-targeting of PARP2. We evaluated the anti-tumor effects and mechanism of action of AZD5305 in breast and gastric cancer cells in vitro.
Methods: To investigate the anti-tumor effects of AZD5305, we used 2 cell lines of breast cancer cells (HCC1395 and MCF7) and 3 cell lines of human gastric cancer cells (SNU-601, SNU-668 and KATO Ⅲ). The cytotoxicity of AZD5305 was evaluated by colony formation assay (CFA) for 14 days with increasing concentration of AZD5305 (doses range: 0-5nM). Cell cycle was analyzed by flow cytometry and apoptotic cell death was assessed by annexin-Ⅴ/PI staining. DNA damage was detected by comet assay and cell immunofluorescence assay.
Results: BRCA1/2 mutated HCC1395 and RAD51C deficient SNU-601 were sensitive to AZD5305 (IC50: 0.25 nM), and SNU-668 was moderately sensitive (IC50: 2.05nM), while MCF7 and KATO III were less-sensitive to AZD5305 (IC50 &gt; 5 nM). AZD5305 induced the G2/M cell cycle arrest in a dose-dependent manner in HCC1395 and SNU-601, but not in MCF7 and KATO Ⅲ. Moreover, AZD5305 increased sub-G1 population in HCC1395 and SNU-601 cells indicating apoptotic cell death, which was also confirmed by annexin-V assay and the cleaved PARP and caspase-7. Phosphorylation of RPA, γH2AX, and the expression of molecules related to DNA damage response were increased in the sensitive cells. Moreover, comet tails which indicate fragmented DNA were observed in the sensitive cells, but not in insensitive cells.
Conclusions: AZD5305, a novel PARP1 selective inhibitor, shows cytotoxic effect in HR defective breast and gastric cancer cells in vitro. AZD5305 accumulates DNA damage which leads to apoptotic cell death in sensitive cell lines, but not in less-sensitive cell lines.
Citation Format: Sujin Ham, So Hyeon Kim, Hae Min Hwang, Minyoung Lee, Youlim Noh, Changyun Lee, Yu-Jin Kim, Jinyong Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im. Antitumor effect of AZD5305, a selective PARP1 inhibitor, in breast and gastric cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B070.
Abstract B091: Overexpression of Muscleblind Like Splicing Regulator 2 (MBNL2) enhances cisplatin resistance in ovarian cancer
Authors: Ju Woong , Sung Hye Youn , Ahn Jung-Hyuck 
Published: December 2023

Abstract
Ovarian cancer is the second most commonly diagnosed gynecological cancer and has the highest mortality rate of all gynecological cancers worldwide. Although cisplatin is one of the most effective antitumor drugs for ovarian cancer, the emergence of chemoresistance to cisplatin is a major barrier to successful therapy. To identify epigenetically regulated genes directly associated with ovarian cancer cisplatin resistance, we compared the expression and methylation profiles of cisplatin-sensitive and -resistant human ovarian cancer cell lines. We identified Muscleblind Like Splicing Regulator 2 (MBNL2) as one of the key candidate genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, MBNL2 mRNA expression was significantly upregulated, and the MBNL2 promoter was associated with hypomethylation of the specific cytosine-phosphate-guanine (CpG) sites. Reduced MBNL2 expression in cisplatin-sensitive cell lines was restored by treatment with a DNA demethylation agent, suggesting epigenetic regulation of MBNL2 expression by promoter methylation. Furthermore, depletion of MBNL2 in cisplatin-resistant cells induced cytotoxicity in response to cisplatin, whereas overexpression of MBNL2 in cisplatin-sensitive cells increased chemoresistance, indicating that MBNL2 plays a vital role in developing chemoresistance in ovarian cancer cells. Furthermore, we performed meta-analysis using fourteen publicly available datasets to assess the association between expression of MBNL2 and overall survival in patients with serous-type ovarian cancer. The pooled Hazard ratios (HRs) estimate was significantly greater than 1 for overall survival (HR=1.09, p-value=0.0034). The association was more significant (HR=1.12, p-value=0.001) when tumor stage was added to the survival analysis as a covariate. The meta-analysis revealed that high expression of MBNL2 was significantly associated with poor prognosis and a higher risk of death in ovarian cancer patients with serous tumor. Additionally, we further validated the MBNL2 mRNA expression in primary ovarian tumor tissues. The statistically significant upregulation of MBNL2 mRNA expression was observed in cisplatin-resistant patients compared to that of cisplatin-sensitive patients. Our findings suggest MBNL2 may be a potential therapeutic target for the prevention of chemoresistance to cisplatin in ovarian cancer.
Citation Format: Woong Ju, Hye Youn Sung, Jung-Hyuck Ahn. Overexpression of Muscleblind Like Splicing Regulator 2 (MBNL2) enhances cisplatin resistance in ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B091.
Abstract B094: Pentraxin 3 promotes the therapy resistance to sorafenib via regulating apoptosis in hepatocellular carcinoma
Authors: Chen Ping-Wen 
Published: December 2023

Abstract
Hepatocellular carcinoma (HCC) is prevalently regarded as an inflammation-related cancer, characterized by persistent inflammation throughout the tumor microenvironment (TME). Currently, Sorafenib is the first-line targeted therapy drug used for advanced HCC patients. Unfortunately, many patients still face the risk of drug resistance after treatment with sorafenib. Pentraxin 3 (PTX3) has been reported as a secretory protein involved in cancer-related inflammation. It has been found to be overexpressed and acts as an unfavorable prognostic factor in the progression of chronic inflammation-related cancers. A recent study indicated that HCC patients who received sorafenib treatment had significantly higher PTX3 expression. However, the detailed role of PTX3 in these sorafenib-treated HCC patients still remains unclear. Therefore, it is intriguing whether elevated PTX3 contributes to sorafenib resistance in HCC patients. In this study, we observed that PTX3 is responsive to sorafenib, and there is a positive correlation between PTX3 expression and sorafenib resistance. Depletion of PTX3 led to increased sensitivity of HCC cells to sorafenib. For the underlying mechanism, sorafenib-induced PTX3 was found to promote resistance by regulating the anti-apoptotic protein MCL-1 and the pro-apoptotic protein BAX. In vivo experiments also revealed that combined treatment of sorafenib and a PTX3 inhibitor significantly reduced the size of HCC tumors, demonstrating that blocking elevated PTX3 increases sensitivity to sorafenib. Overall, targeting PTX3 attenuates resistance to sorafenib through the regulation of apoptosis, providing a novel therapeutic strategy to enhance therapeutic efficacy in HCC patients undergoing sorafenib treatment.
Citation Format: Ping-Wen Chen. Pentraxin 3 promotes the therapy resistance to sorafenib via regulating apoptosis in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B094.
Abstract B115: Preclinical characterization of LY3962673, an orally bioavailable, highly potent, and selective KRAS G12D inhibitor
Authors: Iyer Chandrasekar , Li Binghui , Stewart Trent R , Wang Tao , Capen Andrew , Cavitt Rachel , Anderson Bryan D , Bocchinfuso Wayne , Zhao Gaiying , Rodriguez Michael J , Carballares Santiago , Cooke Andrew , Bondi Robert , Burns Lee , Kelamangalath Lakshmi , Wallace Ross , Kolakowski Gabrielle , Henry James R , Si Chong 
Published: December 2023

Abstract
KRAS G12D mutations are activating oncogenic events that occur in approximately 35%, 13%, and 4% of pancreatic, colorectal, and non-small cell lung cancers, respectively and less commonly in other cancers. Here, we describe LY3962673, a highly potent inhibitor of KRAS G12D that is selective against wild-type (WT) KRAS and orally bioavailable. Compound potency and selectivity were measured using surface plasmon resonance (SPR) and cell-based assays monitoring the inhibition of pERK (Thr202/Tyr204) and cell growth. In SPR assays, LY3962673 had Kd values of 0.058 and 4.7 nM for GDP-bound KRAS G12D and WT KRAS, respectively (81-fold selective). In KRAS G12D-mutant HPAC, LY3962673 inhibited ERK1/2 phosphorylation with an IC50 of 4.2 nM contrasting 231 nM IC50 in WT KRAS MKN45 cells (55-fold selective). Similarly, LY3962673 inhibited cell growth in KRAS G12D and WT KRAS cell lines with IC50 values of 7.7 nM and 1800 nM, respectively (233-fold selective). LY3962673 shows a clean safety profile in a 133 off-target panel screen. LY3962673 demonstrates favorable in vitro ADME properties. LY3962673 shows oral bioavailability across preclinical species when dosed either as freebase or salt form. Tumor growth inhibition and PK/PD studies were performed in mice. In vivo, LY3962673 administered orally demonstrated tumor regressions in KRAS G12D-driven tumor models, without body weight loss. This wide therapeutic index is predicted to allow for maximizing dose intensity and efficacy in patients. These data demonstrate that LY3962673 potently inhibits KRAS G12D while sparing WT KRAS and other off-targets with its selectivity. We hypothesize that LY3962673’s low nanomolar potency, desirable selectivity profile, and oral bioavailability will provide efficacy and tolerability in patients with KRAS G12D-driven cancers. An IND submission is planned in the first half of 2024.
Citation Format: Chandrasekar Iyer, Binghui Li, Trent R Stewart, Tao Wang, Andrew Capen, Rachel Cavitt, Bryan D Anderson, Wayne Bocchinfuso, Gaiying Zhao, Michael J Rodriguez, Santiago Carballares, Andrew Cooke, Robert Bondi, Lee Burns, Lakshmi Kelamangalath, Ross Wallace, Gabrielle Kolakowski, James R Henry, Chong Si. Preclinical characterization of LY3962673, an orally bioavailable, highly potent, and selective KRAS G12D inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B115.
Abstract B141: Evaluation of antigen-agnostic anti-tumor activity and immunological memory induced by CBX-15 (alphalexTM-MMAE) in the rat syngeneic breast cancer model
Authors: Gayle Sophia , Paradis Timothy , Zhang Qing , Tylaska Laurie , Hagen Connor , Pasqualini Theresa , Paralkar Vishwas 
Published: December 2023

Abstract
CBX-15 is a peptide-drug conjugate consisting of alphalexTM-monomethyl auristatin E (MMAE). The alphalexTM is a unique variant of pH-Low Insertion Peptide1 (pHLIP®) designed to target the low pH microenvironment of cancer cells, a universal feature of all rapidly growing tumors. The peptide of CBX-15 forms an alpha helix only in low pH conditions, resulting in unidirectional insertion of the peptide and delivery of MMAE across the cancer cell membrane, and avoidance of delivery to healthy tissues, including immune cells. Efficacy and anti-tumor immunological memory induced by CBX-15 was evaluated in Fischer 344 rats bearing syngeneic 13762 mammary adenocarcinoma tumors. The development of anti-tumor immunological memory was examined in CBX-15-cured animals by in vivo/ex vivo rechallenge with live tumor cells and subsequent assessment of tumor rejection, cytokine release by T cells, tumor immune cell infiltration, and memory T cell composition of the bone marrow. CBX-15 rapidly regressed rat tumors, resulting in complete responses while sparing healthy tissues such as bone marrow. Cured rats rejected live tumor rechallenge and exhibited a doubling of bone marrow-resident CD4 memory T cells 50 days post-dose. Splenocytes and lymph node suspensions derived from cured rats demonstrated formation of a Th1-mediated IFNƳ response when exposed ex vivo to tumor cells. The ability of CBX-15 to induce immunogenic cell death was established by vaccinating syngeneic animals with CBX-15 treated tumor cells and subsequent tumor rechallenge, which demonstrated anti-tumor immunity induced by CBX-15. These preclinical data demonstrate the anti-tumor efficacy of CBX-15 in the rat as well as the ability of CBX-15 to enhance tumor immunogenicity through immunogenic cell death by utilizing a universal pH-based tumor targeting mechanism.1 Wyatt LC et al. 2017. Applications of pHLIP Technology for Cancer Imaging and Therapy. Trends Biotech.
Citation Format: Sophia Gayle, Timothy Paradis, Qing Zhang, Laurie Tylaska, Connor Hagen, Theresa Pasqualini, Vishwas Paralkar. Evaluation of antigen-agnostic anti-tumor activity and immunological memory induced by CBX-15 (alphalexTM-MMAE) in the rat syngeneic breast cancer model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B141.
Abstract B151: Discovery and characterization of a novel small molecule brain penetrant PD-L1 inhibitor
Authors: Zhang Yongxian , Zhang Mingming , Zhao Baowei , Yu Hongping , Xu Yao-Chang , Chen Zhui , Ying Haiyan 
Published: December 2023

Abstract
Introduction: Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for treating various cancers. Small molecule PD-L1 inhibitors with brain-penetrating ability may have potential to overcome the limitations of antibodies and bring benefit for patients with intracranial tumors. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have successfully discovered an innovative orally available small molecule PD-L1 inhibitor ABSK044. In preclinical experiments, this compound demonstrates robust T-cell activating ability, strong anti-tumor efficacy, and brain-penetrating activity.
Method: ABSK044's ability to block PD-1-PD-L1 interaction was evaluated by HTRF assay and cellular luciferase reporter assay. Its biological activity was evaluated in vitro in MLR and in vivo in syngeneic tumor models.
Results: ABSK044 strongly inhibits PD-1-PD-L1 interaction with an IC50 less than 1nM in vitro and very potently rescues PD-L1-induced suppression of T cell activation signaling in cells. Furthermore, it efficiently rescues cytokine production in CD8+ T cells suppressed by PD-L1, reaching a level comparable to that of PD-L1 antibodies. In in vivo studies, oral administration of ABSK044 strongly inhibits tumor growth to an extent similar to therapeutic anti-PD-L1 antibodies. Notably, ABSK044 demonstrates excellent brain penetration with a Kp value exceeding 0.4. DMPK and safety profiling demonstrate excellent drug-like properties of ABSK044.
Conclusion: ABSK044, presented here by Abbisko Therapeutics, is a highly potent and orally available small molecule PD-L1 antagonist with brain-penetrating activity. Its superior profile supports its fast-track preclinical development.
Citation Format: Yongxian Zhang, Mingming Zhang, Baowei Zhao, Hongping Yu, Yao-Chang Xu, Zhui Chen, Haiyan Ying. Discovery and characterization of a novel small molecule brain penetrant PD-L1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B151.