bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB159: Deregulation of CTC-associated RPL/RPS protein expression inhibits melanoma brain metastasis
Authors: Bowley Tetiana Yuriyivna , Merkley Seth , Lagutina Irina , Marchetti Dario 
Published: April 2023

Abstract
Melanoma brain metastasis (MBM) is associated with poor prognosis and low survival rates. MBM is diagnosed clinically in up to 60% of melanoma patients and in up to 80% of patients at autopsy. Circulating Tumor Cells (CTCs) are “seeds” of fatal metastasis and the smallest functional units of cancer. Our previous studies have employed a multilevel approach to identify a common CTC signature for ribosomal protein large/small subunits (RPL/RPS) which is linked to MBM development and progression1. Here, we hypothesized that targeting ribosomal biogenesis prevents MBM onset in CTC-derived xenografts. First, we treated CTC-injected MBM mice with RPL15 inhibitor omacetaxine to monitor metastatic progression. Second, parallel cohorts of mice were treated with CDK4/CDK6 inhibitor palbociclib with or without omacetaxine to assess effects of cell proliferation. Total flux of MBM signal was measured by IVIS and found to be higher in untreated mice. Mouse necropsies revealed decreased levels of MBM, along with metastatic dissemination to other organs. Third, collected mouse blood was analyzed by the FDA-approved ParsortixTM platform to enumerate CTC/CTC clusters (IHC), and evaluate their gene expression (RNA-seq). Lastly, metabolic profiling of inhibitor-treated versus untreated MBM CTC-derived clones was performed in vitro. Collectively, our findings indicate that the deregulation of ribosomal proteins inhibits MBM progression. This implicates a specific vulnerability of aggressive CTC subsets with high RPL/RPS content in MBM patients. RPL/RPS genetic screening could be a prognostic indicator of MBM severity and clinical outcomes. Our work promotes the concept that therapies targeting RPL/RPS proteins merit exploration as potential suppressors of metastatic progression in general, MBM in particular. 1. Bowley T, Lagutina I, Francis C, Sivakumar S, Selwyn R, Taylor E, et al. The RPL/RPS gene signature of melanoma updates CTCs associates with brain metastasis. Cancer Research Communications 2022;2: 1445-57.
Citation Format: Tetiana Yuriyivna Bowley, Seth Merkley, Irina Lagutina, Dario Marchetti. Deregulation of CTC-associated RPL/RPS protein expression inhibits melanoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB159.
Abstract LB177: Tumor sideomics: spatial characteristics and functional deregulation in colorectal cancer
Authors: Burgman Brandon , Pan Xingxin , Yi S. Stephen 
Published: April 2023

Abstract
Clinical evidence suggests that right-sided colorectal cancer (CRC) tends to have a worse prognosis compared to left-sided CRC. The distinct functional mechanisms underlying this “sidedness” remain cryptic and poorly understood. Thus, molecular classification of CRC is of paramount in targeting specific subtypes and personalizing treatment for patients. To identify targetable molecular features to improve treatment regimens, we performed multi-faceted network analyses of hundreds of CRC patients. In our network model, epigenetic features, differential expression of transcript abundance, and mutational frequency were used to identify widespread gene dysregulation and perturbed pathways to reveal disrupted networks distinct to right or left sided colorectal cancer. We discovered histone related genes and distinct epigenetic signals are at play in right-sided CRC. Additionally, our studies reveal “at risk” patient characteristics suggestive of survival differences, to improve diagnostic predictors based on CRC sidedness. Overall, our integrative approach serves to link molecular profiles distinct between left and right sided colorectal cancer, while improving upon previous models of CRC and paving the way towards identifying more effective treatment alternatives from a previously overlooked, readily characterized subtype of colorectal cancer.
Citation Format: Brandon Burgman, Xingxin Pan, S. Stephen Yi. Tumor sideomics: spatial characteristics and functional deregulation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB177.
Abstract LB182: Targeting arginine methylation for improved therapy in triple negative breast cancer
Authors: Li Yang , McGrail Daniel J. , Awasthi Sharad , Yi S. Stephen , Bedford Mark T. , Sahni Nidhi 
Published: April 2023

Abstract
Since the discovery of DNA repair deficiency as risk factors for breast cancer, our knowledge of their function in maintaining human genomic integrity and a normal biological function has greatly advanced, ultimately culminating in development of PARP inhibitors that can specifically target patients who harbor these mutations. However, to date PARP inhibitors have demonstrated only modest clinical success as monotherapy in triple-negative breast cancer. In addition, conventional therapies are often coupled with severe toxicity. Therefore, there is a dire need to develop more effective combination therapies. Although there are many existing tools to predict possible actionable targets, it remains challenging to effectively and systematically identify drug combinations for better breast cancer therapeutics. This is because most tumors carry multiple genetic alterations that cannot be suppressed with mono-therapies; and diverse confounding factors such as intra-tumor and inter-tumor heterogeneity exist across patient populations. Our preliminary proteomics study has revealed a new protein mark called arginine methylation as a novel target for breast cancer. We found that inhibition of arginine methylation can sensitize cancer cells for PARP inhibition treatment. We further assessed and validated this actionable and synergistic drug combination in patient-derived xenograft models. Together, our novel target combinations discovered here may serve as important biomarkers to help develop more effective combination therapy. Furthermore, our results help uncover patient-specific signaling mechanisms, a critical step towards precision medicine in breast cancer therapy, which is a benefit and potential long-term outcome.
Citation Format: Yang Li, Daniel J. McGrail, Sharad Awasthi, S. Stephen Yi, Mark T. Bedford, Nidhi Sahni. Targeting arginine methylation for improved therapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB182.
Abstract LB194: A small molecular-weight anti-lag-3 peptide inhibits colon tumor growth
Authors: Alahmari Mohammed , Mamani Umar-Farouk , Guo Yuhan , Lin Chien-Yu , Ibrahim Mohammed Nurudeen , Li Yongren , Cheng Kun 
Published: April 2023

Abstract
Lymphocyte activation gene-3 (LAG-3) has emerged as a promising target for cancer immunotherapy. It is expressed on activated CD4+ and CD8+ T cells, and on the surface of B cells, natural killer cells, and dendritic cells (DC). It has also been found to be highly expressed on activated T cells upon treatment with monoclonal antibodies targeting the PD-1/PD-L1 pathway, which may explain the resistance mechanism of monotherapy. Several anti-LAG-3 antibodies are being examined in clinical trials to treat different types of cancers. Despite their specificity and affinity, antibody-based checkpoint inhibitors are hampered by poor tumor permeability and high production costs. In this study, we aimed to discover a small peptide-based anti-LAG-3 inhibitor using a novel biopanning technique developed in our laboratory. We discovered several anti-LAG-3 inhibitor peptides, and the CMA16 peptide showed the highest stability and blocking efficacy. The peptides were synthesized by the solid-phase peptide synthesis using PurePepTM Chorus synthesizer (Gyros Protein Technologies, Tucson, AZ). The molecular weights and purity were confirmed by mass spectrometry and HPLC, respectively. To evaluate the function of the CMA16 peptide, a series of in vitro functional assays including binding ELISA, serum stability and cell viability assays were performed. In vivo anti-tumor activity of the peptides was examined in five-week-old C57BL/6 mice bearing MC38 cells. CMA16 significantly inhibited the growth of MC38 tumors. Quantification of CD8+ tumor-infiltrating cells revealed a significant increase in this type of immune cells in the group of mice treated with CMA16. These findings support the further development of the CMA16 peptide as potential anti-LAG-3 inhibitor for cancer immunotherapy.
Citation Format: Mohammed Alahmari, Umar-Farouk Mamani, Yuhan Guo, Chien-Yu Lin, Mohammed Nurudeen Ibrahim, Yongren Li, Kun Cheng. A small molecular-weight anti-lag-3 peptide inhibits colon tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB194.
Abstract LB213: Identification of DM004, a first-in-class anti-5T4/MET bispecific antibody-drug conjugate
Authors: Han Zhenyan , Shang Chengzhang , Dai Wenjuan , An Gao , Zhang Ellen , Lin Qingcong , Yang Yi 
Published: April 2023

Abstract
Aberrant MET signaling is frequently found in various types of solid tumors, and is correlated with oncogenic transformation, treatment resistance and poor prognosis. While MET remains an attractive therapeutic target, it is widely expressed on the surface of epithelial and endothelial cells, including normal tissues and tumors. To date, MET-targeting agents are associated with adverse clinical effects, including hypoalbuminemia, peripheral edema and pneumonitis, indicating that alternate treatments and/or modalities are needed. Intriguingly, MET antigen is commonly co-expressed with the oncofetal antigen 5T4 in various cancer types, including head and neck, lung and pancreatic cancer. While 5T4 is highly expressed on primary and metastatic cancers and is associated with adverse clinical outcomes in solid tumors, expression on normal adult tissues is very limited. Although several therapeutic agents targeting 5T4 antigen are currently being evaluated in human clinical studies, none have yet entered the market. To address these challenges, we hypothesized that targeting both MET and 5T4 with a bispecific antibody-drug conjugate (BsADC) could provide a more targeted therapeutic strategy to effectively eliminate tumor cells and reduce systemic toxicity. Here, we report that we have successfully generated two bispecific antibody candidates targeting both 5T4 and MET. The candidates were conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker to generate DM004 BsADCs, i.e., Top1-MMAE and Top2-MMAE. In vitro, DM004 BsAbs demonstrated enhanced internalization in the NCI-H226 cell line compared to its parental monoclonal and monovalent anti-5T4 and anti-MET antibodies. In vivo, DM004 BsADCs exhibited robust anti-tumor activity in cell line-derived and patient-derived xenografts of gastric cancer and lung cancer, respectively. In particular, DM004 Top2-MMAE outperformed benchmark ADCs in lung BP0508 PDX models. In summary, we have identified a novel BsADC which may be a promising future treatment for cancers co-expressing 5T4 and MET.
Citation Format: Zhenyan Han, Chengzhang Shang, Wenjuan Dai, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. Identification of DM004, a first-in-class anti-5T4/MET bispecific antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB213.
Abstract LB220: S095029: a novel clinical-stage Fc-silenced NKG2A-blocking antibody with best-in-class potential
Authors: Melander Maria , Laugel Bruno 
Published: April 2023

Abstract
NKG2A and its ligand HLA-E are increasingly recognized as an important immune checkpoint restraining multiple lymphocyte populations involved in cancer immunity. Initially described as an NK cell inhibitory receptor, NKG2A’s role in regulating T-cell functions has recently come to the fore and is increasingly viewed as a key component of its immune suppressive functions. In addition, clinical studies have also provided proof-of-concept evidence for the superiority of dual NKG2A/PD-L1 blockade over anti-PD-L1 monotherapy. As of now clinical safety and efficacy results are only available for a single NKG2A-blocking antibody. This is in contrast with other immune checkpoint receptors (e.g., PD-1) where multiple blocking agents with different pharmacological properties have been assessed in the clinic, thereby providing a broad assessment of the target therapeutic potential and benefit to patients.
Here, we report the generation and preclinical characterization of a novel monoclonal antibody (mAb) disrupting the NKG2A/HLA-E interaction. The Fc-attenuated IgG1 mAb S095029 binds NKG2A with a nM-range affinity and reverses the inhibitory effects of the NKG2A/HLA-E interaction in several experimental models, both in vitro and in vivo. As a single agent S095029 enhanced the killing activity and cytokine secretion of NK and γδ T-cells in co-culture with cancer cell lines of multiple tissue origins. We also show that S095029 increased the antibody-dependent cellular cytotoxicity (ADCC) mediated by Fc-competent mAbs in different antigen systems with high HLA-E expression. Of note, these immune-activating properties of S095029 compared favorably in benchmarking experiments with other clinical-stage anti-NKG2A mAbs. Finally, S095029 combination with PD-1 blocking agents, with or without an additional ADCC mAb component, conferred superior anti-tumor activity compared to treatments without NKG2A blockade.
Overall, our in vitro and in vivo data support the clinical development of S095029 in tumor settings with adequate HLA-E expression and suggest potential differentiating characteristics compared to other anti-NKG2A mAbs. S095029 is currently being evaluated in phase 1 dose escalation studies as a single agent or in combination with anti-PD-1 therapy (NCT05162755).
Citation Format: Maria Melander, Bruno Laugel. S095029: a novel clinical-stage Fc-silenced NKG2A-blocking antibody with best-in-class potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB220.
Abstract LB223: Intratumoral administration of modified vaccinia Ankara expressing a tumor associated antigen and the costimulatory molecules IL-12 and 4-1BBL induces potent systemic long-term immune responses against murine tumors
Authors: Langbein Cigdem Atay , Giessel Raphael , Housni Mahmad Ismail , Lämmermann Kerstin , Bathke Barbara , Riedl André , Hausmann Jürgen , Kalla Markus , Chaplin Paul , Hochrein Hubertus , Medina-Echeverz José , Hinterberger Maria 
Published: April 2023

Abstract
In the last decade, immunotherapy has revolutionized cancer treatment. However, the lack of potent therapy-induced immune responses against solid tumors due to the immune-suppressive tumor microenvironment (TME) is still a major drawback. One approach to reprogram TME is virotherapy, which can target tumors via destruction of infected tumor cells as well as activating immune cell populations in the TME. A versatile and safe tool for virotherapy is modified vaccinia virus Ankara (MVA), which has already been approved by the FDA as a non-replicating vaccine against smallpox and monkeypox and is also in clinical trials against other infectious diseases and cancer. In the current study, we deciphered the anti-tumorigenic effect of a novel MVA vector encoding a tumor associated antigen (TAA) and the costimulatory molecules IL-12 and 4-1BBL, called MVA-TAA-4-1BBL-IL12. We could show that repetitive intratumoral (IT) injection of MVA-TAA-4-1BBL-IL12 resulted in strong tumor growth control, shrinkage and/or complete elimination of tumors and induction of tumor-specific CD8 T cell response. Furthermore, MVA-TAA-4-1BBL-IL12 treatment promoted a systemic anti-tumor immune response not only against the treated tumor but also untreated, distant tumors. Importantly, local virotherapy also resulted in the generation of tumor-specific memory response, which protected mice against local recurrence after rechallenge. As a conclusion, our findings show that MVA-TAA-4-1BBL-IL12 IT treatment induces an effective anti-tumorigenic immune response in different solid tumor models, which gives rise to long-term protection against cancer recurrence.
Citation Format: Cigdem Atay Langbein, Raphael Giessel, Mahmad Ismail Housni, Kerstin Lämmermann, Barbara Bathke, André Riedl, Jürgen Hausmann, Markus Kalla, Paul Chaplin, Hubertus Hochrein, José Medina-Echeverz, Maria Hinterberger. Intratumoral administration of modified vaccinia Ankara expressing a tumor associated antigen and the costimulatory molecules IL-12 and 4-1BBL induces potent systemic long-term immune responses against murine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB223.
Abstract LB229: Tinengotinib, a novel fibroblast growth factor receptor (FGFR) inhibitor, is potent against resistance mutations in FGFR1/2/3
Authors: Qiang Xiaoyan , Yu Qi , Fan Jean , Wu Frank , Sun Caixia , Peng Peng 
Published: April 2023

Abstract
Dysregulated FGFR alterations (FGFRalt), including gene amplification, hot spot mutations, and gene fusion or rearrangement, have been reported in 7% of solid tumors, functioning as oncogenic drivers independent of tumor types. First generation of FGFR inhibitors, such as erdafitinib and pemigatinib, have already demonstrated promising efficacy on multiple cancers with prespecified FGFRalt. However, certain kinase mutations identified in the clinics, including gatekeeper mutations and some molecular brake mutations, may cause resistance to first generation FGFR inhibitors and remain challenging for current FGFR inhibitor development. Tinengotinib potently inhibited multiple FGFR1/2/3 resistant mutations both in vitro and in vivo. In the biochemical and cellular assays, tinengotinib exhibited potent inhibitory activities against FGFR2 gatekeeper mutation V564F, and molecular brake mutation N549K, which were known to cause resistance to the first generation FGFR inhibitors in cholangiocarcinoma patients with FGFR2 fusion or rearrangement. Binding kinetics was measured using surface plasmon resonance (SPR) on FGFR2, and tinengotinib demonstrated very tight binding to the target. To understand the underlying mechanism, we conducted co-crystallization of tinengotinib and wild type kinase domain of FGFR2. The resulting high-resolution X-ray diffraction structure revealed a very unique binding mode of tinengotinib in the ATP-binding site of FGFR2 comparing to other FGFR inhibitors. In addition, homology model demonstrated similar binding mode of tinengotinib to FGFR 1 and 3. This is consistent with the finding of tinengotinib showing excellent potency to FGFR 1/3 gatekeeper mutations. Tinengotinib is well tolerated in the clinical trials. Retrospective analysis showed early promising efficacy in treating patients with various solid tumors bearing FGFRalt. It provides an opportunity to investigate tinengotinib as a tumor agnostic therapy in patients with prespecified FGFR 1/2/3 alterations (pan-FGFRalt).
Citation Format: Xiaoyan Qiang, Qi Yu, Jean Fan, Frank Wu, Caixia Sun, Peng Peng. Tinengotinib, a novel fibroblast growth factor receptor (FGFR) inhibitor, is potent against resistance mutations in FGFR1/2/3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB229.
Abstract LB230: Critical role for DAXX in triple negative breast cancer
Authors: Osipo Clodia , Wyatt Debra 
Published: April 2023

Abstract
Breast cancer is the most common diagnosed cancer and second cause of mortality in women. In particular, triple negative breast cancer, a subtype with few targeted therapies, frequently presents with metastatic disease and drug resistance. Nearly half of women with triple negative breast cancer will have metastatic disease. New targets and therapies are needed to prevent drug resistance and metastatic disease. We identified a novel protein, DAXX, in a biomarker window trial as a potent inhibitor of breast cancer stem cells (BCSC). BCSC are responsible for drug resistance, metastases, and tumor relapse. In this current study, the role of DAXX in sensitivity to cytotoxic chemotherapy was investigated in the setting of triple negative breast cancer. DAXX depletion using RNAi increased the proliferative capacity of three triple negative breast cancer cell lines (MDA-MB-231, BT549, and MDA-MB-468). This corresponded with increased PARylation of cellular proteins and PARP-1. DAXX was required to limit cell cycle progression through S-phase. Knockdown of DAXX modulated sensitivity to carboplatin, doxorubicin, and paclitaxel in vitro. Survival of female nude mice-bearing MDA-MB-231 DAXX-depleted tumors was 100% upon paclitaxel treatment compared to vehicle control-treated mice where the survival rate was 0% after 30 days. This survival advantage was not due to differences in tumor burden or tumor growth rates. These results suggest that DAXX is a critical growth regulator of triple negative breast cancer and possible predictor of response to paclitaxel.
Citation Format: Clodia Osipo, Debra Wyatt. Critical role for DAXX in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB230.