bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6050: Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707
Authors: Ji Xiang , Li Huanping , Wu Gang , Zhang Qiguo , He Xiaolin , Wu Yanpeng , Zong Bing , Xu Xiaojin , Liang Chao , Wang Beibei , Zhang Yuwei , Hu Qingyao , Zhou Jiaxin , Guo Weihui , Bai Bing , Wang Lin , Ai Jinchao , Zhang Leduo , Zhou Honggui , Sun Shihao , Wang Yijie , Wang Youhong , Fan Qiming , Chen Dawei , Zhou Tianlun , Lu Jiasheng 
Published: March 2024

Abstract
RAS oncogene mutations are prevalent in approximately 19% of cancer patients, with the most frequent alteration occurring in codon 12 of the KRAS gene, resulting in a variety of G12X oncoproteins. Recent advances in drug discovery have yielded several KRAS G12C inhibitors currently in clinical use, benefiting a subset of patients. However, addressing the high-prevalence G12D mutation remains a substantial unmet medical need. Targeted protein degradation using PROTAC molecules offers a promising approach for treating KRAS G12D-associated tumors, potentially providing superior efficacy and mitigating the development of resistance, a challenge frequently observed with KRAS G12C inhibitors in clinical settings. In the present study, we report a PROTAC compound RP03707 that efficiently induces the degradation of the KRAS G12D mutant protein and inhibits tumor growth. Treatment of AsPc-1 cells with RP03707 results in significant degradation of the KRAS G12D protein, with a DC50 value in the sub-nanomolar range. Within 24 hours, the compound eliminates over 90% of G12D proteins and effectively suppresses downstream cellular MAPK signaling. Additional in vitro experiments demonstrate that RP03707 inhibits cell proliferation in multiple KRAS G12D mutant cell lines, surpassing the anti-tumor efficacy of enzyme inhibitors. In a mouse GP2d xenograft tumor model, a single intravenous administration of RP03707 at 10 mpk results in excellent compound penetration and retention in tumor tissues, followed by 90% reduction of G12D protein levels for 7 days. Profound inhibition of tumor growth is observed not only in mouse GP2d xenograft but also in other mouse KRAS G12D tumor models, even when the compound is administered in low and infrequent doses. Moreover, RP03707 exhibits high selectivity for degrading the KRAS G12D protein and possesses favorable drug-like properties. RP03707, therefore, meets the criteria for advancing into drug development and represents a valuable therapeutic option for treating KRAS G12D-associated tumors.
Citation Format: Xiang Ji, Huanping Li, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Jiaxin Zhou, Weihui Guo, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Qiming Fan, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707 [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 6050.
Abstract 6124: A comprehensive pan-cancer study nominating NF-κB-mediated TNFA signaling-induced hypoxia as a risk factor in Hispanic cancer progression
Authors: Samanta Tagari , Park Jun Hyoung , Kaipparettu Benny Abraham 
Published: March 2024

Abstract
The Hispanic (HA) population is the second largest racial/ethnic group in the United States after non-Hispanic White (NHW). Though the HA population usually has a lower reported incidence of cancers compared to NHW, there are racial disparities exist in the mortality rate of some of the cancers. Factors related to the Social Determinants of Health (SDOH), such as higher poverty rates, less education, and reduced access to health care, are known to increase the risk of diagnosing advanced-stage cancer in HA compared to the NHW population. The contribution of such SDOH in the HA cancer population has been studied in the past years. However, the contribution of biological and genetic mechanisms to HA cancer disparity has not been well understood. Thus, in this study, we performed a comprehensive analysis of different databanks to understand the common genetic and biological factors that contribute to the pan-cancer disparity in the HA population. To identify HA and NHW populations, we used self-reported racial/ethnic information. Analysis of the “All of Us” database suggested a high prevalence of infection-related cancers such as Liver, Stomach, and Cervix Uteri in the HA population compared to the NHW population. SEER database also showed an increased percentage of diagnoses with infection-related cancers and poor survival of the HA population with these cancers compared to the NHW. We then analyzed the TCGA transcriptome data from primary tumors from HA and NHW patients. We only selected cancers with data from at least ten patients in each group. TCGA data confirmed that the tumors from HA cancer patients primarily express high inflammatory and immune-responsive signatures. Specifically, we found a high enrichment of NF-κB induced TNFA signaling in HA tumors. We also observed a significant correlation between TNFA and Hypoxia signature in many HA cancers. Since hypoxia is known to be associated with resistance to radiation and chemotherapy, targeting the increased hypoxia signature in HA tumors may be critical for sensitizing HA patients to cancer therapy. Overall, our pan-cancer analyses suggest an increased prevalence of many infection-related cancers in the HA population. HA tumors are enriched with TNFA, NF-κB, and hypoxic signatures. Specific targeting of these signatures may be critical in managing the HA patients who currently suffer from racial disparity in cancer incidence and survival.
Citation Format: Tagari Samanta, Jun Hyoung Park, Benny Abraham Kaipparettu. A comprehensive pan-cancer study nominating NF-κB-mediated TNFA signaling-induced hypoxia as a risk factor in Hispanic cancer progression [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 6124.
Abstract 6175: Deep learning-based survival prediction for hepatocellular carcinoma using whole slide images
Authors: Lee Sung Hak , Jang Hyun-Jong 
Published: March 2024

Abstract
There is an increasing need for classifiers to effectively stratify prognosis in patients with hepatocellular carcinoma (HCC). Deriving interpretable prognostic features using deep-learning (DL)-based prognostic models from pathology images remains a challenge. In this study, we developed a computational approach based on DL to predict the overall survival (OS) of HCC patients from formalin-fixed paraffin-embedded histopathology whole slide images. A DL model for classifying good and poor prognosis was developed on a total of 460 patients with 2 independent cohorts from Seoul St. Mary's Hospital. The primary outcome was OS. The training set (SSM1, n = 292) included HCC patients that had undergone surgical resection. The classifier was then independently tested on the second HCC dataset (SSM2, n = 168). The area under the curve (AUC) for the receiver operating characteristic (ROC) curves was 0.850 and 0.781 for SSM1 and SSM2 datasets, respectively. In addition, we have tried to establish DL model for prediction of OS based on clinicopathological features, including Edmondson-Steiner grade, pT stage, vascular invasion, Ki-67 index, and cytokeratin 19 immunohistochemical expression. Random forest model was applied to classify the good and poor prognosis groups and The AUROCs for the random forest was 0.705 for the SSM1 dataset, which are inferior to that of DL prediction. These findings suggest that the DL techniques can be applied to refine the prognostic prediction of HCC patients.
Citation Format: Sung Hak Lee, Hyun-Jong Jang. Deep learning-based survival prediction for hepatocellular carcinoma using whole slide 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 6175.
Abstract 6227: A systems biology approach for identifying targetable vulnerabilities in Ewing sarcoma
Authors: Dela Cruz Filemon S. , Mundi Prabhjot S. , Siddiquee Armaan , Guillan Kristina , You Daoqi , Sanchez Glorymar Ibanez , Ndengu Andoyo , Califano Andrea , Kung Andrew L. 
Published: March 2024

Abstract
Background: Targeting fusion oncoproteins like the canonical EWS/ETS fusions in Ewing sarcoma remain an elusive challenge. To circumvent these challenges, we have utilized transcriptome-based systems biology approaches that identify targetable Master Regulator proteins (MRs) critical to maintaining the cancer cell state. OncoTarget analysis generates a rank order list of targetable MRs while OncoTreat analysis uses cognate cell lines matched to patient tumors to identify drugs that invert the MR signature. We used OncoTarget and OncoTreat analyses to identify existing drugs which could be repurposed to target MRs active in Ewing sarcoma.
Methods: A gene regulatory interactome was developed from 122 pediatric sarcoma samples to enable identification of MR targets using OncoTarget. To enable OncoTreat analysis, 2 cognate cell lines were subjected to high-throughput drug perturbational screens. Cells were treated with sub-lethal concentrations of 335 compounds (FDA approved or investigational drugs). Ex vivo drug screens using PDX-derived cells were performed as a complementary assay to validate predictions. In vivo validation was performed in Ewing sarcoma PDXs.
Results: The MR architecture of 3 Ewing sarcoma PDX models was evaluated using OncoTarget. OncoTreat analysis identified 43 drugs predicted to be active in at least 1 Ewing sarcoma PDX while OncoTarget analysis identified 20 MR targets predicted in at least 1 Ewing sarcoma PDX. DOT1L and AURKB were predicted targets across multiple Ewing sarcoma PDXs. Ex vivo screening of dissociated cells from 2 Ewing sarcoma PDXs was performed to select the most potent agents for in vivo validation. Three OncoTreat (clarithromycin, tivozanib and obataclax) and two OncoTarget (DOT1L targeted with EPZ-5676 and AURKB targeted with baracertib) predicted drugs were evaluated in a STAG2 mutant Ewing sarcoma PDX and all demonstrated significant abrogation of tumor growth including complete regression in baracertib-treated animals (p&lt;0.01).
Conclusion: These systems biology approaches can identify non-oncogene encoded vulnerabilities in Ewing sarcoma and hold the potential for expanding the number of therapeutic options for tumors driven by untargetable oncoproteins.
Citation Format: Filemon S. Dela Cruz, Prabhjot S. Mundi, Armaan Siddiquee, Kristina Guillan, Daoqi You, Glorymar Ibanez Sanchez, Andoyo Ndengu, Andrea Califano, Andrew L. Kung. A systems biology approach for identifying targetable vulnerabilities in Ewing sarcoma [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 6227.
Abstract 6265: FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors
Authors: Burke Callie , Bellizzi Justin , Costa-Guda Jessica , Arnold Andrew 
Published: March 2024

Abstract
Parathyroid carcinoma (PC) is rare, poses challenges in definitive diagnosis and treatment, and carries a high rate of recurrence and mortality. Atypical parathyroid tumors (APT) have histopathologic features of malignancy but lack unequivocal evidence of invasion and are of uncertain malignant potential. Analysis of genetic alterations that may play a role in PC development, particularly those that might serve as markers of malignant potential, is important for further understanding this disease. FLCN is a gene found on chromosome 17 that encodes folliculin, a ubiquitously expressed protein with roles in multiple cellular processes such as apoptosis and cell signaling. Inactivating FLCN mutations cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant condition characterized by benign fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, and increased risk of renal cancer. Benign parathyroid tumors had previously been reported in a few BHD patients and recently one study has reported a link between FLCN mutations and parathyroid carcinoma. Germline frameshift mutations in FLCN, accompanied by somatic loss of the normal allele, were reported in two unrelated PC patients, both with clinical features suggestive of BHD, but no established diagnosis of BHD. An identical somatic frameshift FLCN mutation was reported in one PC and one APT. Interestingly, the authors noted low coverage of FLCN on whole exome sequencing, resulting in the failure to detect variants identified by Sanger sequencing, thus raising the possibility that prior studies may have missed FLCN variants. To better understand the frequency of germline or somatic FLCN mutations in PC and APT, we performed Sanger sequence analysis of the entire coding region of the FLCN gene on available tumor DNA from 11 PCs and 15 APTs. We identified no inactivating FLCN mutations in any of the PC or APT samples examined. A germline missense variant, resulting in a p.Gly325Val change, predicted to be benign/tolerated by in silico analyses, was seen in one PC and a synonymous variant (c.1233G&gt;A) was seen in one APT. The absence of pathogenic mutations in our series parathyroid carcinoma and atypical parathyroid tumors suggests that FLCN mutations are rare in these parathyroid tumors. Nevertheless, germline FLCN testing and/or additional screening for BHD-related lesions in parathyroid carcinoma patients merits further consideration and study.
Citation Format: Callie Burke, Justin Bellizzi, Jessica Costa-Guda, Andrew Arnold. FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors [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 6265.
Abstract 627: IL-6 signaling via JAK/STAT axis influences PIM1 expression in renal cell carcinoma
Authors: Meza Kimberly S. , Seymour Kimberly , Holder Sheldon L. 
Published: March 2024

Abstract
Renal cell carcinoma (RCC) is a top ten malignancy in the U.S. Overexpression of the proviral integration site for moloney murine leukemia virus 1 (PIM1) kinase is associated with poor clinical outcomes in RCC patients. PIM1 is a constitutively active serine/threonine kinase promoting cell proliferation, apoptosis resistance, invasion, and migration. The mechanisms underlying PIM1 expression and its function in RCC are not fully delineated. IL-6 is a pleiotropic cytokine that activates the JAK/STAT signaling cascade. High serum IL-6 levels are associated with the poor prognosis of RCC patients and may contribute to RCC invasion and metastasis. STAT3/5 binds directly to the PIM1 promoter inducing PIM1 expression. An IL-6/STAT3/PIM1 axis exists in pancreatic and breast cancer. We previously reported that PIM1 is overexpressed in a panel of human RCC cell lines relative to normal and immortalized renal proximal tubule epithelial cells. We also identified that RCC cells secrete IL-6. Our prior studies suggest that differential expression of PIM1 may be linked to autocrine IL-6 signaling. We thus hypothesize that an IL-6/JAK/STAT pathway regulates the expression of PIM1 in RCC. To understand how IL-6 signaling through the JAK/STAT pathway may regulate PIM1 expression in RCC cells, we examined whether IL-6 blockade using anti-IL-6 antibody or tocilizumab, would modulate PIM1 expression. Similarly, we assessed whether ruxolitinib, and LLL12, a STAT3 inhibitor could regulate PIM1 expression. We then evaluated the effect of ruxolitinib treatment on cell viability. In RCC cell lines, IL-6 blockade through either anti-IL-6 antibody or tocilizumab was sufficient to decrease PIM1 protein levels. Treatment with ruxolitinib leads to a dose and time-dependent decrease in PIM1 levels. Incubation with a STAT3 inhibitor also resulted in decreased PIM1 levels in RCC cells. Treatment with ruxolitinib also appears to decrease cell viability in a dose-dependent manner. These results suggest that differential expression of PIM1 in RCC may be linked to autocrine IL-6 signaling via a JAK/STAT/PIM1 axis. Multiple FDA-approved agents are available that target this pathway. Further investigation is required to determine the efficacy of these agents in pre-clinical models and even clinical trials.
Citation Format: Kimberly S. Meza, Kimberly Seymour, Sheldon L. Holder. IL-6 signaling via JAK/STAT axis influences PIM1 expression in renal cell carcinoma [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 627.
Abstract 6277: Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching
Authors: Al-Kuraya Khawla S. , Parvathareddy Sandeep K. , Siraj Abdul K. , Ahmed Saeeda O. , Siraj Nabil , Manakhan Manal , Aldossari Hassan 
Published: March 2024

Abstract
The tall cell variant of Papillary Thyroid Carcinoma (TCV-PTC) is the most common aggressive variant of PTC. The impact of TCV-PTC on patients’ prognosis still remains controversial. Moreover, the clinico-pathological and prognostic effect of TCV-PTC from Middle Eastern ethnicity remains unexplored. We aimed to study TCV-PTC in comparison to classical PTC in Middle Eastern patients and their impact on prognosis. We performed a retrospective cohort study of tall cell variant (TCV-PTC) and classic variant of papillary thyroid carcinoma (CV-PTC) after post-surgical radioactive iodine therapy. We used the propensity score matching (1:3 matching ratio) to account for differences between recipients of TCV-PTC vs CV-PTC. Univariate and multivariate analysis were performed to assess the independent factors for persistent/recurrent disease. Kaplan-Meier curve analyses were used to compare disease-free survival (DFS). In total, 174 (16.3%) patients with TCV-PTC and 891 (83.7%) patients with CV-PTC were included. After propensity score matching, 174 pairs of patients were selected (TCV-PTC, n = 174; CV-PTC, n = 522). In the matched analysis, higher proportions of TCV-PTC experienced persistent/recurrent disease compared with CV-PTC (25.7% vs 31.4%; p = 0.0119). In multivariate analyses of clinical and tumor characteristics, histological type of TCV-PTC (odds ratio, 2.09; 95% confidence interval, 1.28-3.40; p = 0.0031) was associated with increased risk of persistent/recurrent disease. The five-year DFS rates for the TCV-PTC and CV-PTC groups were 48.5% and 73.1%, respectively. The Kaplan- Meier analysis indicated that the TCV-PTC group (p &lt; 0.0001) had shorter DFS. In conclusion, when other clinico-pathological factors were similar, this propensity score matched analysis showed that histological subtype TCV-PTC is by itself an independent predictive marker of persistent/recurrent disease in Middle Eastern patients. Therefore, individualized therapeutic approaches might be needed for this aggressive PTC subtype.
Citation Format: Khawla S. Al-Kuraya, Sandeep K. Parvathareddy, Abdul K. Siraj, Saeeda O. Ahmed, Nabil Siraj, Manal Manakhan, Hassan Aldossari. Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching [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 6277.
Abstract 6283: Tumor repressive effects of estrogen receptor β mRNA-based therapy in aggressive breast cancers
Authors: Cap Kim Cuong , Phillips Aireana , Pinto Karem A. Court , Zambo Kristina D. , Qian Wei , Zhou Jianying , Chang Jenny , Godin Biana , Thomas Christoforos 
Published: March 2024

Abstract
Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are the most aggressive forms of breast cancer due to their high propensity to develop distant metastases and the lack of specific effective targeted therapies. The failure of previous research to produce viable therapeutic targets combined with the absence of estrogen receptor α (ERα) in TNBC and the majority of IBC led us to explore the second ER (ERβ) as a molecule with targeting potential. We previously reported the anti-metastatic effects of ERβ in both TNBC and IBC. Considering the anti-tumor activity together with the decreased expression of ERβ in IBC and TNBC tumors, we employed an mRNA-based approach to induce tumor-specific upregulation of the receptor and restore its anti-metastatic activity. Our findings show that complexes of ERβ mRNA with lipid nanoparticles (LNPs) enable in vitro translation of a functional protein with strong anti-invasive activity. More importantly, direct administration of ERβ mRNA-LNPs in orthotopically grown IBC and TNBC tumors results in high tumor levels of the receptor and an evident inhibition of metastasis demonstrating for the first time the ability of ERβ mRNA to prevent progression of the disease. Our study may have important clinical implications by establishing ERβ mRNA as a novel and specific therapy intervention that either alone or in combination with existing treatments can substantially repress metastasis, eliminate associated mortality and benefit patients with aggressive breast cancer.
Citation Format: Kim Cuong Cap, Aireana Phillips, Karem A. Court Pinto, Kristina D. Zambo, Wei Qian, Jianying Zhou, Jenny Chang, Biana Godin, Christoforos Thomas. Tumor repressive effects of estrogen receptor β mRNA-based therapy in aggressive breast cancers [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 6283.