bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5990: Microtubule-associated serine/threonine kinase-likeinhibitor, AD1208, as a novel cancer therapeutics
Authors: CHOI SOONGYU , Ahn JS , Baek KS , Choi YL , Im MY , Kim JH , Kim JW , Khoo JH , Lee SH , Yao WL , Park Young-Whan 
Published: March 2024

Abstract
Microtubule-associated serine/threonine kinase-like is an essential regulator of mitosis and emerged as a novel oncogenic kinase. It is upregulated in several cancer types, correlating with chromosome instability and poor patient survival. Here, we are reporting a MASTL inhibitor, AD1208, as a new cancer therapeutics.AD1208 inhibits kinase activity of MASTL with IC50 value of 7nM in competitive manner against ATP and induces apoptosis of colorectal cancer cells with IC50 of 150nM. Selectivity index is higher than 100 folds when the cytotoxicity was measured in normal colon cells. Synthetic lethality with BRCA was observed in knock out studies. Cell panel analysis, consist of 300 cell lines, indicated that the AD1208 is effective in cancers originated from stomach, colon, leukemia, lymphoma, and soft tissue. In vivo efficacy was confirmed in mouse xenograft model in dose dependent manner and synergistic effect with PARP inhibitor was observed. Kinase Assay Panel screening revealed that AD1208 is highly selective against 468 kinases. Inhibition of MASTL resulted in decreasing phosphorylated ENSA, inactivating CDK1 and arresting cell cycle progression at G2/M phase. Clinical adverse drug reactions of AD1208 were predicted by in vitro Safety Functional Panel screening to exhibit no meaningful safety-related issues. Currently, AD1208 is being conducted in IND enabling GLP-Tox studies, including genotoxicity, mutagenicity, safety pharmacology as well as in vivo safety studies. Taken together, AD1208 is identified as a novel and selective MASTL inhibitor exhibiting significant therapeutic potential to be a development candidate.
Citation Format: SOONGYU CHOI, JS Ahn, KS Baek, YL Choi, MY Im, JH Kim, JW Kim, JH Khoo, SH Lee, WL Yao, Young-Whan Park. Microtubule-associated serine/threonine kinase-likeinhibitor, AD1208, as a novel cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5990.
Abstract 5999: Bitter taste receptors trigger pyroptosis and apoptosis through NLRP3 activation in oral cancer cells in response to a dysbiotic bacterial molecule: A possible role as pattern recognition receptors
Authors: Yu Seong , Lee Heesu , Shin Jeong Mu , Song Na-Young 
Published: March 2024

Abstract
Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancers. It has been reported that the composition of the oral microbiome was shifted in OSCC patients compared to healthy subjects. In particular, Pseudomonas aeruginosa is one of the most abundant oral microbes in OSCC patients. Bitter taste receptors (taste 2 receptors, TAS2Rs), known as G protein-coupled receptors (GPCRs), can recognize P. aeruginosa-derived quorum sensing molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12). Therefore, we explored the role of TAS2Rs in oral dysbiosis and cancers. Herein, we observed that TAS2Rs, such as TAS2R4, TAS2R14, and TAS2R38, mediated both pyroptosis and apoptosis, two distinct types of programmed cell death, in human OSCC HSC3 cells exposed to oxo-C12. Unexpectedly, TAS2Rs provoked pyroptosis and apoptosis in a GPCR-independent manner. Instead, TAS2Rs seemed to recruit NLRP3 inflammasome and subsequently activate caspase-8 in response to oxo-C12, implying the TAS2Rs-NLRP3-caspase-8 axis. Notably, the immunofluorescence staining showed considerable expression of TAS2Rs and NLRP3 in oxo-C12-treated HSC3 cells as well as human OSCC tissues, further supporting the presence of the alternative activation pathway of TAS2Rs. Moreover, siRNA knockdown of MyD88 diminished oxo-C12-induced NLRP3 activation, caspase-8 cleavage and cell death marker expression, which implies that MyD88 is involved in activation of the TAS2Rs-NLRP3-caspase-8 axis. This also suggests that TAS2Rs might function as potential pattern recognition receptors, similar to toll-like receptors responsible for recognition of pathogen and their molecules. Based on The Cancer Genome Atlas analysis, downregulation of TAS2Rs was correlated with poor prognosis in OSCC patients. Taken together, TAS2Rs might trigger the host defense mechanism against microbial dysbiosis-induced cancer development. Thus, TAS2Rs could be promising chemotherapeutic targets for OSCC treatment, particularly via disconnecting interkingdom molecular links between microbial alterations and carcinogenesis.
Citation Format: Seong Yu, Heesu Lee, Jeong Mu Shin, Na-Young Song. Bitter taste receptors trigger pyroptosis and apoptosis through NLRP3 activation in oral cancer cells in response to a dysbiotic bacterial molecule: A possible role as pattern recognition receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5999.
Abstract 6014: PLK1-dependent phosphorylation of PRMT5 promotes DNA damage response in prostate cancer
Authors: Peng Jia , Zhang Yanquan , Wang Jianlin , Li Qianjin , He Daheng , Wang Xinyi , Rao Xiongjian , Wu Meng , Mo Pingli , Wang Lei , Wu Sai , Wang Ruixin , Liu Jinghui , Nouri Mansoureh , Tadahide Izumi , Liu Xiaoqi 
Published: March 2024

Abstract
Prostate cancer stands out as the most frequently diagnosed cancer in men and is projected to be the second leading cause of cancer-related deaths among men in the US. Consequently, there is an urgent need for studies focusing on innovative therapeutic approaches. DNA Damage Response (DDR) is critical for cell survival, as it promotes genomic stability and reduces the risk of inheriting damage. DDR also promotes cancer cells' survival, making it a therapeutic target in cancer. PRMT5, an enzyme in the methyltransferase family, is frequently activated and overexpressed in various cancers, including prostate cancer. Furthermore, research has revealed that PRMT5 has been implicated in DDR in prostate cancer, and the regulation of PRMT5-dependent DDR is influenced by its phosphorylation. Polo-like kinase 1 (PLK1) is a serine/threonine kinase also reportedly involved in DDR in prostate cancer. Our preliminary study found that PRMT5 is positively correlated with PLK1 in prostate cancer based on the TCGA database. Nonetheless, the mechanism through which PRMT5 is regulated needs to be clarified. Here, we found that PLK1 phosphorylates PRMT5 at the S470 site, and this specific phosphorylation is required for maintaining the enzymatic activity of PRMT5. Moreover, Plk1-associated phosphorylation of PRMT5 subsequently promotes DNA damage repair, indicated by the decreasing level of γH2AX after DNA double-strand breaks (DSB). Our RNA-seq analyses of prostate cancer cells with wild-type or mutant S470 sites indicate that Plk1-associated phosphorylation on the S470 site exerts an influence on DNA replication and DDR pathways. These findings shed light on a novel perspective regarding the roles of PLK1-mediated PRMT5 phosphorylation in DDR, offering potential therapeutic strategies in prostate cancer.
Citation Format: Jia Peng, Yanquan Zhang, Jianlin Wang, Qianjin Li, Daheng He, Xinyi Wang, Xiongjian Rao, Meng Wu, Pingli Mo, Lei Wang, Sai Wu, Ruixin Wang, Jinghui Liu, Mansoureh Nouri, Izumi Tadahide, Xiaoqi Liu. PLK1-dependent phosphorylation of PRMT5 promotes DNA damage response in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6014.
Abstract 6047: Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader
Authors: Havens Courtney G. , Xu Guozhang , Lowenstein Cass , Samanta Debangshu , Vidal Brian , Behshad Elham , Nagilla Rakesh , Russell Mike , Orth Peter , Wu Winston , Jolivette Larry , Priestley Scott , Mohammad Helai , Sui Zhihua 
Published: March 2024

Abstract
The estrogen receptor α (ERα) is a clinically validated target for the treatment of estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. However, resistance to early line endocrine treatments due to mutations of the ESR1 gene encoding ERα is associated with poor prognosis and remains an area of unmet clinical need. ERα degradation using heterobifunctional degraders has emerged as a promising approach to tackle endocrine resistance through proteasome mediated degradation of the receptor. Here, we present the preclinical results for the development candidate, PVTX-321, an ERα heterobifunctional degrader. PVTX-321 is a rapid and potent ER heterobifunctional degrader as well as a full ERα antagonist. Both properties translate into potent antiproliferative activity across multiple ER+ breast cancer cell lines bearing either wild-type or clinically relevant ERα mutations (E380Q, Y537S and D538G). PVTX-321 demonstrates favorable oral bioavailability across different species and effectively induces dose-dependent degradation of ERα in vivo. Moreover, PVTX-321 achieves tumor regression as an oral agent at 10 mg/kg in MCF-7 mouse xenograft model. Furthermore, PVTX-321 possesses excellent in vitro and in vivo safety profiles and warrants further development for the treatment of ER+/HER2- breast cancer.
Citation Format: Courtney G. Havens, Guozhang Xu, Cass Lowenstein, Debangshu Samanta, Brian Vidal, Elham Behshad, Rakesh Nagilla, Mike Russell, Peter Orth, Winston Wu, Larry Jolivette, Scott Priestley, Helai Mohammad, Zhihua Sui. Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader  [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6047.
Abstract 6070: Identification of a molecular glue degrader that engages a cancer-specific E3 ligase
Authors: Liu Yuan , Larsen Mads , Lin Bo , Cardenal Irene A. , Kennerdell Jason R. , Finkel Toren , Chen Bill B. 
Published: March 2024

Abstract
To date, most successful molecular glues have leveraged ubiquitously expressed E3 ligases, most notably Cereblon in the case of the thalidomide derivatives. However, a number of specific E3 ligases are highly over-expressed in certain tumors. Compounds that engage such tumor-specific E3 ligases might provide a unique opportunity to develop molecular glues with higher therapeutic indexes. One such tumor-specific E3 ligase is FBXO5, a member of the F-box family of E3 ligases. Expression analysis suggests this E3 ligase is highly expressed in a wide array of tumor tissues when compared to the corresponding normal tissue, and that within a given tumor type, higher FBXO5 expression correlates with advanced tumor stage and worse disease-free survival. Here, we describe a small molecule (MW~400 Daltons) that uses FBXO5 to function as a molecular glue degrader. This compound, CL-200, exerts cytotoxicity in the nanomolar range across a number of diverse tumor types. The cytotoxicity of CL-200 is abrogated when FBXO5 is knockdown using siRNA. We have further determined that CL-200 induces the FBXO5-dependent proteasomal degradation of at least two critical neosubstrates. One identified neosubstrate is the p150 isoform of ADAR1, an enzyme that catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA). Evidence suggests that ADAR1p150 is the isoform that confers oncogenic and immune modulating effects in many tumors. Another neosubstrate targeted by CL-200 is c-myc, a critical transcription factor linked to a wide array of tumors. Of note, both p150 ADAR1 or c-myc have been viewed as difficult-to-drug if not undruggable targets. As such, these data suggests that CL-200 functions as a novel molecular glue degrader that engages the cancer-specific E3 ligase FBXO5 to degrade both p150 ADAR1 and c-myc. Structural alteration of CL-200 suggest that chemical modifications can be made that retain the engagement with FBXO5 while altering the neosubstrate profile. Together, these results demonstrate the possibility of leveraging cancer-specific E3 ligases to develop novel molecular glues.
Citation Format: Yuan Liu, Mads Larsen, Bo Lin, Irene A. Cardenal, Jason R. Kennerdell, Toren Finkel, Bill B. Chen. Identification of a molecular glue degrader that engages a cancer-specific E3 ligase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6070.
Abstract 6071: Identification of a molecular glue degrader targeting the full-length AR and AR-V7 splice variant
Authors: Liu Yuan , Larsen Mads B. , Lin Bo , Cardenal Irene A. , Kennerdell Jason , Finkel Toren , Chen Bill B. 
Published: March 2024

Abstract
Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effective therapy has been demonstrated for patients with metastatic prostate cancer bearing the AR-V7 signature. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to a wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that are bound to AR-V7. One such molecule, AR-600, directly bound to AR-V7 and moreover, induced proteasomal-mediated targeted protein degradation of both AR-V7 and AR-FL. In prostate cancer cell lines expressing AR-FL, AR-600 induced a gene expression profile similar to cells treated with Enza including a marked reduction in KLK3 (PSA) expression. Moreover, AR-600 inhibited the growth of 22RV1 cells (IC50=23 nM), a cell line that predominantly expresses AR-V7, as well as C4-2 cells that express predominantly full-length AR (IC50=51 nM). In contrast, the compound did not affect the growth of a wide variety of non-tumorigenic cells, non-prostate tumor cell lines or PC3 cells, a prostate cell line that exhibits AR-independent cell growth (IC50&gt;100uM). Preliminary exploration of the mechanism of action of AR-600 (M.W. ~300 Daltons) demonstrates the compound works as a molecular glue. These results thereby identify a small molecule glue degrader that can specifically induce the targeted protein degradation of the AR-V7 splice variant. Given the strong association of this isoform with treatment resistance, this approach would appear to provide an attractive strategy for patients with metastatic castration resistant prostate cancer.
Citation Format: Yuan Liu, Mads B. Larsen, Bo Lin, Irene A. Cardenal, Jason Kennerdell, Toren Finkel, Bill B. Chen. Identification of a molecular glue degrader targeting the full-length AR and AR-V7 splice variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6071.
Abstract 6177: Machine learning enables prediction of ADC targets from whole slide H&E images
Authors: McCaw Zachary Ryan , Shcherbina Anna , Shah Yajas ,   insitro Research Team, Tagari Philip , Koller Daphne , Probert Christopher 
Published: March 2024

Abstract
Background: The efficacy of antibody-drug conjugates (ADCs) depends on the expression and specificity of the target antigen by tumor cells. Although H&E-stained slides are routinely collected during cancer care, specialized IHC staining is typically required to ascertain antigen expression. Such stains are not always available or readily deployed. The need to perform separate IHC tests for each candidate ADC may burden clinical labs and can hinder access to care in resource-limited settings. Here we develop an ensemble of machine learning models to accurately predict the expression of 166 distinct ADC targets directly from H&E images.
Methods: For each ADC-targeted gene, patients with copy-number amplifications (CNAs) were identified from somatic whole exome sequencing. Genes differentially expressed in patients with CNAs were identified from bulk transcriptomics. For each gene, an expression signature was developed based on the expression levels of differentially upregulated genes. Next, whole-slide, H&E-stained histopathology images were embedded into a lower-dimensional representation via a transformer model trained with self-supervised learning. Neural networks were developed to predict a patient’s probability of having a CNA in an ADC-targeted gene, as indicated by an expression signature exceeding the p90. All evaluation metrics were ascertained by 5-fold cross-validation, with training and evaluation on independent patients.
Results: For each of the 166 ADC-targeted genes, a median of 154 patients were found to harbor a CNA, and the expression signature included a median of 180 genes. In all cases, patients with CNAs had significantly higher expression signatures than those without. For predicting likely CNA status directly from H&E histopathology images, the mean AUROC was 0.888 (95% CI, 0.876-0.900) and the mean AUPRC was 0.571 (95% CI, 0.531-0.611). Among the 166 ADC-targeted genes, the AUROC exceeded 0.95 for 31.3%, 0.8 for 80.7%, and 0.725 for 100%. The best-predicted ADC target was SLC7A5 (AUROC: 0.995 [95% CI, 0.994-0.998]; AUPRC: 0.967 [95% CI, 0.963-0.976]).
Conclusion: We have developed models that accurately predict the likely expression of ADC targets based solely on H&E images. The ability to accurately discern the presence of ADC antigens from H&E images has numerous potential applications, including cohort refinement, computer-aided diagnosis, and personalized treatment planning.
Citation Format: Zachary Ryan McCaw, Anna Shcherbina, Yajas Shah, insitro Research Team, Philip Tagari, Daphne Koller, Christopher Probert. Machine learning enables prediction of ADC targets from whole slide H&E images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6177.
Abstract 6180: Tumor microenvironment phenotypes predict recurrence in African Americans diagnosed with colorectal cancer: A comparative study of manual grading with digital pathology
Authors: Wu Dongling , Xia Rong , Alawad Mouyed , Lee Lili , Gonda Tamas , Cao Wenqing , Hacking Sean 
Published: March 2024

Abstract
African Americans face a higher rate of colorectal cancer (CRC) incidence and mortality compared to other ethnicities. Identifying key prognostic factors is essential for better outcomes in this group. This study focused on the prognostic value of stromal grading in the tumor microenvironment (TME) of African American CRC patients, using both manual grading and digital pathology. A retrospective analysis of CRC cases in African Americans was conducted. Two cohorts were established: a control cohort (patients without recurrence) and a recurrence cohort (patients with recurrence). Stromal grading was performed manually, categorizing tumors into Grade 1 (low risk), Grade 2 (moderate risk), and Grade 3 (high risk), and we also quantified the TME percentages by digital pathology: myxoid, collagen, immune and tumor. In the control cohort (N=40), stromal grading identified 30 Grade 1, 7 Grade 2, and 3 Grade 3 cases. Conversely, the recurrence cohort (N=17) demonstrated a starkly different distribution, with 1 Grade 1, 3 Grade 2, and 13 Grade 3 cases. The Chi-square statistic was notably significant (p&lt;0.0001), indicating a strong association between higher stromal grades and the likelihood of recurrence. By unpaired t-test, high myxoid stroma (p&lt;0.0001), low collagen (p&lt;0.0001), and low tumor (p=0.0002) by digital pathology were associated with recurrence. TME phenotypes are a significant prognostic and recurrence indicator in African American patients with CRC. The marked difference in stromal grades and digital pathology features between the control and recurrence cohorts suggests that higher stromal grades, along with higher myxoid, lower collagen and lower tumor percentages are associated with an increased risk of recurrence. These findings underscore the need for tailored therapeutic strategies and more vigilant surveillance in African American patients exhibiting high-risk TME phenotypes. The efficacy of manual and digital pathology evaluation of the TME also warrants further exploration to enhance prognostic accuracy and treatment personalization.
Citation Format: Dongling Wu, Rong Xia, Mouyed Alawad, Lili Lee, Tamas Gonda, Wenqing Cao, Sean Hacking. Tumor microenvironment phenotypes predict recurrence in African Americans diagnosed with colorectal cancer: A comparative study of manual grading with digital pathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6180.