bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1956: In vitro and in vivo characterization of novel MAT2A allosteric inhibitors
Authors: Pei Zhonghua , Alam Muzaffar , Bhola Neil , Cleary Leah , Drummond Jake , Fisher Marcus , Fleury Melissa , Garcia Candy , Givmanesh Atieh , Linghu Xin , McSpadden Ethan , Mounir Zineb , Neilan Claire , Newby Zach , Perumal Senthil , Steel Richard , Sutton James , Vaidya Kedar , Wagle Marie-Claire , Wang Jianhong , Yao Bing , Lackner Mark , Dillon Michael P. 
Published: September 2020

Abstract
Background: MAT2A (Methionine adenosyltransferase 2A) catalyzes the formation of S-adenosylmethionine (SAM) from methionine and ATP. PRMT5, a highly conserved protein arginine methyltransferase that is required for cell proliferation, uses SAM as its methyl donor. PRMT5 activity is inhibited by increased MTA levels in methylthioadenosine phosphorylase (MTAP)-deleted tumor cells. MTAP-deleted tumor cells are thus more vulnerable to MAT2A inhibition compared to MTAP-WT cells. This synthetic lethality between MTAP and MAT2A suggests that MAT2A inhibitors may be useful as anti-tumor agents in the MTAP-deleted cancers, which occurs in ~ 15% of all cancers.
Results: We have designed, synthesized and evaluated a novel series of small-molecule MAT2A inhibitors that are very potent in biochemical assays. Co-crystal structures of inhibitor-MAT2A complexes were solved and shed light on binding mode and key interactions. Biochemical mechanistic studies suggested that these compounds are allosteric inhibitors of MAT2A and are non-competitive inhibitors of MAT2A with respect to both ATP and methionine. These compounds displayed potent cellular anti-proliferation activity as well as cellular SAM modulation along with desired DMPK properties. Optimized compounds, upon oral dosing, demonstrated significant PD marker modulation and tumor growth inhibition in HCT116 MTAP-null and several endogenous MTAP-null xenograft mouse models. These agents demonstrated an acceptable safety profile in 7-day oral repeat dose tolerability studies in the rat.
Citation Format: Zhonghua Pei, Muzaffar Alam, Neil Bhola, Leah Cleary, Jake Drummond, Marcus Fisher, Melissa Fleury, Candy Garcia, Atieh Givmanesh, Xin Linghu, Ethan McSpadden, Zineb Mounir, Claire Neilan, Zach Newby, Senthil Perumal, Richard Steel, James Sutton, Kedar Vaidya, Marie-Claire Wagle, Jianhong Wang, Bing Yao, Mark Lackner, Michael P. Dillon. In vitro and in vivo characterization of novel MAT2A allosteric inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1956.
Abstract 1960: Targeted androgen receptor (AR) protein degradation for the treatment of metastatic castration-resistant prostate cancer (mCRPC)
Authors: Han Xin , Zhao Lijie , Xiang Weiguo , Qin Chong , Miao Bukeyan , Xu Tianfeng , Lu Jianfeng , Wang Mi , Wang Shaomeng 
Published: September 2020

Abstract
Androgen receptor (AR) and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer. As a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC), previous strategies that successfully target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition of AR function by AR antagonists such as enzalutamide and apalutamide (ARN-509). However, such agents become ineffective in advanced prostate cancer with AR gene amplification, mutation and alternate splicing. It is very clear however that in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent upon AR signaling.
Here we describe our design, synthesis and evaluation of small-molecule AR degraders based on the proteolysis targeting chimera (PROTAC) concept and our investigation of their therapeutic potential and mechanism of action in vitro and in vivo. In vitro, our potent AR degraders effectively induce degradation of AR protein in AR+ LNCaP, VCaP and 22Rv1 prostate cancer cell lines with DC50 values as low as 1 nM. AR degraders are capable of reducing the AR protein level by &gt;95% in these AR+ cancer cell lines and effectively reduces AR-regulated gene expression suppression. In vivo, our AR degrader showed potent AR degradation effects and anti-tumor activities in multiple murine xenograft models of prostate cancer at well-tolerated dosing schedules. Our data provides clear evidence that targeting AR for degradation by the PROTAC methodology is a novel and very exciting therapeutic approach for the treatment of mCRPC.
Citation Format: Xin Han, Lijie Zhao, Weiguo Xiang, Chong Qin, Bukeyan Miao, Tianfeng Xu, Jianfeng Lu, Mi Wang, Shaomeng Wang. Targeted androgen receptor (AR) protein degradation for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1960.
Abstract 1972: The significance of liquid biopsy in colorectal cancer via GeneReader NGS Systems
Authors: Mujde Cem , Hanta Abdullah , Sonmezler Ozge , Rencuzogullari Ahmet , Boga Ibrahim , Bisgin Atil 
Published: September 2020

Abstract
Background: In terms of precision medicine, not only tumoral tissue samples but also with liquid biopsy for somatic variants detection, have been used routinely. It also helps to overcome the resampling difficulties that require an invasive procedure with the problem of tumor heterogeneity. With the Next Generation Sequencing (NGS) method which is accepted as the gold standard in molecular genetic testing, colorectal cancer patients ccfDNA (Circulating Cell-Free DNA) samples were next generation sequenced via a targeted multigene panel.
Methods: In our study, liquid biopsy samples of 63 colorectal cancer patients whom referred to Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center) were sequenced via GeneReader NGS Systems (Qiagen). The multi-gene panel which includes cancer related actionable 11 genes (KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, ERBB3, ESR1 and RAF1) were used to identify the variants of drug sensitivity and resistance. Sequencing data were analyzed by QCI-Analyze and QCI-Interpret bioinformatics tools.
Results: Forty-three clinically significant variants detected in 53.96% (n=34) of 63 patients. Total of 43 clinically significant variants in 7 genes (KRAS, NRAS, KIT, BRAF, EGFR, PDGFRA and ERBB2) were detected according to the ACMG (American College of Medical Genetics) and AMP (Association for Molecular Pathology) criteria in which 13.95%, 41.86% and 41.86% prospectively related to drug resistance, treatment sensitivity, and both treatment sensitivity and drug resistance. Moreover, 2.33% were classified as uncertain clinical significance due to data mining. Variants detected upon gene names were listed in Table 1.
Table 1:Genes and variants distribution in colorectal cancer patientsGene NameVariantsTotal %KRASp.G12A,p.G12C,p.G12D,p.G12V,p.G13S,p.G15S,p.A18V,p.I21M,p.A59T,p.A146T32.56KITp.M541L20.93BRAFp.T559I,p.V600E,p.K601R,p.R603*,p.P632S,p.639I20.93EGFRp.E282K,p.H773R,p.H773P,p.V834A,p.G863D11.63PDGFRAp.E241A,p.Y555H4.65NRASp.G13C,p.E31V,p.Q61R6.98ERBB2p.P1170V2.33
Conclusion: In terms of identifying potential target therapy options without the need of a invasive intervention becomes available with NGS multigene panel studies within high reliability that also have an effect on the quality of life in colorectal cancer patients.
Citation Format: Cem Mujde, Abdullah Hanta, Ozge Sonmezler, Ahmet Rencuzogullari, Ibrahim Boga, Atil Bisgin. The significance of liquid biopsy in colorectal cancer via GeneReader NGS Systems [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1972.
Abstract 1982: Development of reference material for blood tumor mutational burden measurement
Authors: Butler Matthew G. , Konigshofer Yves , Clement Omoshile , Anfora Andrew , Brudzewsky Dan , Anekella Bharathi , Garlick Russell 
Published: September 2020

Abstract
Tumor mutational burden (TMB) is a measurement of the somatic mutations acquired by a tumor genome that cause nonsynonymous changes in proteins. TMB is a biomarker that serves as a proxy for the potential to produce neoantigens that will be recognized by T cells. Despite some reports to the contrary, TMB has successfully categorized the likelihood that an individual will respond positively to immune checkpoint inhibitors in some clinical trials. Although most TMB measurements are made from genomic DNA extracted from formalin-fixed and paraffin-embedded tissue sections, some diagnostic tests measure TMB in circulating tumor DNA (ctDNA) extracted from blood samples; an approach referred to as blood TMB (bTMB). Blood TMB is an attractive biomarker since it bypasses many of the obstacles encountered with resected and hard to biopsy tumors. Only a handful of diagnostic laboratories measure bTMB and their analytic validations rely on hard to obtain specimens acquired from ongoing drug trials or tissue repositories. This specimen scarcity impedes in depth analytic assay validation and the generation of harmonized bTMB data. For bTMB measurements to become routine, robust, and accessible to all diagnostic laboratories, we developed contrived patient-like bTMB reference materials. Blood TMB reference materials were formulated by blending and sizing genomic DNA purified from tumor and corresponding normal cell lines by proprietary methodology. Fragment analysis demonstrated that the bTMB reference materials mimic the size distribution typical of purified ctDNA. Sequencing by a targeted gene panel showed the bTMB reference materials had variant allele frequencies (VAFs) characteristic of ctDNA. For example, bTMB reference materials produced with either 2.0 or 0.5% tumor content had mean VAFs of approximately 1.0 and 0.3 %, respectively. Additional sequencing of bTMB reference materials by other gene panels demonstrated comparable results. Evaluation of contrived bTMB reference materials with various cancer gene panels will assist in the standardization of the measurement of bTMB, an emerging biomarker for clinical utility of immune checkpoint inhibitor therapy.
Citation Format: Matthew G. Butler, Yves Konigshofer, Omoshile Clement, Andrew Anfora, Dan Brudzewsky, Bharathi Anekella, Russell Garlick. Development of reference material for blood tumor mutational burden measurement [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1982.
Abstract 2008: Pan-cancer profiling of the effect of biopsied site on tumor mutational burden measurements in a real-world data cohort
Authors: Papillon-Cavanagh Simon , Gao Chuan , Han G. Celine , Walsh Alice M. 
Published: September 2020

Abstract
Background: Tumor mutational burden (TMB) has been associated with efficacy of immune checkpoint therapy and is being investigated as a potential biomarker in several tumor types. The foundational studies evaluating TMB in clinical trials have not examined factors that may affect TMB estimates in real-world practice, such as the site of biopsy relative to the tumor tissue of origin.
Methods: We used the Flatiron Health/Foundation Medicine Clinico-Genomic Database (Presley CJ, et al. JAMA 2018; Singal G, et al. JAMA 2019), which contains deidentified patient-level clinical records from Flatiron Health (New York, NY), combined with genomic sequencing test results of tissue TMB from Foundation Medicine (Cambridge, MA). We examined patient records from 7 advanced cancer types: non-small cell lung cancer (NSCLC), breast cancer (BC), gastric/esophageal cancer (G/EC), melanoma (MEL), metastatic castration-resistant prostate cancer (CRPC), head and neck cancer (H&N), and small cell lung cancer (SCLC). We performed a multivariate mixed-model linear regression to test for associations between the site of tissue biopsy and TMB measurement. We used a cutoff of 10 mutations per megabase (mut/Mb) to classify specimens as high TMB.
Results: TMB data were available for 11,928 biopsy specimens from 11,567 patients: NSCLC, n = 5556; BC, n = 3381; G/EC, n = 1335; MEL, n = 528; CRPC, n = 506; H&N, n = 342; SCLC, n = 280. In multiple cancer types, we found that TMB estimates were significantly associated with the biopsied site. For example, brain metastasis specimens from patients with NSCLC had higher TMB (median 11.3 mut/Mb) than specimens collected from primary lung tissue (median 7.0 mut/Mb) or from pleura or pleural fluid (median 3.5 mut/Mb). TMB measurements were higher in brain metastases than in samples from the primary tissue across multiple cancer types. In contrast, biopsies from lymph nodes showed different TMB patterns depending on the cancer type. Consistent with those results, the proportion of patients with high TMB differed significantly by biopsied site.
Conclusion: We used a real-world database of clinical data linked with genomic tests to evaluate TMB values across tissue biopsy sites for multiple cancer types. Our results highlight the biopsied site as a potential source of variation for TMB results measurements in a cancer type–specific manner. This will be important to consider when performing research in heterogenous data sets.
Citation Format: Simon Papillon-Cavanagh, Chuan Gao, G. Celine Han, Alice M. Walsh. Pan-cancer profiling of the effect of biopsied site on tumor mutational burden measurements in a real-world data cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2008.
Abstract 2041: Lesion pathology and oral-cancer associated pain in the 4NQO oral carcinogenesis model
Authors: Naik Keyur , Janal Malvin N. , Chen Jason , Bandary Daniel E. , Brar Branden , Bhattacharya Aditi 
Published: September 2020

Abstract
Oral cancer is a painful and debilitating type of cancer. Oral cancer patients frequently experience severe pain while eating and talking. Pain is attributed to neuronal sensitization by the release of chemical mediators from the cancer cells and cancer microenvironment. Not all oral cancers are painful. Patients with painful oral cancers are more likely to have worse prognosis and metastatic disease, and their pain is not well managed with NSAIDs or opioid analgesics. Therefore, there is an unmet clinical need to identify the underlying mechanisms of oral cancer pain. This study was designed to identify pathological lesions associated with increased pain in a preclinical model of oral cancer and pain. Forty C57BL/6 female mice were treated with 4-nitroquinoline 1-oxide (4NQO) for 16 weeks, and followed for the development of tongue lesions for 12 weeks. Concurrently, change in nociceptive behavior (i.e., the animal equivalent of pain behavior) was measured using a validated operant assay and device for measuring functional mechanical allodynia (the dolognawmeter). Nociception (pain) scores and histopathological data were obtained from 36 animals. Mice developed a spectrum of tongue and esophageal lesions including hyperkeratoses, papillomas (exophytic lesions), dysplasias and cancers. Papillomas included lesions with benign and dysplastic pathological features, indicating that both lesion types were in the continuum of malignant transformation. Mice harbored lesions associated with low pain scores (n=9), intermediate pain scores (n=16) and high pain scores (n=11). Three pathological subsets of squamous cell carcinomas (SCCs) were identified that displayed stromal invasion (iSCC), deep stromal invasion &gt;1.5mm depth (diSCC) and cancers with exophytic and invasive morphology associated with papillary lesions (pSCCs). Increased nociceptive behavior was associated with pSCCs in univariate and multivariate analyses. Cancers of the pSCC subtype are expected to be enriched for expression and release of nociceptive mediators. The study demonstrates that the 4NQO model recapitulates human cancer with respect to development of cancers differing in level of cancer associated nociception.
Citation Format: Keyur Naik, Malvin N. Janal, Jason Chen, Daniel E. Bandary, Branden Brar, Aditi Bhattacharya. Lesion pathology and oral-cancer associated pain in the 4NQO oral carcinogenesis model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2041.
Abstract 2079: Ceramide nanoliposomes a novel therapeutic option for androgen receptor negative prostate cancer
Authors: Costa-Pinheiro Pedro , Heher Abigail , Raymond Michael , Jividen Kasey , Fox Todd , Kester Mark 
Published: September 2020

Abstract
Prostate cancer (PCa) is estimated to account for 20% of newly diagnosed cancers and 10% of cancer-related deaths in US men during 2019. Prostate is a hormone-responsive gland that depends on male hormones, such as testosterone, for its normal growth and development. These hormones also play a role on the onset and progression of PCa. The androgen receptor (AR) is the main nuclear receptor activated by these hormones and regulates several key cellular pathways that contribute to worsening of the disease. Several antagonists for AR have been developed, as well as drugs that block the conversion of precursor steroids to testosterone. These drugs are extremely efficacious in patients, however within 24 months virtually all tumors recur and progress to castration resistant PCa (CRPC), a stage of disease that ultimately leads to death from PCa. To address this lack of efficacy and lack of therapeutics for CRPC, we decided to investigate the potential of ceramide nanoliposomes (CNL) as a new modality for PCa in preclinical models. Ceramide is a sphingolipid, a class of bioactive lipids that serve to keep membrane structure intact but also have the ability to trigger signaling cascades. CNL have been shown to be efficacious as a treatment in several tumor models including a successful phase 1 clinical trial in solid tumors. Strikingly, we observed that in vitro CNL is very efficacious against AR-negative PCa cells, which represent the later stages of the disease. However, in AR-positive this efficacy was reduced, but improved upon combination treatment with AR inhibitors. By combining CNL with Enzalutamide (AR antagonist) or Abiraterone acetate (testosterone synthesis inhibitor) we observed enhanced efficacy and synergistic effects. We then sought to understand the molecular mechanism underlying this synergistic effect. We observed that by blocking AR, cells were able to synthesize sphingolipids de novo and adding CNL further magnified this effect. We then looked at the expression of the key enzymes in this synthesis pathway and determined that AR negatively regulates an important subunit (SPTSSB) and this negative regulation hinders the efficacy of CNL. In conclusion, we have not only found a promising therapeutic for patients that currently have no treatment options, but also a novel molecular pathway regulated by AR in prostate cells.
Citation Format: Pedro Costa-Pinheiro, Abigail Heher, Michael Raymond, Kasey Jividen, Todd Fox, Mark Kester. Ceramide nanoliposomes a novel therapeutic option for androgen receptor negative prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2079.
Abstract 2080: Tissue-specific tumorigenesis in multiple endocrine neoplasia type I
Authors: Gardiner Juliet C. , Libutti Steven K. 
Published: September 2020

Abstract
While a germline heterozygous mutation in the Multiple Endocrine Neoplasia type 1 (MEN1) gene predisposes tumor formation in specific tissues such as the endocrine pancreas, parathyroid glands and anterior pituitary, this tissue-specific tumorigenesis is not dependent on MEN1 mutations alone. In fact, a homozygous deletion of Men1 in mouse pancreatic exocrine tissue does not result in tumor formation, suggesting a tissue-specific mechanism. Loss of menin activates a menin-interacting protein retinoblastoma-binding-protein 5 (RBBP5). Since RBBP5 transcriptionally regulates DNA methyltransferase 1 (DNMT1), this causes global DNA hypermethylation and subsequent tumorigenesis in MEN1-target endocrine tissues. We hypothesize that while RBBP5 is ubiquitously expressed, it exclusively binds to the DNMT1 promoter in MEN1-target-tissues through its recruitment by tissue-specific factors. Using chromatin immunoprecipitation, we demonstrated that Rbbp5 is bound to the Dnmt1 promoter in MEN1-target-tissues, while not in non-target tissues. Following a high-throughput genome-wide approach, we identified two candidate factors that may recruit Rbbp5 to the Dnmt1 promoter. Immunohistochemistry showed MEN1-target-tissue-specific expression of these target factors. Co-immunoprecipitation revealed MEN1-target-tissue-specific binding of Rbbp5 to the factors. In conclusion, Rbbp5 binds the Dnmt1 promoter in MEN1-target-tissues and we have identified candidates for Rbbp5 recruitment to the Dnmt1 promoter that must be tested further to determine their role in the observed tissue specificity of MEN1-related tumorigenesis.
Citation Format: Juliet C. Gardiner, Steven K. Libutti. Tissue-specific tumorigenesis in multiple endocrine neoplasia type I [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2080.