bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2642: BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation
Authors: Wan Weili , Zhao Shuwen , Zhuo Shi , Zhang Yong , Chen Lan , Li Gangrui , Renshaw Blair , Khalili Jahan Salar , Xiao Sa , Zhu Yi 
Published: April 2023

Abstract
EGFR and HER3, members of the human epidermal growth factor receptor (ErbB) family, are targeted in cancer therapy due to their over-expression and pathway dependence in common human epithelial carcinoma tumors. To develop a promising therapeutic anti-tumor agent, we generated BL-B01D1, an EGFR×HER3-targeting ADC, which can bind to EGFR and/or HER3 positive cells and is expected to be superior to anti-EGFR and anti-HER3 ADCs. It is comprised of a bispecific antibody against EGFR/HER3 (SI-B001), a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04), which is a derivative of the alkaloid camptothecin, driving cell cycle arrest at the S phase and subsequent apoptosis. BL-B01D1 achieves a high drug-to-antibody-ratio (DAR=8) with a highly stable linker.
The pharmacological potential of this ADC was evaluated in comparison to its parental single antigen-targeting ADCs in xenograft models composed of either the human colorectal cancer cell line SW620 or pancreatic cancer cell line BxPC3. The tumor inhibition activity of BL-B01D1 was compared with ADCs prepared from each parental anti-EGFR or anti-HER3 mAb conjugated with the same linker and payload. The bispecific ADC, BL-B01D1 exhibited stronger tumor inhibition capacity than the anti-EGFR ADC and the anti-HER3 ADC separately.
The preclinical studies suggest BL-B01D1, as an EGFR×HER3-targeting ADC, might be a promising novel agent with activity toward a broad range of human cancers. The clinical phase I has been progressing and the available data exhibit excellent efficacy but low levels of targeted toxicity in the non-small cell lung cancer (NSCLC) treatment setting. Overall, these data suggest BL-B01D1 has potential to serve as a novel, efficacious therapeutic agent for NSCLC with similar therapeutic impact as DS-8201 has in breast cancer treatment.
Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Gangrui Li, Blair Renshaw, Jahan Salar Khalili, Sa Xiao, Yi Zhu. BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2642.
Abstract 2693: Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models
Authors: Knoerzer Deborah , Reddy Anupama , Box Jessica A. , Groover Anna , Kreider Brent , Teresk Martin , Emery Caroline M. 
Published: April 2023

Abstract
The BRAFV600E mutation occurs in approximately 7% of colorectal cancer (CRC). BRAF plus EGFR inhibition (encorafenib with cetuximab) is an FDA approved treatment option for adult patients with metastatic CRC. Ultimately, patients develop resistance leading to disease progression. The addition of a MEK inhibitor, binimetinib, did not confer overall survival benefit. We hypothesized that addition of ERK inhibition would increase magnitude and duration of response to BRAF plus EGFR inhibition by overcoming MAPK-related acquired resistance mechanisms. ERK is the terminal master regulator kinase of the RAS-MAPK pathway, therefore, targeting this node is likely to be effective in the context of numerous mechanisms of acquired resistance that reactivate the MAPK pathway.
Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other therapeutics. Ulixertinib has demonstrated efficacy in patients with tumors harboring alterations within the RAS-MAPK pathway. The efficacy of ulixertinib, in combination with EGFR inhibition (cetuximab), plus BRAF inhibition (encorafenib), was assessed in CRC cell line derived xenograft models harboring BRAFV600E mutations. The triple combination resulted in superior tumor growth inhibition compared to dosing of any single agent or doublet. RNA sequencing was performed on treated tumor samples. Expression of the mutant BRAF allele was readily confirmed from RNA sequencing data. Gene expression analysis showed differential expression of MAPK pathway genes in triple combination treated groups versus single or doublet therapy.
A complete response to ulixertinib in combination with cetuximab and encorafenib for the treatment of a patient with metastatic CRC has been reported (Stuhlmiller, Timothy Joseph, et al. "Updated clinical outcomes from ULI-EAP-100, an intermediate expanded access program for ulixertinib (BVD-523)." (2022): e15101-e15101). The patient was treated under the Expanded Access Protocol (NCT04566393) for compassionate use access to ulixertinib. Preclinical data and clinical complete response warrants further investigation of ulixertinib plus BRAF and EGFR inhibition.
Citation Format: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery. Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2693.
Abstract 2889: Novel subset of granulocytic MDSCs as immunosuppressive regulators and therapeutic targets in gastric cancer
Authors: Iwasawa Takumi , Yamauchi Suguru , Fukunaga Tetsu , Orita Hajime , Kato Kazunori 
Published: April 2023

Abstract
The development and progression of cancers are frequently promoted by immunosuppressive cells, such as Treg and myeloid-derived suppressor cells (MDSCs) mediated by various immune checkpoint molecules. Recently, the immune checkpoint inhibitor anti-PD-1 neutralizing antibody has become available for the first-line treatment of gastric cancer (GC) in Japan. However, there is no correlation between PD-1 or PD-L1 expression in Treg or GC tissues and clinical responses to anti-PD-1 antibody. MDSCs are immature myeloid cells thought to suppress immune cell action, but the functional cell surface markers that define MDSCs correlated with cancer progression has not yet been clarified well. In this study, we identified a new subset of potential therapeutic and diagnostic targets for MDSCs in GC patients. Significantly higher levels of immune checkpoint molecules, PD-1 and PD-L1, were expressed on granulocytic MDSCs from advanced than early-stage of GC patients. Interestingly, we found that a subset of G-MDSCs expressed not only PD-1 but also PD-L1 and the pretreatment of G-MDSCs with anti-PD-1 antibody ameliorated T cell responses in vitro. We also found that G-MDSCs isolated from patients treated with anti-PD-1 antibody had a lower ability to suppress T cells. These data indicate that a novel subset of G-MDSCs expressing PD-1 found in advanced GC could be novel therapeutic targets.
Citation Format: Takumi Iwasawa, Suguru Yamauchi, Tetsu Fukunaga, Hajime Orita, Kazunori Kato. Novel subset of granulocytic MDSCs as immunosuppressive regulators and therapeutic targets in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2889.
Abstract 2977: A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy
Authors: Shang Chengzhang , An Gao , Guo Yuming , Zhang Ellen , Lin Qingcong , Yang Yi 
Published: April 2023

Abstract
Antibody-drug conjugates (ADC) are a therapeutic modality that combines the advantages of potent killing from small molecule cytotoxic payload and highly specific targeting from monoclonal antibodies. By targeting dual tumor-associated antigens (TAA), the bispecific ADC (BsADC) serves as a promising therapeutic strategy that can further increase tissue specificity and selectivity. HER2 and TROP2 are two TAAs that are commonly expressed and co-expressed by multiple tumor types, including gastric, colorectal, bladder, breast, and non-small-cell lung cancer (NSCLC). Of note, TROP2 expression has been detected in a wide range of HER2-low expressing tumors. These data led us to predict that targeting HER2 and TROP2 with a BsADC would provide therapeutic benefit, especially for patients with HER2-low cancers. Hence, we generated YH012, a first-in-class BsADC that contains a fully human bispecific anti-HER2/TROP2 antibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, YH012 demonstrated enhanced affinity, internalization, and tumor selectivity compared to its parental monoclonal and monovalent anti-HER2 or anti-TROP2 antibodies. In vivo, YH012 showed strong anti-tumor activity in multiple cell line-derived and patient-derived xenografts (CDX and PDX) of NSCLC, gastric, pancreatic, and breast cancer. Moreover, YH012 exhibited superior anti-tumor efficacy than benchmark antibodies in both HER2-positive and HER2-low xenograft models, indicating that YH012 has a potent and broad therapeutic effect. In summary, YH012 has the advantages of increased potency, tissue specificity, and reduced toxicity as a novel BsADC that can be further exploited to treat HER2 and TROP2 co-expressing tumors, especially HER2-low tumors.
Citation Format: Chengzhang Shang, Gao An, Yuming Guo, Ellen Zhang, Qingcong Lin, Yi Yang. A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2977.
Abstract 4298: Machine learning-based model for survival prediction after immunotherapy in patients with solid tumor
Authors: Fala Salma Y. , Osman Mohamed 
Published: April 2023

Abstract
Background: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in solid tumors treatment. However, not all patients respond favorably to these drugs, highlighting the need for reliable predictions to achieve more personalized care and better management. This study aimed to create and validated ML model to predict survival in solid tumors patients receiving ICIs.
Methods: We obtained clinical and genomic data from cBio Cancer Genomics Portal. Data were randomly divided into a training set (80%) and a validation set (20%). light gradient boosting algorithm was trained to predict patients’ survival at different time points.
Results: We identified 1660 patients with a median survival of 18 months. LGB yielded AUCs of 67.91% at 1 year, 79.89.6% at 2 years, and 79.75% at 3 years, respectively. The most important predictors that influenced the performance of the model in predicting 3-year-survival were: Age (22.89%), tumor mutational burden (18.24%), and tumor purity (13.23%). Moreover, multivariate analysis was performed and drug type was identified as an independent prognostic indicator (P&lt; .001). So, a Subgroup analysis was done and the OS rates were: 98.57%, 75.55%, 33.84% in patients who received CTLA-4, 98.57%, 75.55%, 33.84% with PD-1/PD-L1, and 97.99%, 9.94%, 4.62% with combo treatment, at 1-, 3-, and 5 years, respectively.
Conclusion: Our ML-based model that integrates both clinical and genomic data is an improved tool for survival prediction, enabling an accurate risk classification and leading to a more precise decision-making. Moreover, this study highlights the importance of age and tumor microenvironment as the main contributors in making survival prediction in patients receiving ICIs. Table. Performance in survival prediction among training and testing sets
Table 1. Survival Average AUC Average Accuracy Survival Duration Positive Predictive Value (Precision) Sensitivity (Recall) 1-year 67.91% 63.18% &lt;12 months 58% 54% &gt;=12 months 67% 70% 2-years 79.89% 78.70% &lt;24 months 86% 84% &gt;=24 months 62% 65% 3-years 79.75% 86.02% &lt;36 months 95% 89% &gt;=36 months 45% 65%
Citation Format: Salma Y. Fala, Mohamed Osman. Machine learning-based model for survival prediction after immunotherapy in patients with solid tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4298.
Abstract 432: Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader
Authors: Teh Jessica , Bessonett Shannon , Wu Wendy , Kuhlberg Christopher , Wynne Alissa , Landrette Sean , Andreoli Monica , Bortolon Elizabeth , Pizzano Jennifer , Gedrich Richard , Taylor Ian 
Published: April 2023

Abstract
ARV-471 is an orally bioavailable cereblon (CRBN)-based PROteolysis-TArgeting Chimera (PROTAC®) small molecule that demonstrates superior ER degradation and anti-tumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER-positive breast cancer patients. Innate and acquired drug resistance limits the response to and durability of many cancer therapies. To identify potential mechanisms of resistance to ARV-471, we generated ARV-471-resistant MCF7 cell lines which were then characterized using DNA, RNA and functional proteomic profiling. Acquired resistance to ARV-471 was associated with downregulation of ER protein expression and signaling and upregulation of HER family (EGFR, HER2, HER3) and MAPK/AKT signaling. NRAS copy number gain was also observed, which was accompanied by increased NRAS expression. Although EGFR, HER2 and HER3 expression and activation were upregulated, no corresponding genomic alterations were observed in resistant cells. Importantly, we show that NRAS and EGFR overexpression in MCF7 cells conferred resistance to ARV-471 in vitro. Furthermore, ARV-471-resistant cells with HER pathway upregulation were sensitive to EGFR and pan-HER inhibitors. Unlike recent reports indicating the association of E3 ligase alterations with PROTAC resistance, CRBN mutations/loss were not detected, nor were ESR1 mutations. CRBN knockout in ER+ breast cancer cells did not confer resistance to ARV-471, consistent with ARV-471 possessing ER antagonist activity independent of its degrader activity. Together, these data suggest that acquired resistance to ARV-471 may be associated with alterations within Receptor Tyrosine Kinase/MAPK signaling pathways rather than ER signaling or E3 ligase machinery.
Citation Format: Jessica Teh, Shannon Bessonett, Wendy Wu, Christopher Kuhlberg, Alissa Wynne, Sean Landrette, Monica Andreoli, Elizabeth Bortolon, Jennifer Pizzano, Richard Gedrich, Ian Taylor. Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 432.
Abstract 4500: Enedione derivates as a potential cancer treatment through the inhibition of COPZ1
Authors: Martins Allana C. , Barbosa Barbara Mitsuyasu , da Silveira Ingridhy O. Maia Freitas , Gomes Roberto 
Published: April 2023

Abstract
Cancer is a leading cause of death worldwide; it was responsible for approximately 10 million deaths in 2020. Besides surgery for tumor removal, the most common treatments available are chemotherapy and radiation, which are not selective, resulting in side effects such as pain, hair loss, nausea, and vomiting. They are also ineffective against stem-like and dormant tumor cells, which could lead to a relapse and/or metastasis. Consequently, the development of drugs with tumor-specific targets is needed. COPI is a coatomer responsible for the retrograde transport from Golgi complex (GC) to the endoplasmic reticulum (ER). In this context, we developed four compounds targeting disruption of GC through inhibition of COPI and previous results showed that compounds 1-4 significantly decrease cell viability of pancreatic cancer cell lines MIA PaCa-2 and AsPC-1, compared to hTERT-HPNE normal pancreatic cell line. In the present work, RT q-PCR confirmed that the two isoforms of the COPI ζ subunit COPZ1 and COPZ2 are expressed at similar levels in normal cells while COPZ2 is downregulated in tumor cell lines. Our in vitro results demonstrated that compounds 1-4 decreased cell viability of breast cancer (HCC1143) and melanoma (A-395) cell lines. The tested compounds are able to target COPZ1-dependent tumor cells, therefore they are great candidates for further studies aiming to develop a selective treatment for cancer.
Citation Format: Allana C. Martins, Barbara Mitsuyasu Barbosa, Ingridhy O. Maia Freitas da Silveira, Roberto Gomes. Enedione derivates as a potential cancer treatment through the inhibition of COPZ1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4500.
Abstract 4991: Phosphorylation of MERTK is required for nuclear localization in non-small cell lung cancer (NSCLC)
Authors: Tanim K.M. , DeRyckere Deborah , Graham Douglas K. 
Published: April 2023

Abstract
MERTK is a transmembrane receptor that belongs to the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. The role of MERTK in cancer progression and resistance to therapies are reported in many cancer types, including non-small cell lung cancer (NSCLC). In canonical signaling, MERTK is localized at the cell membrane and mediates intracellular signal transduction pathways. Non-canonical signaling of receptor tyrosine kinases (RTKs) has been reported, including signaling which occurs when RTKs translocate to the nucleus. Our group previously reported nuclear localization of MERTK in leukemia cells and we now extend these findings to non-small cell lung cancer. We found exogenous MERTK localized to the nucleus in cells transfected with a plasmid expressing wild-type MERTK. Additionally, endogenous nuclear MERTK was phosphorylated, suggesting that MERTK may have a functional role in the nucleus. MERTK kinase inhibitor MRX-2843 modulates its nuclear translocation. Introducing point mutations to MERTK autophosphorylation sites diminished nuclear translocation in comparison to cells transfected with wild-type MERTK. Our analysis of proteins that may interact with MERTK to regulate nuclear localization and function demonstrated co-immunoprecipitation of nuclear MERTK and STAT1. Current studies are underway to further explore nuclear MERTK functions and how these roles may be modulated upon interaction with STAT1.
Citation Format: K.M. Tanim, Deborah DeRyckere, Douglas K. Graham. Phosphorylation of MERTK is required for nuclear localization in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4991.
Abstract 5496: Glutaminase inhibition induces replication stress in ovarian cancer cells and inhibition of replication checkpoint causes synthetic lethality
Authors: Luna Pamela , Acharya Ganesh , Ochola Damieanus , Peddibhotla Swetha , Mani Chinnadurai , Reedy Mark B. , Palle Komaraiah 
Published: April 2023

Abstract
Ovarian cancer (OC) is a highly aggressive disease and the most lethal gynecologic malignancy in women. Although the majority of OC patients respond to chemotherapeutic drugs, more than 70% of the patients relapse and die as a result of chemoresistance. Therefore, novel therapeutics are warranted to prevent chemoresistance and treat the relapsed disease to improve prognosis. Many cancer cells depend on Glutamine as major carbon source and these cells have high Glutaminase (GLS) expression, an enzyme that converts Glutamine to Glutamate. Chemo-resistant OC cells have elevated levels of GLS, which confirms their increased dependency on glutamine metabolism. Based on these observations, we postulated that GLS inhibition may attenuate the aggressive growth of GLS high OC cells and may sensitize to the agents that can further potentiate these effects. Interestingly, GLS inhibition using a clinical-stage drug CB839 caused replication stress and activated DNA damage checkpoint protein 1 (CHK1) mediated cell cycle arrest. These novel findings suggested a role for CHK1 in protecting GLS inhibition-induced DNA damage by facilitating the timely repair of DNA breaks. Based on these observations, we hypothesized that GLS inhibition in combination with CHK1 inhibition may cause synergistic lethality in chemo-resistant and GLShigh OC cells. We evaluated the combination of GLS inhibitor CB839 and CHK1 inhibitor Prexasertib. Our results demonstrate that GLS inhibition-induced CHK1 phosphorylation is significantly attenuated by Prexasertib treatment. Similarly, combined treatment of CB839 and Prexasertib showed significantly elevated levels of DNA damage as measured by COMET assays, replication stress-mediated DNA damage responses, and synergistic OC cell lethality compared to individual drug treatments. Furthermore, CB839 and Prexasertib combination was more synergistic in cells that expressed high GLS compared to low GLS-expressing OC cells indicating the specificity of the combination of these drugs. Together, our studies identified a novel connection between metabolic and DNA damage checkpoint pathways in OC and propose a novel synergistic lethality-based combination therapy to treat chemo-resistant and aggressive OC.
Citation Format: Pamela Luna, Ganesh Acharya, Damieanus Ochola, Swetha Peddibhotla, Chinnadurai Mani, Mark B. Reedy, Komaraiah Palle. Glutaminase inhibition induces replication stress in ovarian cancer cells and inhibition of replication checkpoint causes synthetic lethality. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5496.