bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7044: Transcriptome and TCR repertoire in human telomerase reverse transcriptase peptide vaccine treated metastatic prostate cancer patients
Authors: Nätkin Reetta , Simensen Julia Elisabeth , Engedal Nikolai , Ellingsen Espen Basmo , Westhrin Marita , Westgaard Ingunn , Hovig Eivind , Lilleby Wolfgang , Nykter Matti , Urbanucci Alfonso 
Published: March 2024

Abstract
Human telomerase reverse transcriptase (hTERT) vaccine has found to be effective for most of the participated de novo metastatic prostate cancer patients in clinical studies. Nevertheless, the molecular mechanisms behind the immune response induced by the hTERT vaccine are not fully elucidated. Among the cohort of 21 patients treated with androgen deprivation therapy, radiotherapy and hTERT vaccine, we used RNA-sequencing and TCR-sequencing (20 and 14 pre-treatment and 20 and 21 post-treatment samples, respectively) to inspect the changes in transcriptome and TCR-repertoire after the hTERT vaccine treatment and differences between patients that had early response and patients that had late or no response. We found multiple hallmarks being shifted after the treatment and being different between early and late responders. Also, a change in activity of multiple gene set signatures was detected after the treatment and activity of part of the gene set signatures predicted survival. Deconvolution of cell type composition from RNA-sequencing data revealed changes in immune cell abundances after the treatment. TCR-sequencing revealed changes in composition and diversity of TCR repertoires after the treatment and these differed between early and late responders. The results of this study will help to predict patients’ responses to the cancer vaccine and to further understand the mechanisms behind successful cancer vaccines.
Citation Format: Reetta Nätkin, Julia Elisabeth Simensen, Nikolai Engedal, Espen Basmo Ellingsen, Marita Westhrin, Ingunn Westgaard, Eivind Hovig, Wolfgang Lilleby, Matti Nykter, Alfonso Urbanucci. Transcriptome and TCR repertoire in human telomerase reverse transcriptase peptide vaccine treated metastatic prostate cancer patients [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 7044.
Abstract 7054: L1-ATP8B1 exacerbates high-level reduction-oxidation homeostasis to promote carcinogenesis via affecting PHB1 sumoylation in LUSC
Authors: Zhang Rui , Zhang Xiao , Sun Zeguo , Liu Pengpeng , Chen Guidong , Zhang Weijia , Yu Jinpu 
Published: March 2024

Abstract
Long Interspersed Nuclear Element-1 (LINE-1, L1) plays important roles in carcinogenesis. However, the function of LINE-1 in lung squamous cell carcinoma (LUSC) remains unclear. Here we found that L1-ATP8B1 was overexpressed in LUSC patients with short survival and associated with mitochondrial dysfunction in both the TCGA dataset and the TJMUCH cohort. Overexpression of L1-ATP8B1 promoted cell proliferation and invasion in vitro and facilitated LUSC xenograft growth in vivo. L1-ATP8B1 affected mitochondrial complex enzyme I activity via affecting cardiolipin-dependent PHB1 sumoylation and promoting PHB1 ubiquitination, inducing high-level cellular reduction-oxidation (redox) homeostasis. Synergetic therapy with an L1 inhibitor and an antioxidant dramatically interfered with redox homeostasis and restored mitochondrial function, abolishing L1-ATP8B1-induced growth and metastasis of LUSC xenografts in vivo. In conclusion, we for the first time demonstrated that metabolic disorder plays a vital role in L1-related carcinogenesis and identified L1-ATP8B1 as a promising prognostic biomarker and therapeutic target for LUSC.
Citation Format: Rui Zhang, Xiao Zhang, Zeguo Sun, Pengpeng Liu, Guidong Chen, Weijia Zhang, Jinpu Yu. L1-ATP8B1 exacerbates high-level reduction-oxidation homeostasis to promote carcinogenesis via affecting PHB1 sumoylation in LUSC [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 7054.
Abstract 7093: Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics
Authors: Xu Kailun , Yin Xiaoyang , Guo Tiannan , Zheng Shu , Shao Yingkuan 
Published: March 2024

Abstract
The use of adjuvant therapy in stage II-III colon cancer (CC) has been controversial for decades. No markers or models now is satisfactory enough to be adopted widely by the medical community. Here, we analyzed the proteomics of paraffin-embedded tissue (FFPE) biopsy samples from 230 CC patients (stages II-III) with up to 10 years of survival by using pressure cycling technology (PCT) and data-independent acquisition (DIA) mass spectrometry. Using machine learning, we established a novel and practical protein-based clinical classification system for CC prognosis which was further verified in an independent validation cohort. Using the nine protein-based clinical model, we improved the area under the curve (AUC) value to 0.926 in the training cohort and 0.872 in the validation cohort. Our promising model will be a potential approach to prognostication to aid in rational follow-up schedule-making and risk-adaptive individualized therapies.
Citation Format: Kailun Xu, Xiaoyang Yin, Tiannan Guo, Shu Zheng, Yingkuan Shao. Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics [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 7093.
Abstract 7131: Base excision repair regulation of replication stress induced poly(ADP-ribose) checkpoints
Authors: Ibrahim Md , Khan Md Maruf , Al-Rahaleh Rasha Q. , Clark Jennifer , Hayat Faisal , Fang Qingming , Koczor Christopher A. , Migaud Marie E. , Sobol Robert W. 
Published: March 2024

Abstract
PARP-inhibitors (PARPi) have been developed to treat homology-directed repair deficient cancers such as BRCA1/2-defective breast and ovarian tumors. However, acquired resistance to PARPi is now common, suggesting the need to identify new protein targets. To that end, a missed opportunity is found in the PARP1/PARP2 activation mechanism in response to DNA damage and replication stress and the resulting protein complexes and enzymes that depend on and coordinate PARP-mediated DNA repair processes. We have found that PARP1/PARP2 activation, whether from acute DNA damage, from replication stress or both triggers a temporal and coordinated interplay of base excision repair and single-strand break repair (BER/SSBR) proteins and enzymes. In turn, the recruitment of these BER and SSBR proteins suppresses PARP1/PARP2 activation, thereby functioning as a network of PARP1/PARP2 regulators, modulating the PARP-mediated response to replication stress. To that end, we find that loss of expression of these key BER/SSBR proteins releases a break on replication-stress induced PARP1/PARP2 activation, triggering un-restrained PARP1/PARP2 activation and elevated levels of replication-dependent poly(ADP-ribose) (PAR). We next confirmed that the loss of these downstream BER enzymes render cancer cells responsive to PARPi’s when the BRCA1/2 pathways are restored. Further, we show that BER expression regulates the cellular response to inhibitors of the PAR degrading enzyme PARG, suggesting that XRCC1-dependent BER proteins regulate replication-stress dependent PAR accumulation. The increase in PAR due to PARG inhibition, that is further regulated by BER, drives a strong intra-S phase response, indicated by activation of ATR and CHK1 signaling. As the checkpoint governed by ATR and CHK1 functions as a protective mechanism, we show that PARG inhibition is synthetically lethal with ATR and CHK1 inhibition and this may be explained by our demonstration of PARGi-mediated trapping of essential BER proteins at the site of damage and PAR accumulation. Together, these studies reveal a significant role for BER/SSBR proteins in regulating replication stress induced PARylation and the resulting intra-S phase checkpoint.
Citation Format: Md Ibrahim, Md Maruf Khan, Rasha Q. Al-Rahaleh, Jennifer Clark, Faisal Hayat, Qingming Fang, Christopher A. Koczor, Marie E. Migaud, Robert W. Sobol. Base excision repair regulation of replication stress induced poly(ADP-ribose) checkpoints [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 7131.
Abstract 7156: Targeting the β-catenin signaling axis in osteosarcoma
Authors: Curcic Marina , Gaikwad Shreyas , Srivastava Sanjay K 
Published: March 2024

Abstract
Osteosarcoma, an aggressive bone malignancy predominantly affecting children, poses a formidable challenge for therapeutic interventions. Here we evaluated a recently approved FDA drug, PCT, for potential anti-cancer effect in osteosarcoma model. Initial assessments of cytotoxicity encompassing various human and murine osteosarcoma cell lines—OS-17, OS-25, U2OS, SAOS2, MG63, and K7M3—revealed an IC50 ranging 1-3 µM. Subsequent investigations demonstrated significant anti-clonogenic activity and G2M phase cell cycle arrest. Annexin-PI assay showed a notable apoptotic effect of PCT, shedding light on the mode of cell death. Given the pivotal role of β-catenin signaling in human osteosarcoma pathogenesis and metastasis, targeting β-catenin components holds promise for therapeutic intervention. In silico docking studies suggested that PCT may have similar anti-cancer effect compared to β-catenin inhibitors (e.g., MSAB, ICG001). Our western blot analyses in multiple osteosarcoma cell lines demonstrated that PCT inhibits β-catenin pathway. Fluorescence microscopy and PCR analyses substantiated PCT's ability to hinder the nuclear translocation of β-catenin, providing mechanistic insights into its anti-tumor properties. Our preliminary data also suggests that AXL, an upstream regulator of β-catenin pathway, was modulated by PCT. In summary, our findings indicate that PCT exhibits therapeutic potential against osteosarcoma by targeting the β-catenin pathway. Further mechanistic studies are currently underway in our lab.
Citation Format: Marina Curcic, Shreyas Gaikwad, Sanjay K Srivastava. Targeting the β-catenin signaling axis in osteosarcoma [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 7156.
Abstract 7160: Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE
Authors: Shen Fei , Jiang Guanglong , Philips Santosh , Cantor Erica , Gardner Laura , Xue Gloria , Cunningham Geneva , Kassem Nawal , Oneil Anne , Cameron David , Suter Thomas , Miller Kathy , Sledge George , Schneider Bryan 
Published: March 2024

Abstract
Introduction: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions.
Methods: We performed post-hoc analyses to evaluate the association in 3,124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n=346) and SBP ≥ 180 mmHg (hypertensive crisis) (n=69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis.
Results: Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10−9; OR = 5.2).
Conclusion: Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity.
Citation Format: Fei Shen, Guanglong Jiang, Santosh Philips, Erica Cantor, Laura Gardner, Gloria Xue, Geneva Cunningham, Nawal Kassem, Anne Oneil, David Cameron, Thomas Suter, Kathy Miller, George Sledge, Bryan Schneider. Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE [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 7160.
Abstract 7167: Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung cancer
Authors: Kong Stephanie M. , Minocha Mukul , Chen Po-Wei , Martinez Pablo , Anderson Erik S. , Parkes Amanda , Houk Brett E. , Lin Chih-Wei 
Published: March 2024

Abstract
Background: Tarlatamab is a first in class, half-life extended delta-like ligand (DLL3) targeted bispecific T-cell engager (BiTE) immunotherapy that has shown antitumor activity with durable objective responses and promising survival outcomes in the ongoing studies in patients with previously treated small-cell lung cancer (NCT03319940, NCT05060016) (Ahn et al, 2023; Paz-Ares et al, 2023). Here we describe the effects of patient specific factors [age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status, emergence of anti-drug antibodies (ADA)] on tarlatamab exposures.
Methods: Tarlatamab serum concentrations were available from 420 subjects (8509 samples) pooled across the ongoing Phase 1 DeLLphi-300 study (dose range 0.003 mg to 100 mg Q2W and 200 mg Q3W) and Phase 2 DeLLphi-301 study (10 mg and 100 mg Q2W). The data were analyzed using a nonlinear-mixed effects modeling approach implemented in NONMEM (v7.5) software. Model selection and evaluation was guided by standard statistical and graphical approaches. Impact of key baseline demographic variables on tarlatamab clearance and volume of distribution were evaluated.
Results: Tarlatamab exposures increased in a dose-proportional manner and were not impacted by age, sex, ethnicity, estimates of renal and hepatic function, prior lines of therapy or baseline disease status. Asian race resulted in 14% higher peak serum concentrations relative to Caucasian subjects. Higher body weight (99 kg; 90th percentile) was associated with a 24% decrease in Day 28 pre-dose concentration (Ctrough) relative to median bodyweight (73 kg). Lower body weight (54 kg; 10th percentile) was associated with a 27% increase in Ctrough relative to median bodyweight. Positive ADA status resulted in a 24% decrease in Ctrough. However, at the recommended dose of 10 mg Q2W, neither body weight nor ADA status had a clinically relevant impact on tarlatamab efficacy or safety measures (Ahn et al, 2023).
Conclusion: Overall, based on these analyses, no dose adjustment for tarlatamab is required based on age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status or emergence of ADA.
Citation Format: Stephanie M. Kong, Mukul Minocha, Po-Wei Chen, Pablo Martinez, Erik S. Anderson, Amanda Parkes, Brett E. Houk, Chih-Wei Lin. Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung 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 7167.
Abstract 7219: Preclinical investigations of concomitant tumor treating fields (TTFields) with cisplatin for treatment of cervical cancer
Authors: Frechtel-Gerzi Roni , Gerasimova Daria , Zeevi Einav , Monin Roni , Fishman Hila , Schlachet-Drukerman Inbar , Mumblat Helena , Martinez-Conde Antonia , Engelman Rotem , Dor-On Eyal , Tzchori Itai , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram , Palmer Greg M. , Secord Angeles Alvarez 
Published: March 2024

Abstract
Introduction: Cervical cancer, although largely preventable, continues to be a significant health concern. Early-stage treatment is commonly surgery; while advanced, recurrent, or metastatic disease often requires systemic therapy. Chemotherapy, mainly cisplatin is the backbone of first-line therapy. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. In other tumor types, TTFields applied with cisplatin has exhibited benefit. This in vitro study assessed the preclinical efficacy of TTFields for cervical cancer and explored efficacy for concurrent use with cisplatin.
Methods: Effects on cell count in cervical cancer cell lines exposed to TTFields (0.5 V/cm for Ca Ski cells, 1 V/cm RMS for HeLa and SiHa cells; 72 h) across a range of frequencies (100-400 kHz) were evaluated. TTFields (200 kHz) were then applied with varying cisplatin doses followed by cell count, colony formation, and apoptosis assays. Overall effect was calculated as the product of percent reductions in cell count and colony formation. TTFields-treated cells were evaluated for formation of the DNA damage marker γH2AX using fluorescent microscopy; and for the expression of Fanconi Anemia (FA)-BRCA pathway proteins through Western blotting.
Results: TTFields treatment reduced cell count in all cervical cancer cell lines tested. Cisplatin exhibited dose-response effects, which were enhanced when TTFields were co-applied. TTFields led to downregulated expression of FA-BRCA pathway proteins, which are involved in repairing cisplatin-induced DNA damage, resulting in increased DNA damage.
Conclusions: These preclinical results suggest that TTFields should be further explored as a potential treatment for cervical cancer. TTFields-induced downregulation of the FA-BRCA pathway possibly explains the enhanced efficacy when TTFields are applied together with cisplatin, providing mechanistic insight.
Citation Format: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Roni Monin, Hila Fishman, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Rotem Engelman, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg M. Palmer, Angeles Alvarez Secord. Preclinical investigations of concomitant tumor treating fields (TTFields) with cisplatin for treatment of cervical 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 7219.
Abstract 7228: In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine prostate cancer
Authors: Purcell Connor , Srinivasan Praveen , Pinho-Schwermann Maximilian , MacDonald William , Ding Elizabeth C. , Tajiknia Vida , El-Deiry Wafik 
Published: March 2024

Abstract
Neuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype associated with poor prognosis that commonly arises in later stages as a mechanism of treatment resistance. Activation of oncogenic drivers, in combination with epigenetic changes (such as EZH2 overexpression and DNA methylation) further promotes tumor proliferation and expression of downstream neuroendocrine lineage pathways (in part controlled by transcription factors, including SOX2, ASCL1, and BRN2). Importantly, EZH2 inhibitors (EZH2i) can restore AR expression in CRPC (Ku et al., 2017). Imipridones, including Dordaviprone (ONC201), show promise in treating neuroendocrine tumors by interacting with DRD2 and CLpP (Anderson et al., 2022). These results warrant investigation into the potential for synergism in imipridone/EZH2i combination therapies.
In the PCa cell lines LNCap, PC3, 22Rv1, and DU145 the combination of ONC201 and EZH2i GSK126 was assessed. Cell viability data after treatment with ONC201 and GSK126 reveals several dose ranges with potential synergistic activity after 72h. Preliminary western blots after 72 hours of GSK126 treatment indicate modulation of proteins relevant to the mechanism of action of imipridones, specifically DR5 and CLpP, in LNCap, PC3, and 22Rv1. Notably, the decrease in DR5 expression warrants investigation into the effects of EZH2i on TRAIL sensitivity and whether imipridones may rescue DR5 expression to maintain TRAIL sensitivity.
Subsequent experiments will investigate dosing and time point-based effects on viability and protein expression, in addition to assessing the synergy of other imipridones and EZH2i’s. Further, while the cell lines PC3, 22Rv1, and DU145 are castration-resistant, the neuroendocrine prostate cell line NCI-H660 will be used as a positive control as it expresses higher neuroendocrine features, including DRD2. Additionally, the modulation in DR5 expression warrants inquiry into the effects of combination therapy on tumor-immune cell interactions. Further, we will manipulate the expression of neuroendocrine transcription factors to assess changes in therapy sensitivity.
Citation Format: Connor Purcell, Praveen Srinivasan, Maximilian Pinho-Schwermann, William MacDonald, Elizabeth C. Ding, Vida Tajiknia, Wafik El-Deiry. In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine 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 7228.
Abstract 7230: A novel platform for identifying therapeutic index in pancreatic cancer
Authors: Pantazopoulou Vasiliki , Engle Dannielle 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) remains highly aggressive with a mere 12% 5-year survival rate, which underscores the urgent need for improved therapeutic approaches. The current standard of care primarily includes surgery and chemotherapy. However, existing therapies often result in severe side effects and offer limited success. The limitations are not only due to the development of treatment resistance but also due to the killing of normal cells, and as such a low therapeutic index. Targeted therapies aimed at the primary drivers of PDA, such as the KRASG12D mutation or the activated ErbB pathway, have shown promise in providing novel treatment options. We have previously demonstrated that combining targeted therapies, specifically KRASG12D and EGFR inhibitors, results in reduced tumor growth in both human and murine PDA organoid models in vitro. However, less is known about how these targeted therapies affect normal cells. Here, we are using co-cultures of normal pancreas and PDA organoids to create a platform that allows us to identify combinations of targeted therapies that can achieve a higher therapeutic index. Our goal is to identify treatment combinations that allow for the use of lower individual drug dose, while exhibiting enhanced anti-tumor efficacy and minimizing toxicities to normal organoids. This approach holds significant promise for improving patient outcomes and addressing the challenges associated with current PDA treatments.
Citation Format: Vasiliki Pantazopoulou, Dannielle Engle. A novel platform for identifying therapeutic index in pancreatic 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 7230.