bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1963: High expression of Cyclin D1 is an independent marker for favorable prognosis in Middle Eastern breast cancer
Authors: Al-Kuraya Khawla S. , Siraj Abdul K. , Parvathareddy Sandeep K. , Siraj Sarah , Azam Saud , Annaiyappanaidu Padmanaban , Sabido Maria Angelita , Diaz Mark Ranier 
Published: July 2021

Abstract
Cyclin D1 protein regulates cell cycle progression which is mediated by its interactions with cyclin-dependent kinases. Over-expression of Cyclin D1 has been observed in several human cancers. This study was conducted to evaluate Cyclin D1 expression in a large cohort of Middle Eastern breast cancers and determine its prognostic significance. Cyclin D1 expression was assessed immunohistochemically and its association with clinico-pathological parameters was analyzed. Cyclin D1 was over-expressed in 59.4% (596/1003) of cases and significantly associated with a subset of breast cancers having favorable prognostic features such as low grade (p &lt; 0.0001), low stage (p = 0.0276), estrogen receptor positive (p &lt; 0.0001) and progesterone receptor positive (p &lt; 0.0001) tumors. An inverse association was found with triple negative breast cancers (p &lt; 0.0001). More importantly, Cyclin D1 expression was an independent predictor of favorable overall survival in our cohort (Hazard ratio = 0.69; 955 confidence interval = 0.48 - 0.98; p = 0.0405). Also, tumors that highly expressed cyclin D1 had a longer recurrence free survival. However, recurrence free survival was only significant in univariate analysis. In conclusion, our results reinforced the role of cyclin D1 in breast cancer pathology and revealed its expression as a valuable independent prognostic indicator for breast cancer from Middle Eastern ethnicity.
Citation Format: Khawla S. Al-Kuraya, Abdul K. Siraj, Sandeep K. Parvathareddy, Sarah Siraj, Saud Azam, Padmanaban Annaiyappanaidu, Maria Angelita Sabido, Mark Ranier Diaz. High expression of Cyclin D1 is an independent marker for favorable prognosis in Middle Eastern breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1963.
Abstract 1969: PTEN plays a role in histone modifications during mitosis
Authors: Choi Byeong Hyeok , Colon Tania Marlyn , Lee Eunji , Kou Ziyue , Dai Wei 
Published: July 2021

Abstract
The tumor suppressor PTEN plays an important role in the regulation of cell survival, proliferation, and angiogenesis. Deregulated expression and/or activities of PTEN frequently result in tumor development. PTEN is a plasma-membrane lipid-phosphatase, functioning to antagonize the PI3K/AKT signaling pathway. It also has a role in the nucleus regulating mitotic progression and suppressing chromosomal instability during cell division. To date, the exact function of nuclear PTEN remains not entirely clear. Several recent studies have revealed that PTEN physically interacts with histones and regulates their post-translational modifications. We previously found that PTEN is heavily phosphorylated by Plk1, which regulates mototic progression and chromosomal instability through its physical interaction with mitotic checkpoint complex (MCC). Therefore, we asked whether PTEN directly interacted with epigenetic regulators and mediated histone modifications and whether PTEN-mediated histone modifications functioned as an important regulatory mechanism during the cell cycle. Here we demonstrated that PTEN was associated with Chromobox Homolog proteins (CBXs) which are part of PRC1 complex that mediates histone modifications. Among CBXs, CBX8 levels were high in mitosis, which were correlated with an increase in PTEN mono-ubiquitination, suggesting its potential involvement in mitotic progression. Supporting this notion, we showed that CBX8 was required for cell proliferation and mitotic progression. Moreover, CBX8 was associated with PTEN/MCC during mitosis and mediated histone H2AK119 mono-ubiquitination. Combined, these results strongly suggest that CBX8/PTEN/MCC plays a significant role in modifying histones and suppressing chromosomal instability during mitotic progression.
Citation Format: Byeong Hyeok Choi, Tania Marlyn Colon, Eunji Lee, Ziyue Kou, Wei Dai. PTEN plays a role in histone modifications during mitosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1969.
Abstract 1975: Tumor treating fields triggers OFD1 removal from primary cilia to promote glioma cell survival
Authors: Shi Ping , Tian Jia , Sarkisian Matthew R. 
Published: July 2021

Abstract
Tumor Treating Fields (TTFields) significantly prolongs the survival of patients with glioblastoma, but glioma cells can still escape this therapy creating significant problems. Recent studies suggest glioma cells resist TTFields exposure by triggering AMP activated protein kinase (AMPK)-dependent autophagy pathway activation. Our group has been studying primary cilia, microtubule-based ‘antenna' whose growth is stimulated by autophagy-activated removal of Oral-Facial-Digital Syndrome 1 protein (OFD1) from the cilia base. Here we asked whether TTFields affect glioma primary cilia and/or play any role in the prosurvival response to TTFields. Using a low grade (S7) glioma cell line, we found that 1 or 3 intermittent cycles of 72hr 200kHz TTFields treatment in vitro caused a significant lengthening of primary cilia after cells were allowed to recover 3-4 days after TTFields. At the cilia base, TTFields led to recruitment of microtubule-associated protein 1A/1B light chain 3B (LC3B) and phospho-AMPK, and removal of OFD1, changes associated with autophagy pathway activation. Acutely after TTFields, we observed fewer cilia and apparent ‘ciliophagy' because the cilia appeared to detach or ‘dissolve' from the basal body. In U87 cells, TTFields induced a significant reduction of extranuclear clusters of OFD1 while increasing a dramatic formation of nuclear islands of OFD1, two phenomena that were disrupted by addition of the autophagy inhibitor chloroquine (CQ). TTFields also stimulated surprising growth of primary cilia in U87 cells which normally rarely elaborate cilia. Further, we found that TTFields was less effective at killing cilia-depleted S7 cells. Finally, TTFields plus inhibition of autophagy using CQ or a histone deacetylase 6 (HDAC6) inhibitor led to dramatically fewer cells and cilia, thus promoting TTFields toxicity. Altogether, our results suggest that primary cilia are potential membrane ‘hotspots' triggered by TTFields to promote glioma cell survival via OFD1.
Citation Format: Ping Shi, Jia Tian, Matthew R. Sarkisian. Tumor treating fields triggers OFD1 removal from primary cilia to promote glioma cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1975.
Abstract 1976: Ras-Raf-MEK-ERK signaling pathway: a novel target of ERRα and tamoxifen in TNBC cells
Authors: Musheyev David , Ronen Adi , Lattin Miriam T. , Alayev Anya 
Published: July 2021

Abstract
TNBC, or triple-negative breast cancer, is an aggressive type of breast cancer that is associated with a worse prognosis, higher rates of metastases, and a poorer outcome. Historically, TNBC has been proven challenging to treat, due to disease heterogeneity and the fact that the breast cancer tests negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) protein, and thus does not respond to traditional therapies. As such, treatment options for TNBC patients are extremely limited and there is a tremendous need to identify molecular targets and biomarkers that can offer novel targeted approaches. Additionally, due to disease heterogeneity in TNBC, it is important to subclassify TNBC based on prognostic markers and create tailored targeted therapies. ERRα, an orphan nuclear receptor, is an example of a prognostic marker that is correlated with a more aggressive disease progression and a worse outcome. However, ERRα is also a predictive marker for patient response to tamoxifen treatment of ER-negative and TNBC patients, indicating that there may be an alternative use for the selective estrogen modulator (SERM) tamoxifen in the context of TNBC. This led us to investigate whether there is a common pathway that is regulated by both ERRα and tamoxifen that would explain tamoxifen response in the context of TNBC cells. We performed a phosphoproteomic analysis of MDA-MB-231 cells, treated with either tamoxifen or XCT-790, an inverse agonist of ERRα, to identify common downstream targets of both ERRα and tamoxifen. Our findings indicate that the Ras-Raf-MEK-ERK signaling pathway is a common target of both XCT-790 and tamoxifen. This provides a novel treatment strategy that should be investigated for the treatment of TNBC patients, opens the door for investigation of novel targeted therapies, and highlights the need for the use of prognostic markers to identify sub-populations that benefit from individualized treatment strategies.
Citation Format: David Musheyev, Adi Ronen, Miriam T. Lattin, Anya Alayev. Ras-Raf-MEK-ERK signaling pathway: a novel target of ERRα and tamoxifen in TNBC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1976.
Abstract 2015: Interplay of the pH regulator, carbonic anhydrase IX and the glutamine transporter, ASCT2 in hypoxic tumor microenvironment
Authors: Venkateswaran Geetha , Chafe Shawn , Awrey Shannon , Nemirovsky Oksana , Dedhar Shoukat 
Published: July 2021

Abstract
Solid tumors are characterized by poor vasculature, thereby causing insufficient oxygen and nutrient supply within the tumor. To thrive in such conditions, hypoxic tumor cells stimulate the expression of nutrient transporters to support cell metabolism and pH regulators to buffer the intracellular pH changes caused by metabolic by-products. Carbonic Anhydrase IX (CAIX) is a membrane-bound enzyme that plays a vital role in the pH regulation of hypoxic tumor cells. CAIX is highly expressed in several solid tumors, and is an indicator of poor prognosis and response to therapy. Although the importance of CAIX's role in mediating tumor progression is well-known, the underlying mechanism remains unclear. To identify the interactors of CAIX in the hypoxic tumor microenvironment, we performed a proteomic analysis using proximity dependent biotin identification (BioID) and found the Alanaine, Serine, Cysteine transporter (ASCT2) to be a high confidence interactor of CAIX from this analysis. ASCT2, which predominantly acts as a glutamine transporter is upregulated in several cancers and is shown to support tumor growth by facilitating increased glutamine uptake. In this study, using a panel of solid tumor cell lines, we validate the interaction of CAIX with ASCT2 in the hypoxic microenvironment. Functionally, loss of CAIX causes an increased glutamine uptake via ASCT2 and an increased capacity of cells to utilize glutamine for mitochondrial respiration. Concomitantly, ROS and glutathione (GSH) levels also increase upon CAIX inhibition. Cytotoxicity studies show a robust cell death in the absence of glutamine, following treatment with the CAIX/XII small molecule inhibitor SLC-0111. A similar effect on cell death is observed by blocking glutamine metabolism using inhibitors such as V-9302 (ASCT2 inhibitor) or CB-839 (Glutaminase-1 inhibitor) with SLC-0111. Furthermore, blocking GSH synthesis using BSO (Glutamylcysteine synthatase inhibitor) with SLC-0111 causes significant cell death. These results suggest that CAIX depletion causes increased cellular stress and to overcome this, cells increase glutamine uptake in part for GSH synthesis. In summary, we show that CAIX and ASCT2 coordinate their functions in hypoxic cancer cells to support tumor growth, and co-targeting them could be beneficial in treating solid tumors.
Citation Format: Geetha Venkateswaran, Shawn Chafe, Shannon Awrey, Oksana Nemirovsky, Shoukat Dedhar. Interplay of the pH regulator, carbonic anhydrase IX and the glutamine transporter, ASCT2 in hypoxic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2015.
Abstract 2051: Inhibiting CDC7 kinase for the treatment of Ewing sarcoma
Authors: Martin Jeffrey C. 
Published: July 2021

Abstract
Ewing Sarcoma is a malignant tumor of the bone and soft tissue that is primarily driven by the fusion protein EWS-FLI1. With no current targeted therapy, treatment options remain limited and toxic. Recent reports have shown that Ewing tumors harbor large amounts of transcription-associated replication stress and that this offers an attractive therapeutic intervention point. Our group has shown that inhibition of the kinase complex DDK (CDC7-DBF4) results in apoptosis and a significant reduction in cell viability in EWS-FLI1-harboring Ewing's sarcoma cell lines. Also, low dose DDK inhibition in Ewing's sarcoma cells caused an S/G2 cell cycle accumulation at 24 hours, followed by re-entry into G1 and appearance of sub-G1 DNA. This suggests a failure to properly progress through S-phase followed by premature mitotic entry and mitotic catastrophe resulting in cell death. To this end, there was a significant increase in the formation of micronuclei and other aberrant mitotic structures upon DDK inhibition in Ewing's cells. Interestingly, there was minimal signs of mitotic accumulation, despite clear evidence of mitotic stress, indicating a failure to properly enforce a G2-M checkpoint. Importantly, these phenotypes were not mimicked with the use of the CDK2 inhibitor Roscotivine, suggesting an origin firing-independent basis for the sensitivity to DDK inhibition. Furthermore, we show that DDK inhibition synergizes with the TOP1 inhibitor Camptothecin and with the PARP1 inhibitor Talazoparib to kill Ewing Sarcoma cells in vitro. We have hypothesized this to be due to DDK's potential role in replication fork instability/restart. Together, these results suggest that Ewing sarcoma cells rely on the activity of DDK to maintain cell viability independently from its role in the regulation of replication origin initiation and suggest that DDK inhibition may prove to be a viable treatment option for patients with Ewing's sarcoma.
Citation Format: Jeffrey C. Martin. Inhibiting CDC7 kinase for the treatment of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2051.
Abstract 2054: Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models
Authors: Yanbin Hu , Xiquan Zhang , Ling Yang , Xin Tian , Gang Li , Lihong Hu , Ding Charles Z. , Yuanfeng Xia , Wei Li , Shanshan Yin , Ying Chen , Songliang Wu , Shuhui Chen 
Published: July 2021

Abstract
Objective: Homology-directed repair (HDR) pathway is the major DNA double-strand break repair pathway. BRCA-deficiency impairs this pathway, and combination with Poly(ADP-ribose) polymerase (PARP) inhibition results in cell death. This process is known as “synthetic lethality”. A proportion of breast cancer, ovarian cancer and other solid tumor patients carrying BRCA-mutated gene receive benefits from PARP inhibitors. In this study, we present in vitro activity and in vivo efficacy data of a novel small molecule PARP inhibitor, TQB3823 to support it as our clinical candidate.
Method: Enzyme inhibition activities of TQB3823 were determined in PARP1/PARP2/Tankyrase 1 assays. Cellular anti-proliferative activity and selectivity were evaluated in MDA-MB-436 cell line with BRCA1 mutation and BRCA wild type MDA-MB-231 cell line. Antitumor efficacy of TQB3823 was investigated in BRCA1 mutated MDA-MB-436 breast cancer CDX model.
Result: TQB3823 showed high potency and selectivity at both enzymatic and cellular level. IC50 of TQB3823 in PARP1/PARP2/Tankyrase 1 assays are 2.8/0.9/629.3 nM, respectively. It inhibited proliferation of BRCA1 mutant MDA-MB-436 cell with IC50 of 9.6 nM. In contrast, TQB3823 showed little anti-proliferative activity in BRCA-wild type MDA-MB-231 cell with IC50 &gt;10 μM. TQB3823 demonstrated antitumor efficacy in dose dependent fashions with tumor regression was observed at 25 mg/kg in MDA-MB-436 CDX model. The level of antitumor effects was superior to niraparib at the same dose in the same study. DNA trapping experiments revealed similar potency to olaparib indicative of low toxicity.
Conclusion: We have identified a novel, potent and selective PARP inhibitor TQB3823, which inhibits the proliferation of BRCA mutant cells but spares the wild type cells. In vivo study in a BRCA-deficiency tumor model confirms the high in vivo efficacy of this molecule. In conclusion, TQB3823 represents a promising differentiated clinical candidate for treating solid cancers with homology directed repair.
Citation Format: Hu Yanbin, Zhang Xiquan, Yang Ling, Tian Xin, Li Gang, Hu Lihong, Charles Z. Ding, Xia Yuanfeng, Li Wei, Yin Shanshan, Chen Ying, Wu Songliang, Chen Shuhui. Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2054.
Abstract 2064: Homologous recombination repair somatic/germline mutation detection in plasma by next-generation sequencing in Chinese solid tumor patients
Authors: Zhu Wei , Chen Hui , Zhang Bei , Zhao Xiaochen , Bai Yuezong 
Published: July 2021

Abstract
Purpose: PARP inhibitors (PARPis) have been approved for germline and/or somatic BRCA-mutated ovarian cancer, breast cancer, pancreatic cancer and homologous recombination repair gene (HRR)-mutated prostate cancer. Emerging evidence has shown that antitumor activity of PARPis could expand to other HRR-mutated solid tumors. Therefore, efficient and timely methods to detect both somatic and germline HRR mutations using tissue or blood are urgently needed. Here, we first specially reported the prevalence of HRR mutation in plasma samples using Next-generation sequencing (NGS).
Methods: A total of 1601 paired plasma-white blood cell samples and 3404 paired tumor-white blood from Chinese solid tumor patients were collected between October 2019 and October 2020. The samples were assessed with targeted NGS of circulating tumor DNA (ctDNA) or tumor tissue DNA (ttDNA) to detect deleterious somatic and germline mutations in 16 core HR genes in a CLIA-certified laboratory.
Results: Overall, 165/1601 (10.3%) patients had at least one somatic or germline HRR gene mutations by ctDNA-based NGS analysis. The most commonly mutated tumor types were endometrium (42.9%, n=7), ovary (38.5%, n=13), prostate (27.8%, n=108), neuroendocrine (20%, n=5), breast (19%, n=42), melanoma (16.7%, n=6), stomach (15.8%, n=101), biliary tract (15.6%, n=64), cervix (12.5%, n=8), pancreas (11.4%, n=70), colorectum (9.8%, n=174) and bladder urinary tract (9.5%, n=21). Except for the four tumor types (endometrium, neuroendocrine, melanoma and cervix) with less than ten samples, the prevalence of HRR mutation was comparable with the ttDNA-based NGS data. Among HRR mutations, BRCA2 was the most commonly mutated gene (3.2%), followed by ATM (2.4%), BRCA1 (1.4%), CHEK2 (1.2%), BARD1 (0.7%), PALB2 (0.7%), CDK12 (0.7%) and FANCA (0.5%). Most of these data was similar to the results of ttDNA-based NGS. Moreover, slightly higher prevalence was found in BRCA2 (3.2% vs 2.5%) and CHEK2 (1.2% vs 0.7%), and slightly lower prevalence was found in ATM (2.4% vs 3.2%) and CDK12 (0.7% vs 1.4%).
Conclusion: We first described the prevalence of somatic and/or germline HRR mutations detected by ctDNA-based NGS in a Chinese solid tumor cohort. Further prospective study is needed to compare the impact of the HRR status identified by ctDNA and ttDNA NGS on PARPis efficacy.
Citation Format: Wei Zhu, Hui Chen, Bei Zhang, Xiaochen Zhao, Yuezong Bai. Homologous recombination repair somatic/germline mutation detection in plasma by next-generation sequencing in Chinese solid tumor patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2064.
Abstract 2068: Radiotherapy is associated with a deletion signature that contributes to poor cancer patient outcomes
Authors: Kocakavuk Emre , Anderson Kevin J. , Johnson Kevin C. , Varn Frederick S. , Amin Samirkumar B. , Sulman Erik P. , Barthel Floris P. , Verhaak Roel G. 
Published: July 2021

Abstract
Diffuse gliomas are highly aggressive brain tumors that invariably relapse despite treatment with chemo- and radiotherapy. Treatment with alkylating chemotherapy can drive tumors to develop a hypermutator phenotype. In contrast, the genomic effects of radiation therapy (RT) remain unknown.
We analyzed the mutational spectra following treatment with ionizing radiation in sequencing data from 190 paired primary-recurrent gliomas from the Glioma Longitudinal Analysis (GLASS) dataset and 2116 post-treatment metastatic tumors from the Hartwig Medical Foundation.
We identified a significant increase in the burden of small deletions following radiation therapy that was independent of other factors and was significantly associated with the clinically applied RT-dosage in Gy (P = 1e-02, multivariable log-linear regression). These novel deletions demonstrated distinct characteristics when compared to pre-existing deletions present prior to RT-treatment and deletions in RT-untreated tumors. Radiation therapy-acquired deletions were characterized by a larger deletion size (GLASS and metastatic cohort, P = 1.2e-02 and P = 8e-11, respectively; Mann-Whitney U test), an increased distance to repetitive DNA elements (P &lt; 2.2e-16, Kolmogorov-Smirnov test) and a reduction in microhomology at breakpoints (P = 3.2e-02, paired Wilcoxon signed-rank test). These observations suggested that canonical non-homologous end joining (c-NHEJ) was the preferred pathway for DNA double strand break repair of RT-induced DNA damage. Furthermore, radiotherapy resulted in frequent chromosomal deletions and significantly increased frequencies of CDKN2A homozygous deletions. Finally, a high burden of RT-associated deletions was associated with worse clinical outcomes (GLASS and metastatic cohort, P &lt; 1e-04 and P = 2.6e-02, respectively; Wald test).
Our results collectively suggest that effective repair of RT-induced DNA damage is detrimental to patient survival and that inhibiting c-NHEJ may be a viable strategy for improving the cancer-killing effect of radiotherapy. Taken together, the identified genomic scars as a result of radiation therapy reflect a more aggressive tumor with increased levels of resistance to follow up treatments.
Citation Format: Emre Kocakavuk, Kevin J. Anderson, Kevin C. Johnson, Frederick S. Varn, Samirkumar B. Amin, Erik P. Sulman, Floris P. Barthel, Roel G. Verhaak. Radiotherapy is associated with a deletion signature that contributes to poor cancer patient outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2068.