bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3997: Inhibiting ribosomal proteins with a small molecule: Therapeutic strategy for triple negative breast cancer
Authors: Dheeraj Arpit , Tailor Dhanir , Resendez Angel , Marques Fernando Jose , Bermudez Abel , Pitteri Sharon , Malhotra Sanjay 
Published: June 2022

Abstract
Aberration in the protein translation can lead to changes in the protein expression that can serve as the drivers of tumor progression. Ribosomes are a molecular machine that acts as a hub for protein synthesis, and dysregulation of ribosome function is causative for cancer formation. Our investigation on the causes of breast cancer progression has identified a small molecule ‘SU056’ that shows efficacy against TNBC models. SU056 treatment inhibits growth and clonogenic potential of TNBC cells (MDA-MB-231, MDA-MB-468, SUM159, 4T1, EMT6 and E0771), by arresting the cell cycle progression through G2/M phase. Proteomics analysis suggested translational process as a target of SU056 in these cells. We found that its treatment modulated expression of several molecules of translational complex such as RPL (RPL9, RPL11, RPL15), RPS (RPSA, RPS9, RPS16, RPS20), and translation initiation factors (eIF6, eIF5, eIF4A, eIF4G), which leads to overall inhibition. This was further confirmed by tumor xenograft study with different TNBC models, which also showed that metastatic nodules in the lungs were inhibited by SU056 compared to control group. The results were further confirmed in a Patient Derived Xenograft (PDX) model SUTI151. Overall, our study has identified a lead candidate SU056, and provides strong foundation to further develop a new therapy for treatment of patients with TNBCs.
Citation Format: Arpit Dheeraj, Dhanir Tailor, Angel Resendez, Fernando Jose Marques, Abel Bermudez, Sharon Pitteri, Sanjay Malhotra. Inhibiting ribosomal proteins with a small molecule: Therapeutic strategy for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3997.
Abstract 4010: Analytical concordance of 3 independent diagnostic assays for the detection of FGFR alterations in urothelial carcinoma tumor tissue
Authors: Major Christopher , Wang Songbai 
Published: June 2022

Abstract
Background: The Qiagen therascreen® companion diagnostic is FDA approved to aid identifying patients with urothelial carcinoma who harbor susceptible fibroblast growth factor receptor (FGFR) gene alterations and are therefore eligible for treatment with erdafitinib, an FGFR inhibitor. We examined analytical concordance between the Qiagen assay against 2 next-generation sequencing (NGS) platforms used to identify molecular targets for tailored treatment, including FGFR alterations.
Methods: Formalin-fixed paraffin-embedded tumor tissue samples (N = 54: muscle-invasive bladder cancer [n = 18], non-muscle-invasive bladder cancer [n = 23], cholangiocarcinoma [n = 12], non-small-cell lung cancer [n = 1]) were obtained commercially. FGFR alterations were detected using the Qiagen therascreen FGFR RGQ RT-PCR Kit and tested for concordance vs NGS platforms from Thermo Fisher Scientific (Oncomine Comprehensive™ assay) and Illumina (TruSight™ Oncology 500 [TSO500]). Concordance assessment of positive, negative, and overall agreement was done.
Results: 54 samples yielded valid results using the Qiagen assay. 51 met quality control metrics with the Thermo Fisher assay, and 47 with the Illumina assay. FGFR alterations were found in 17 samples, including 16 with single nucleotide variants (SNVs): R248C (n = 1), S249C (n = 7), and Y373C (n = 8), 1 with an FGFR3:TACC3 fusion and 1 with both FGFR3:TACC3 fusion and S249C mutation. Qualitative positive agreement (100%), negative agreement (100%), and overall agreement (100%) between the Thermo Fisher NGS assay and the Illumina NGS assay vs the Qiagen assay for SNVs was observed (Table). 2 fusions detected as positive by the Qiagen assay were not identified as the TACC3v1 fusion by NGS assays.
Conclusions: There was a high level of analytical concordance in detection of FGFR alterations indicated for erdafitinib between the Qiagen companion diagnostic assay and 2 commercially available NGS platforms.
Table. Concordance in detection of FGFR alterations Qiagen therascreen RT-PCR Positive Negative NGS Thermo Fisher Oncomine Dx Positive 17/17 (100%); 95% CI, 86.3%-100% 0/34 (0) Negative 0/17 (0) 34/34 (100%); 95% CI, 92.6%-100% Overall 51/51 (100%); 95% CI, 95.0%-100% NGS Illumina TSO500 Positive 17/17 (100%); 95% CI, 86.3%-100% 0/30 (0) Negative 0/17 (0) 30/30 (100%); 95% CI, 91.7%-100% Overall 47/47 (100%); 95% CI, 94.6%-100%
Citation Format: Christopher Major, Songbai Wang. Analytical concordance of 3 independent diagnostic assays for the detection of FGFR alterations in urothelial carcinoma tumor tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4010.
Abstract 4102: Vulnerability signature guided glioblastoma umbrella trial
Authors: Berens Michael E. , Peng Sen , Lee Matthew , Tang Nanyun , Ahluwalia Manmeet S. , Fonkem Ekokobe , Fink Karen L. , Raizer Jeffrey , Walker Christopher , Dhruv Harshil 
Published: June 2022

Abstract
Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. A glioblastoma umbrella signature trial (GUST) posits multiple investigational treatment arms based on corresponding biomarker signatures. One contingency for an efficient umbrella trial is a suite of orthogonal signatures to classify patients into the likely most-beneficial arm. Assigning optimal thresholds of vulnerability signatures to classify patients as “most-likely responders” for each specific treatment arm is a crucial task. We utilized relative expression orderings (REO), entropy-regularized logistic regression (ERLR) and random forest classifier, to predict vulnerability classification. By applying semi-supervised algorithms to the TCGA GBM cohort, we were able to transform the samples with the highest certainty of predicted response into a self-labeled dataset and thus augment the training data. In this case, we developed a predictive model with a larger sample size and potentially better performance. Our GUST design currently includes four treatment arms for GBM patients: Arsenic Trioxide, Methoxyamine, Selinexor and Pevonedistat. Each treatment arm manifests its own signature developed by the customized machine learning pipelines based on selected gene mutation status, whole transcriptome data and real world outcomes from clinical trials. In order to increase the robustness and scalability, we also developed a multi-class/label classification ensemble model that’s capable of predicting a probability of “fitness” of each novel therapeutic agent for each patient. Such a multi-class model would also enable us to rank each arm and provide sequential treatment planning. By expansion to four independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients labeled 56% of all cases into at least one “high likelihood of response” arm. Predicted vulnerability using genomic data from preclinical PDX models correctly placed 4 out of 6 models into the “responder” group. Our utilization of multiple vulnerability signatures in a GUST trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM.
Citation Format: Michael E. Berens, Sen Peng, Matthew Lee, Nanyun Tang, Manmeet S. Ahluwalia, Ekokobe Fonkem, Karen L. Fink, Jeffrey Raizer, Christopher Walker, Harshil Dhruv. Vulnerability signature guided glioblastoma umbrella trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4102.
Abstract 4232: TLR2 agonist as a novel therapeutic approach to treat pancreatic adenocarcinoma
Authors: Dheeraj Arpit , Shukla Chandreshwar , Tailor Dhanir , Jain Nayan K. , Stefan Kirsten , Patel Chintan D. , Modi Rajiv , Khamar Bakulesh M. , Malhotra Sanjay V. 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with an overall 5-year survival rate of &lt;10% due to late stage diagnosis and poor clinical outcome with existing therapies. PDAC displays a high degree of tumor heterogeneity and immunosuppressive tumor microenvironment with lower tumor infiltrating lymphocytes (TIL). These factors contribute to resistance against chemotherapies and immunotherapies. Immunotherapies have shown activities across different tumor types including chemotherapy or targeted therapy resistant cancers however these options have little efficacy in the PDAC tumor. Here, in this study we tested the efficacy of gemcitabine in combination with Cadi-05 (TLR2 agonist) against established murine PDAC tumor models (Pan02 in C57/BL6 and 688M in B6129SF1/J). Animals were randomized to receive gemcitabine, Cadi-05, their combination or no treatment when they had tumor size ≈ 50 mm3, 65mm3 and 100 mm3. The weekly treatment of gemcitabine, Cadi-05 and their combination inhibited the tumor progression across all tumor sizes. At the end of study, PBMC and tumors were collected and analyzed for different immune parameters. Results revealed that Cadi-05 treatment alone was associated with increase in CD4+ and CD8+ T cells in PBMC as well as amongst TIL with significant decrease in their expression of immunosuppressive markers like FOXP3 and PD-1. Its combination with gemcitabine synergized the effect of each other. There was further increase in absolute TIL as well as TIL expressing CD4+ and CD8+ markers with decrease in FOXP3 and PD-1 expressing CD4+ and CD8+ TIL. Inhibition of tumor progression was associated with improved effector function of PBMC. Synergy between Cadi-05 and gemcitabine was also evident in effector function. In presence of established tumor, TLR2 agonist Cadi-05 improves effector function, increases CD4+ and CD8+ expressing TIL, decreases immune suppressive TIL and retards tumor growth. Our study suggests that combination of gemcitabine and Cadi-05 inhibits the tumor growth irrespective of its size and it is coupled with increased anti-tumor response and decreased immunosuppressive function
Citation Format: Arpit Dheeraj, Chandreshwar Shukla, Dhanir Tailor, Nayan K. Jain, Kirsten Stefan, Chintan D. Patel, Rajiv Modi, Bakulesh M. Khamar, Sanjay V. Malhotra. TLR2 agonist as a novel therapeutic approach to treat pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4232.
Abstract 4251: Development and characterization of an epiregulin antibody-drug conjugate for targeting colorectal cancer cell plasticity
Authors: Jacob Joan , Liang Zhengdong , Carmon Kendra 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States. This is largely due to metastasis, tumor relapse, and the vast heterogeneity of CRC tumors leading to treatment failure. Cancer stem cells (CSCs) are a small population of tumor-initiating cells thought to act as immortal seeds that can form metastases and contribute to tumor relapse. CSCs have been shown to exhibit plasticity or the ability to transition between differentiated and undifferentiated states to evade treatment and to promote tumor progression. Epiregulin (EREG) is an EGFR family ligand that is highly expressed in both states, as well as in treatment resistant CRCs of various mutation statuses. We showed that knock-out of EREG in a CRC cell line resulted in significant tumor inhibition in vivo, suggesting EREG is a promising target for therapeutic development. Therefore, we generated EREG-targeted antibody-drug conjugates (ADCs) to act as guided missiles for the delivery of cytotoxic drugs into EREG-expressing tumors to overcome plasticity and resistance in CRC. To develop a novel EREG ADC, we cloned and produced three separate EREG monoclonal antibody (mAbs) and tested them for binding, the ability to internalize into CRC cells, and to neutralize EREG activity. All three EREG mAbs were shown to bind with high affinity to EREG tethered to the surface of CRC cells and internalize to the lysosome, which is important for processing the release of drug from the ADC. We then conjugated the highest affinity EREG mAb and a non-targeting isotype control antibody to a highly cytotoxic drug via a cleavable peptide linker. EREG ADCs were evaluated in vitro against a wide panel of CRC cell lines of various Kras, Braf, and PI3CKA mutational statuses and different levels of EREG expression. Drug efficacy was determined using cytotoxicity assays to measure changes in CRC cell survival with escalating doses of unconjugated control antibody and EREG mAb, as well as control ADC (cADC) and EREG ADC. EREG mAb alone did not result in significant CRC cell death. However, EREG ADCs exhibited potent cell-killing in EREG-expressing CRC cells, whereas minimal effects were observed with cADC. Future progress will involve testing the safety and efficacy of EREG ADCs against patient-derived tumor xenograft models of CRC in vivo. These preliminary results demonstrate the therapeutic potential of EREG ADCs for targeting plasticity and drug resistance in CRC.
Citation Format: Joan Jacob, Zhengdong Liang, Kendra Carmon. Development and characterization of an epiregulin antibody-drug conjugate for targeting colorectal cancer cell plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4251.
Abstract 4263: A novel pegylated biparatopic antibody-drug conjugate (pb-adc) targeting cancers with low HER2+ expression
Authors: Liu Shumin , Yin Shuqiang , Lyu Weidong , Lei Yang , Zhuo Qiudong , Wu Zibin , Tan Shuangyu , Zheng Liling , Wen Yu (Yvonne) , Wu David 
Published: June 2022

Abstract
ADCs have demonstrated much improved target selectivity and efficacy comparing to the nonspecific cytotoxic small molecule drug. The goal of ADC technology is to resolve the toxicity issue inherent in potent small molecule drugs. Yet, the main problem facing current ADC technology is still a toxicity issue, evidenced by 9 out of 12 FDA approved ADCs carrying black box warning labels and many failed clinical programs due to their toxicities. Many factors contribute to the ADC’s toxicity including but not limited to random conjugation of payloads to the antibody, premature release of payload, Fc related toxicity, on-target/off-tumor toxicity etc. In this study, we developed a novel pegylated BsAb-ADC formed by site-specific conjugating a fusion protein of two scFvs that target at two different epitopes of Her2, with PEG-MMAE, a pegylated cytotoxic payload MMAE. As expected, the compound is homogeneous without any Fc related toxicity. Although the compound showed lower affinity to Her2 positive cells, it demonstrated higher in vitro cytotoxicity than T-DM1, especially for Her2 low expressing cell lines when its DAR is 4. Furthermore, the compound was comparable to or better than T-DM1 or DS-8201 in inhibiting xenograft tumor models (including Her2+ low expressing models) even when DAR is only 2. The compound also demonstrated efficient internalization without detectable efflux, suggesting improved endosome and lysosome trafficking, most probably due to the lack of Fc promoted efflux mechanism and formation of complex between biparatopic Her2 antibody and Her2. In addition, unlike T-DM1 and DS-8201, the compound did not generate cytotoxicity to megakaryocyte cell line Dami, and is less toxic to the non-cancerous HaCaT cells than T-DM1 or DS-8201. The compound is stable with no detectable release of the payload when incubating with human Plasma for a week at 37°C. The circulation T1/2 of the compound in rat is about 30 hours. In conclusion, our pegylated BsAb-ADC compound demonstrated improved efficacy with better safety profile than T-DM1 and DS-8201.

Citation Format: Shumin Liu, Shuqiang Yin, Weidong Lyu, Yang Lei, Qiudong Zhuo, Zibin Wu, Shuangyu Tan, Liling Zheng, Yu (Yvonne) Wen, David Wu. A novel pegylated biparatopic antibody-drug conjugate (pb-adc) targeting cancers with low HER2+ expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4263.
Abstract 474: Integrating imaging and multi-omics data to elucidate racial differences in breast tumor biology to optimize precision oncology approaches and patient outcome
Authors: Liadis Nicole , Earnest Tyler , Braun Eduardo , Antony Anu , Munn Lance , Hallock Michael , Cook Daniel ,   The SimBioSys Team
Published: June 2022

Abstract
Background: Racial disparities in breast cancer incidence and clinical outcome have been well characterized. In particular, African American (AA) patients have higher mortality rates than other racial groups. Research into these racial disparities has primarily focused on socioeconomic determinants, with some studies exploring potential molecular determinants and limited biological differences found between AA and Caucasian patient tumors. Tumor intrinsic and extrinsic factors that promote racial differences in breast cancer development and patient outcome are not fully understood and strategies to address this are scarce. As a result, we have developed a platform that combines patient-specific imaging and multi-omics data to elucidate how biological differences integrate to promote racial disparities in tumor behavior and patient outcome.
Methods: Imaging and transcriptomic data from over 500 patients were integrated within the SimBioSys TumoScope biophysical modeling software to understand racial differences in tumor biology and coordinated tumor behavior.
Results: AA patients have tumors that display higher growth rates, characteristically have higher adipose tissue around the tumor, higher spatial variation in drug secretion, lower spatial variation in blood flow/and increased tumor stiffness.
Conclusion: Using a transdisciplinary approach, our results show that metabolic and structural tumor features are associated with the disproportionately poor survival rates observed in AA breast cancer patients. By characterizing racial-specific tumor intrinsic and extrinsic biological factors and their potential interactions, strategies may emerge to personalize clinical management based on racial differences. In this way, precision oncology approaches can be applied to increase life-expectancy for racial minorities with breast cancer.
Citation Format: Nicole Liadis, Tyler Earnest, Eduardo Braun, Anu Antony, Lance Munn, Michael Hallock, Daniel Cook, The SimBioSys Team. Integrating imaging and multi-omics data to elucidate racial differences in breast tumor biology to optimize precision oncology approaches and patient outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 474.
Abstract 50: Multi-omics and immune cell profiling of metastatic uveal melanomas
Authors: Moser Justin C. , Shao Yusra F. , Xiu Joanne , Baca Yasmine , Sato Takami , Dalvin Lauren A. , Darabi Sourat , Korn Michael , Eisenberg Burton , Gibney Geoff , Domingo-Musibay Evidio , In Gino , Hoon Dave , Gordon Michael S. 
Published: June 2022

Abstract
Background: Uveal melanoma (UM) is a rare tumor of the eye which is biologically distinct from cutaneous melanoma (CM) and carries a poor prognosis once metastatic. We aimed to examine a multi-omics profile of UM as compared to CM.
Methods: A total of 277 UM and 1,297 CM metastatic or primary samples were analyzed using next-generation sequencing (NextSeq, 592 genes and WES, NovaSeq, &gt;700 genes) and whole transcriptome sequencing (WTS; NovaSeq) (Caris Life Sciences). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cutoff &gt;10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. T- cell inflamed score was calculated using gene expression data. Pathway gene enrichment analysis using WTS data was performed using GSEA. Biostatistical significance was determined using chi-square/Fisher-Exact or Wilcoxon rank sum test and adjusted for multiple comparisons.
Results: For all cases (primary and metastatic), UM compared to CM had a higher rate of GNAQ/11 (93.8% vs. 2.1% p≤0.001), SF3B1 (20.4% vs 3% p≤0.001), and BAP1 (52.9% vs. 1.5% p≤0.001) mutations. UM also had higher levels of MYC (7% vs 0.9% p≤0.001), NCOA2 (3.1% vs 0.1% p≤0.001), and RUNX1T1 genomic amplifications (2.3% vs 0.2% p≤0.001). Assessing only samples of liver metastases, UM was shown to have higher abundance of M2 macrophages (P≤0.0001) and less abundance of M1 macrophages(P≤0.0001), monocytes(P≤0.0001), CD4 T-cells(P≤0.0001), and regulatory T-cells (p = 0.0003) as compared to CM. GSEA comparison between liver metastases of UM and CM samples showed G2M checkpoint (NES score, 1.60 p≤0.0001) and E2F targets (NES score, 1.58 p=0.002) to be higher in metastatic CM. When comparing T-cell inflamed, intermediate, and non-inflamed tumors from any site, CM or UM, the average Z scores for both G2M and E2F were highest for inflamed and lowest for non-inflamed, P≤0.0001. A similar trend of higher Z score was seen for TMB high vs TMB low tumors, p≤0.0001.
Conclusions: UM and CM are characterized by significantly different genomic and transcriptomic alterations, and cellular composition of TME. Further understanding of these characteristics may lead to better treatment strategies for metastatic UM.
Citation Format: Justin C. Moser, Yusra F. Shao, Joanne Xiu, Yasmine Baca, Takami Sato, Lauren A. Dalvin, Sourat Darabi, Michael Korn, Burton Eisenberg, Geoff Gibney, Evidio Domingo-Musibay, Gino In, Dave Hoon, Michael S. Gordon. Multi-omics and immune cell profiling of metastatic uveal melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 50.