bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C134: The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC)
Authors: Ananthapadmanabhan Varsha , Chutake Yogesh , Filiatrault Jessica , Schalm Stefanie , McDonald Alice , DeCaprio James A 
Published: December 2023

Abstract
Background and aims: MCC is a highly aggressive neuroendocrine carcinoma of the skin with a high fatality rate. Clonal integration of Merkel cell polyomavirus (MCPyV) occurs in about 80% of all MCCs. These virus positive MCC (MCCP) tumors have a low tumor mutational burden and usually express wild type (WT) p53 (TP53). In contrast, virus negative MCC (MCCN) tumors present a predominantly UV mutational signature, a high mutational burden and often have alterations in p53. MCCP tumors express MCyV small T antigen (ST) and a truncated form of large T antigen (LT). The MCyV ST in MCCP tumors, recruits MYCL and EP400 to form the SLaP complex that specifically trans-activates several genes. A direct target of the SLaP complex is MDM2, an E3 ubiquitin ligase of p53 that inhibits p53-mediated tumor suppression. The use of MDM2 inhibitors can stabilize p53 in p53 WT tumors. However, currently, no MDM2 inhibitors are approved for treatment of MCC. Furthermore, MDM2 degraders have not been studied in the context of MCC. Here, we aim to analyze the efficacy of KTX-049, a potent MDM2 degrader, in MCC and compare its efficacy to the previously reported and highly potent MDM2 inhibitor, DS-3032.
Experimental procedures: Established MCCP cell lines with functional p53, non-functional p53 and two p53 WT MCCP patient derived cell lines (PDCLs) were treated with KTX-049 or DS-3032 and the effect on cell viability was analyzed using a luminescence-based assay. Apoptosis induction was studied using the caspase 3-7 Glo assay. The p53 response in MCC cells post KTX-049 or DS-3032 treatment was assessed by western blot (WB) analysis of p53 and its downstream effectors.
Results: KTX-049 and DS-3032 reduced cell viability of p53 WT MCCP cell lines but not cell lines with non-functional p53. Notably, all sensitive cell lines had ≥100-fold lower absolute IC50 values for KTX-049 as compared to DS-3032. Additionally, KTX-049 effectively reduced cell viability of the sensitive cell lines even after brief exposures. KTX-049 also triggered a rapid and sustained p53 response and apoptosis induction in p53 WT MCC cells.
Conclusions: KTX-049 is a promising MDM2 degrader effective against p53 WT MCC cell lines. These results provide evidence for in vivo exploration of KTX-049 in models of MCC.
Citation Format: Varsha Ananthapadmanabhan, Yogesh Chutake, Jessica Filiatrault, Stefanie Schalm, Alice McDonald, James A DeCaprio. The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C134.
Abstract C159: ALK signaling primes the DNA damage response allowing exploitation of ATR inhibition in ALK-driven Neuroblastoma
Authors: Borenäs Marcus , Umapathy Ganesh , Lind Dan E. , Lai Wei-Yun , Guan Jikui , Johansson Joel , Jennische Eva , Schmidt Alexander , Gabre Jonatan , Bemark Mats , Hall Michael N. , Eynden Jimmy Van den , Hallberg Bengt , Palmer Ruth H. 
Published: December 2023

Abstract
High-risk neuroblastoma currently presents significant clinical challenges. Oncogenes such as MYCN and ALK, which are often involved in high-risk neuroblastoma, result in increased replication stress in cancer cells, offering therapeutically exploitable options. We previously identified an ATR/ALK inhibitor combination as an effective therapeutic approach in two independent genetically modified mouse neuroblastoma models. Here we show that ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. Remarkably, the importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to ALKi/ATRi combination treatment that resulted in robust and sustained responses. Here, we describe the mechanism underlying the remarkable tumor response to combined ATR/ALK inhibition. Our results identify a unique ability of ATR inhibition to trigger tumor regression in neuroblastoma and underscore the importance of further exploring combined ALK/ATR inhibition in neuroblastoma, particularly in high-risk patient groups with oncogene-induced replication stress.
Citation Format: Marcus Borenäs, Ganesh Umapathy, Dan E. Lind, Wei-Yun Lai, Jikui Guan, Joel Johansson, Eva Jennische, Alexander Schmidt, Jonatan Gabre, Mats Bemark, Michael N. Hall, Jimmy Van den Eynden, Bengt Hallberg, Ruth H. Palmer. ALK signaling primes the DNA damage response allowing exploitation of ATR inhibition in ALK-driven Neuroblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C159.
Abstract IA008: Mechanisms and consequences of pancreatic cancer stromal evolution
Authors: Sherman Mara 
Published: December 2023

Abstract
The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. In solid tumors featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant stromal cell types may facilitate the development of new and effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have developed a novel mouse model to track PSC differentiation and function during pancreatic tumor progression in vivo. This model revealed that PSC-derived CAFs in fact give rise to a numerically minor but functionally significant subset of PDAC CAFs, and may represent a viable therapeutic target. We adapted our mouse model to enable targeted ablation of PSCs and derivative CAFs within their host tissue for the first time. Functional studies in this model reveal non-redundant functions for PSC-derived CAFs in shaping the PDAC microenvironment, and highlight the significance of mesenchymal lineage heterogeneity for pancreatic tumorigenesis. Further, we find that tumor genotype with respect to p53 status dictates stromal evolutionary routes with respect to cell of origin, a finding that may extend to additional cancer cell-intrinsic genomic alterations. Together, these findings shed light on mechanisms that shape the tumor microenvironment during pancreatic cancer progression, and may hold relevance in additional solid tumor types.
Citation Format: Mara Sherman. Mechanisms and consequences of pancreatic cancer stromal evolution [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA008.
Abstract LB_B06: Single cell transcriptomics guided identification of antigen combinations for the design of logic-gated CAR therapies
Authors: Madan Sanna , Chang Tiangen , Wang Binbin , Schäffer Alejandro A. , Ruppin Eytan 
Published: December 2023

Abstract
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant efficacy in treating hematological cancers but faces challenges in treating solid tumors due to antigen heterogeneity and off-tumor, on-target expression in normal tissues. To combat these challenges, we developed a novel genetic algorithm approach to analyze patient tumor single-cell transcriptomics data. This algorithm identifies combinations of cell surface antigens specific to cancer cells by incorporating "AND," "OR," and "NOT" logic. Our method is generalizable to combinations of any size and demonstrates rapid convergence across different parameter choices. When applied to breast cancer datasets, our algorithm identified optimal combinations of triplet antigens that outperformed clinically tested single target antigens in discriminating tumor cells from non-tumor cells across patient samples. In sum, our approach may guide the design of logic-gated CAR therapies aimed at multiple target antigens, thereby increasing the safety and selectivity of these therapies.
Citation Format: Sanna Madan, Tiangen Chang, Binbin Wang, Alejandro A. Schäffer, Eytan Ruppin. Single cell transcriptomics guided identification of antigen combinations for the design of logic-gated CAR therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B06.
Abstract LB_B09: Loss of folate enzyme ALDH1L1 promotes cancer cell proliferation and xenograft tumor growth
Authors: Fogle Halle M , You Mikyoung , Sharma Jaspreet , McCormac Jonathan , Krupenko Natalia I , Krupenko Sergey A 
Published: December 2023

Abstract
Background: ALDH1L1 (aldehyde dehydrogenase 1 family member L1, or cytosolic 10-formyltetrahydrofolate dehydrogenase), an enzyme in folate metabolism, is abundantly expressed in several tissues. This enzyme converts 10-formyltetrahydrofolate to tetrahydrofolate (THF) and CO2 while reducing NADP+ to NADPH. ALDH1L1 is ubiquitously downregulated human cancers through DNA promoter methylation, while one cancer cell line, RT4 (derived from papillary bladder cancer), maintains high expression of ALDH1L1. Aims: We tested the hypothesis that loss of ALDH1L1 expression could provide a proliferative and survival advantage for cancer cells and tumor growth.
Methods: The ALDH1L1 gene in RT4 cells was knocked down using the shRNA technique. Proliferation was evaluated using MTT assays and xCELLigence real-time cellular analysis (RTCA). Cell migration was assessed by wound healing assays. NADP+/NADPH levels and reduced folate pools were measured by ELISA and the ternary complex assays, respectively. RT4 tumors were generated in nude mice from RT4 lines by subcutaneous injections into both flanks of athymic nude mice. Tumor growth was monitored every week for 12-weeks, after which the tumors were harvested. ALDH1L1 levels in tumors were measured by Western Blot assays, while tumor proliferation was assessed by the Ki-67/H&E staining of the tumor tissue sections.
Results: We found that doubling time did not differ between the wild-type (RT4) and shControl (shC) cell lines. Doubling time for the sh506 and sh572 clones was shorter than the controls by 68% and 79%, respectively. Proliferation and migration were significantly increased in sh506 and sh572 cells compared to the control lines. NADP+/NADPH levels were significantly increased for only the sh572 clone. Interestingly, tumor volume and weight were increased in both sh506 and sh572 derived tumors compared to shC tumors. The sh506 and sh572 tumors also showed a slightly increased Ki-67 proliferation index. The ALDH1L1 protein expression was completely lost in sh572 tumors but only partially decreased in sh506 tumors.
Conclusions: Our study indicates that RT4 clones lacking ALDH1L1 have increased cell proliferation and tumor growth compared to wild-type RT4 cells, supporting the role of ALDH1L1 as a metabolic regulator of proliferation.
Citation Format: Halle M Fogle, Mikyoung You, Jaspreet Sharma, Jonathan McCormac, Natalia I Krupenko, Sergey A Krupenko. Loss of folate enzyme ALDH1L1 promotes cancer cell proliferation and xenograft tumor growth [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B09.
Abstract LB_C15: PI3Kδ/γ inhibitor as a novel immune-regulatory radiosensitizer
Authors: Yoon Yi Na , Kim Jae-Sung 
Published: December 2023

Abstract
Radiotherapy is known to augment anti-tumor immunity, yet its concurrent induction of immunosuppressive responses presents a significant obstacle to efficacious treatment. This study showed that a new PI3Kδ/γ inhibitor along with irradiation promotes systemic anti-tumor immunity and abscopal response by reducing activity of immune suppressive cells. The combination systemically decreased proliferation of regulatory T cells (Tregs) and enhanced the number of tumor specific CD8a+ T cells in tumor microenvironment, thereby leading to tumor regression. Interestingly, this effect lasts for 14 days after radiation and even causes distant tumors to regress, known as the abscopal effect. Moreover, molecular analysis shows that the combination treatment creates immune-stimulatory tumor microenvironment in tumors, suggesting that the combined therapy converts immune cold tumor into hot. These findings highlight the promise of using PI3Kδ/γ inhibitors to enhance anti-tumor immunity in solid tumors treated with radiotherapy, providing the evidence for the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.
Citation Format: Yi Na Yoon, Jae-Sung Kim. PI3Kδ/γ inhibitor as a novel immune-regulatory radiosensitizer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C15.
Abstract LB_C17: Spatial tumor immune microenvironment analysis of KRAS-mutated Non-Small Cell Lung Cancer and immunotherapy outcome
Authors: Zhao Dan , Li Haiqing , Mambetsariev Isa , Mirzapoiazova Tamara , Chen Chen , Fricke Jeremy , Wheeler Deric , Arvanitis Leonidas , Pillai Raju , Afkhami Michelle , Chen Bihong T. , Sattler Martin , Erhunmwunsee Loretta , Massarelli Erminia , Kulkarni Prakash , Amini Arya , Armstrong Brian , Salgi Ravi 
Published: December 2023

Abstract
Targeting KRAS in lung cancer is promising and the immune modulatory effects of KRAS inhibition is interesting. Understanding the local tumor immune architectures are important to overcome the treatment resistance of immunotherapy and targeted therapy. We conducted spatial immune tumor microenvironment (iTME) profiling using FFPE samples of 25 KRAS mutated non-small cell lung cancer patients treated with immune checkpoint inhibitors (ICIs), which included 12 responders and 13 non-responders. We used an eleven-markers panel (CD3, CD4, CD8, Foxp3, CD68, Arginase-1, CD33, HLA-DR, Pan-Keratin (PanCK), PD-1 and PD-L1). We studied the tumor and immune cell compositions and spatial features at single cell level with cellular neighborhood and fractal analysis. We found spatial features and the different subgroups of CD68 positive cells and Foxp3+ cells associated with responses and resistance to ICIs. We found that CD68+ cells, CD33+ cells and Foxp3+ cells are associated with resistance to ICIs of KRAS mutated lung cancer. Interestingly, we found that cells had non-nuclear expression of Foxp3 were associated with ICIs resistance. We identified a population of CD68 weakly positive cells in the tumor tissues were associated with responses to ICIs. We identified two different groups of non-responders: one with high diversity of cells and one with low diversity, while all the responders had high diversity. We identified nine cellular neighborhoods (C0-C8) with C0 in majority of non-responders, which was enriched with PanCK+, CD33+, and Foxp3+ T regulartory cells. Conversely, most responders were enriched with C3 and C6-C7, which contained CD8+ T cells and CD68 weakly positive cells. Our study had revealed the spatial immune features of KRAS mutated lung cancer and their association with immunotherapy outcome which could be helpful for KRAS targeting and immunotherapy.
Citation Format: Dan Zhao, Haiqing Li, Isa Mambetsariev, Tamara Mirzapoiazova, Chen Chen, Jeremy Fricke, Deric Wheeler, Leonidas Arvanitis, Raju Pillai, Michelle Afkhami, Bihong T. Chen, Martin Sattler, Loretta Erhunmwunsee, Erminia Massarelli, Prakash Kulkarni, Arya Amini, Brian Armstrong, Ravi Salgi. Spatial tumor immune microenvironment analysis of KRAS-mutated Non-Small Cell Lung Cancer and immunotherapy outcome [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C17.
Abstract PR017: Discovery and clinical evaluation of a potent and selective A2A/2B dual receptor antagonist
Authors: DeMong Duane , Ranganath Sheila , Cumming Jared , Larsen Matthew , Zhang Yonglian , Plummer Christopher , Ali Amjad , Palmieri Anthony , Barry Evan , Daublain Pierre , Gupta Pranav , Chatterjee Manash , Giranda Vincent , Presland Jeremy , Schneider Sebastian , Ciaccio Paul , Tatosian Daniel , Sather Aaron , Turnbull Ben , Silverman Steven , Chobanian Harry , Krishnamurthy Harini , Wnek Richard , Afshar Roshi , Crowley Stephen , Miller Alita , Ayers Mark , Whitehead Alan , Hinton Marlene , Chiang Derek , Orr Robert , Chrencik Jill 
Published: December 2023

Abstract
Elevated adenosine levels present in the tumor microenvironment (TME) produce a net immunosuppressive effect through inhibition of T cell function by two mechanisms of action: Direct T cell effects via A2A receptor agonism and indirect T cell effects via agonism of A2A and A2B receptors on myeloid cells. Our team sought to identify a small molecule dual antagonist of the A2A and A2B receptors with the ability to decrease the immunosuppressive effects of adenosine in the TME and restore anti-tumor immune response. Drawing on our prior experience in the design of A2A receptor antagonists for the potential treatment of Parkinson’s disease, we developed a molecule with sub-nanomolar and single-digit nanomolar affinities for the A2A and A2B receptors respectively and greater than 100-fold selectivity over the related A1 and A3 receptors. A single dose assessment of this molecule in human subjects demonstrated the ability to achieve &gt;99% target engagement (TE) at the A2A receptor and &gt;90% TE at the A2B receptor at trough concentration. This presentation will, for the first time, describe the discovery and early clinical evaluation of this molecule, including disclosure of the structure, human pharmacokinetics, safety, and tolerability.
Citation Format: Duane DeMong, Sheila Ranganath, Jared Cumming, Matthew Larsen, Yonglian Zhang, Christopher Plummer, Amjad Ali, Anthony Palmieri, Evan Barry, Pierre Daublain, Pranav Gupta, Manash Chatterjee, Vincent Giranda, Jeremy Presland, Sebastian Schneider, Paul Ciaccio, Daniel Tatosian, Aaron Sather, Ben Turnbull, Steven Silverman, Harry Chobanian, Harini Krishnamurthy, Richard Wnek, Roshi Afshar, Stephen Crowley, Alita Miller, Mark Ayers, Alan Whitehead, Marlene Hinton, Derek Chiang, Robert Orr, Jill Chrencik. Discovery and clinical evaluation of a potent and selective A2A/2B dual receptor antagonist [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR017.
Abstract A012: Perceptions about the need for colorectal cancer screening among male refugees in Salt Lake City
Authors: Onigbogi Olanrewaju , Kah Kebba 
Published: December 2023

Abstract
Background: Colorectal Cancer (CRC) disproportionately affects Blacks in the United States (US) with an incidence rate &gt;20% compared with Whites. In addition, Blacks are diagnosed at an earlier age and with more advanced disease. The population of migrants from Africa and the Middle East increased about four-fold over the past three decades. Therefore, increasing the uptake of CRC screening in this population may be critical in reducing the disparities in cancer-related morbidity and mortality in the US in the future. This study was therefore designed to elicit the perceptions of immigrants about the need for CRC screening. Methods: Twenty-three willing participants who identified as refugees from Africa or the Middle East who arrived within the past 2 years were recruited into three Focus Group Discussion (FGD) sessions in Salt Lake City. The discussions were audio-taped, transcribed and coded using the Dedoose software. Inter-observer variability was 74%. Results: Nineteen respondents (82%) reported awareness of the existence of CRC screening possibilities. Ten (43%) indicated that they will be willing to do the test if readily offered. Five major themes were identified: (1) Mistrust- Distrust of the system due to unfulfilled promises as refugees (2) Fear- fear of cancer based on past experiences (3) Fatalism-the belief that screening cannot lead to cure of cancer and (4) Doubts- doubts about whether Western culture can truly manage cancer. Conclusion: Perceptions about the need for CRC screening are accompanied by myths based on past experiences. There is also a need to explore targeted CRC prevention education with culture or religion specific inputs to improve CRC screening uptake among this population.
Citation Format: Olanrewaju Onigbogi, Kebba Kah. Perceptions about the need for colorectal cancer screening among male refugees in Salt Lake City [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A012.