bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6296: Biomarkers associated with atherosclerosis-related cardiovascular dysfunction in cancer survivors treated with anthracyclines
Authors: Reding Kerryn W. , Vasbinder Alexi , O'Connell Nathaniel , Demissei Biniyam , Szewczyk Warren , Cheng Richard , Ladd Amy , Lucas Alexander , Meyer Juergen , Bowen Stephen , Salloum Fadi , D'Agostino Ralph , Lesser Glenn , Weaver Kathryn , Ky Bonnie , Tang W. H. Wilson , Hundley W. Gregory 
Published: March 2024

Abstract
Introduction: Cancer survival has increased in part due to treatment advances. However, anthracycline chemotherapy increases cardiovascular (CV) morbidity risk, including atherosclerotic CV disease (ASCVD). Among those receiving anthracyclines, it is yet unclear who is at greatest risk of ASCVD, a major cause of CV mortality. Elucidating pathophysiologic processes involved in the development ASCVD could shed light on strategies to identify those at risk.
Methods: Analyses were performed on 279 lymphoma and breast cancer survivors enrolled in the PREVENT study [clinical trial WF-98213) through Wake Forest NCI Community Oncology Research Base (NCORP) and Alliance (A221501)]. CV dysfunction was measured via cardiac MRI (cMRI) at baseline (pre-treatment) and 6-months post-diagnosis to ascertain aortic distensibility and wall thickness in the descending aorta. Biomarkers were measured at baseline and 6-months and were log-transformed to base 2. Multiple linear regression was used to determine associations between biomarker and outcome at 6 months, adjusted for baseline biomarker and cMRI outcome, age, race, sex, body mass index, and smoking history.
Results: The mean age (SD) of cancer survivors 49 (12) years; 92% were women. The mean aortic distensibility and mean wall thickness at baseline was 0.002 (0.0014) and 2.99 (0.41), respectively. Table 1 shows the associations between biomarkers and aortic distensibility and wall thickness of the descending aorta. After adjustment for confounders, Arginine, CRP, MPO, and ornithine were associated with 6-month aortic distensibility, and the HDL and SDMA were associated with aortic wall thickness.
Conclusions: The findings of this study suggest that biomarkers in oxidative stress and inflammatory pathways may be involved in pathophysiology of ASCVD among cancer survivors receiving anthracyclines. These results require further study in larger cohorts to better define mechanistic pathways involved.
Association of Biomarkers with Atherosclerosis-Related Cardiovascular Dysfunction
Citation Format: Kerryn W. Reding, Alexi Vasbinder, Nathaniel O'Connell, Biniyam Demissei, Warren Szewczyk, Richard Cheng, Amy Ladd, Alexander Lucas, Juergen Meyer, Stephen Bowen, Fadi Salloum, Ralph D'Agostino, Glenn Lesser, Kathryn Weaver, Bonnie Ky, W. H. Wilson Tang, W. Gregory Hundley. Biomarkers associated with atherosclerosis-related cardiovascular dysfunction in cancer survivors treated with anthracyclines [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 6296.
Abstract 632: AKT supports cancer cell survival through modulation of cholesterol homeostasis
Authors: Vivanco Igor , Myint Khine N. , Wallace Sean , Lazaro Glorianne , Kostaras Eleftherios , Palaskas Nikolaos 
Published: March 2024

Abstract
AKT is a critical effector kinase downstream of PI3K activation. It has been shown to regulate a variety of cellular processes important for homeostasis, many of which are altered during oncogenesis. Not surprisingly, AKT is constitutively activated in a large number of human cancers, and has consequently been pursued as a therapeutic target for many years. Some of these functions are directly involved in establishing one or more hallmarks of cancer including sustained proliferative signaling, resisting cell death, and reprogrammed cellular metabolism. Although AKT inhibitors have demonstrated clinical benefit (most recently in a phase III trial) in combination with other therapies, single agent activity has been limited to a few cases with relatively infrequent activating AKT1 mutations. We have previously proposed that the clear disconnect between the high frequency of AKT activation in cancer and the lack of broad clinical activity of AKT inhibitors is due, at least in part, to the inability of existing compounds to block non-catalytic functions. We have found that while allosteric AKT inhibitors are partial suppressors of these functions, ATP-competitive inhibitors fail to suppress these functions to any significant extent. We now provide evidence that one important non-catalytic function of AKT that impinges on its oncogenic function is the regulation of cholesterol metabolism. We show that AKT represses the activation of LXRβ, thereby maintaining a level of intracellular cholesterol that is compatible with cancer cell viability, and that this repression does not require catalytic activity. Consistently, we find that allosteric AKT inhibitors induce LXRβ activation, and that genetic or pharmacological suppression of LXRβ function limit the growth inhibiting effects of these drugs. Our findings suggest that through a kinase-independent activity, AKT may play a significant role in the regulation of cholesterol homeostasis, and that the therapeutic potential of AKT inhibitors could be broaden by optimizing their ability to interfere with these functions.
Citation Format: Igor Vivanco, Khine N. Myint, Sean Wallace, Glorianne Lazaro, Eleftherios Kostaras, Nikolaos Palaskas. AKT supports cancer cell survival through modulation of cholesterol homeostasis [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 632.
Abstract 6320: CAR-T cells targeting LGR5: An effective treatment for chemotherapy resistant ovarian cancer
Authors: Wang Wanqi (Jady) , Bandara Veronika , Lokman Noor A. , Price Zoe K K. , Noye Tannith M. , Napoli Silvana , Gundsambuu Batjargal , Oehler Martin K. , Barry Simon C. , Ricciardelli Carmela 
Published: March 2024

Abstract
Ovarian cancer is the second leading cause of cancer-related mortality among gynaecological cancers in the Western world. CAR-T cell therapy is an adoptive immunotherapy used to treat some blood cancers. This study has investigated whether leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a suitable target for CAR-T cell therapy for ovarian cancer. We assessed the cytotoxic effects of LGR5-targeting CAR-T cells on a range of ovarian cancer cell lines and primary serous ovarian cancer cells derived from patient ascites (at diagnosis and following relapse with chemotherapy resistant disease) in monolayer culture, 3D spheroid assays and patient-derived explant assays. OVCAR3 and a chemoresistant patient-derived xenograft (PDX) models have been used to assess whether LGR5-targeting CAR-T cells can inhibit growth and metastasis in vivo. We found that LGR5 is highly expressed in high-grade serous ovarian carcinoma (HGSOC) cancer cell lines and LGR5 expression was increased in chemotherapy resistant primary ovarian cancer cells. We demonstrated that LGR5-targeting CAR-T cells were cytotoxic and significantly inhibited the survival of ovarian cancer cell lines and chemotherapy-resistant primary ovarian cancer cells with high LGR5 expression levels in both monolayer culture and 3D spheroids compared to un-transduced CD3+ T cells. In patient-derived explant assays, we observed increased apoptosis in HGSOC tissues expressing high LGR5 following treatment with LGR5-targeting CAR-T cells. In vivo, LGR5-targeting CAR-T cell treatment decreased the tumour burden in mice with OVCAR3 xenografts and a chemotherapy-resistant PDX model with high LGR5 expression, compared to CD3+ T cells. In summary, LGR5-targeting CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.
Citation Format: Wanqi (Jady) Wang, Veronika Bandara, Noor A. Lokman, Zoe K K. Price, Tannith M. Noye, Silvana Napoli, Batjargal Gundsambuu, Martin K. Oehler, Simon C. Barry, Carmela Ricciardelli. CAR-T cells targeting LGR5: An effective treatment for chemotherapy resistant ovarian 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 6320.
Abstract 6340: Novel conditionally active tetravalent B7-H3 x CD3 T-cell engagers targeting solid tumors
Authors: Cugnetti, PhD Ana Paula , Liu Haizhen , McNeeley Patricia , Woodard Kathryn , Chang Cathy , Frey Gerhard , Boyle William J. , Short Jay M. 
Published: March 2024

Abstract
B7-H3, also known as CD276, is an immune-checkpoint molecule and a type 1 transmembrane protein that exerts a variety of biological functions. In cancer biology, the overexpression of B7-H3 is correlated with tumor cell invasion and metastasis, decreased T-cell infiltration and function, poor prognosis, and resistance to therapy. As B7-H3 is expressed in multiple solid tumors and plays an important role in modulating anti-tumor immune response as well as promoting cancer cell formation, it became an important target for the development of antibody-based immunotherapy. Many forms of bispecific antibodies targeting B7-H3 have shown antitumor response in preclinical studies. However, bispecific T-cell engagers (TCE) targeting B7H3 and CD3 have been correlated with cytokine release syndrome and hepatic adverse events, a common toxicity observed using TCEs which has limited the development of this immunotherapeutic in clinic. We leveraged BioAtla’s Conditionally Active Biologic (CAB) platform (1) to develop a DualCAB T-cell engager targeting B7-H3 and CD3. This DualCAB-TCE molecule, BA3142, was engineered to bind with high affinity to both recombinant B7-H3 and CD3 receptor/antigens under conditions that mimic the acidic tumor microenvironment, but with low affinity in alkaline physiological conditions. In vitro and in vivo efficacy and toxicity data for the clone BA3142 will be presented. Our data demonstrated that BA3142 promotes cytotoxicity of B7-H3-expressing cancer cells in vitro and induces significant tumor regression in vivo. In Non-Human Primates BA3142 bispecific antibody was tolerated up to 25 mg/kg with minimal cytokine release and no clinical and histopathological signs of toxicities. The CAB technology offers the opportunity to expand the number of targets suitable for drug development in a new class of DualCAB TCEs with superior safety margin and potency in the clinic.
(1) Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ, and Short, J.M. Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc Natl Acad Sci U S A 2021;118.
Citation Format: Ana Paula Cugnetti, PhD, Haizhen Liu, Patricia McNeeley, Kathryn Woodard, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active tetravalent B7-H3 x CD3 T-cell engagers targeting solid tumors [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 6340.
Abstract 6446: ResponderID™ KRAS: Biology-driven machine learning to personalize KRAS inhibitor therapeutics
Authors: Wheeler Josh , Lovše Anže , Žiberna Klemen , Štajdohar Miha , Ausec Luka , Kokošar Janez , Pointing Daniel , Pai Aditya , Rosengarten Rafael , Uhlik Mark 
Published: March 2024

Abstract
Breakthroughs in targeted KRAS therapeutics (KRASi) have the potential to transform the treatment landscape for several of the most common cancers including lung, colorectal, and pancreatic. Despite the recent approvals of KRASi and the anticipation of more to come, both the rate of patient response and the durability of these responses remain significant areas requiring improvement. Biomarkers that can predict response to KRASi and guide effective patient selection and drug combination strategies will be key to realizing the full potential of this emerging therapeutic field. While most biomarkers predominantly rely on a single analyte (e.g. KRAS mutation status), Genialis’ biomarkers are constructed using high-dimensional and/or multimodal data that capture the underlying biological complexity unique to each individual patient. Genialis' ResponderID™ is a machine learning-based biomarker discovery framework that models fundamental aspects of cancer biology to predict the clinical benefit based on the patient’s own biology. Here we report progress towards the development of a first-in-class, RNA-based biomarker, ResponderID™ KRAS, capable of stratifying KRAS G12C inhibitor response in lung cancer patients using RNA sequencing data. Trained on thousands of lung cancer samples, our biomarker models therapeutic response by unifying two core KRAS biologic axes, dependency and activation, to identify those patients most likely to respond. The performance characteristics of ResponderID™ KRAS thus far has been evaluated on a real world dataset of lung cancer patients treated with Sotorasib. ResponderID™ KRAS serves as an independent biomarker designed to inform clinical trial design, select for therapeutic efficacy, identify rational combination strategies, and expedite approvals across various therapeutic contexts.
Citation Format: Josh Wheeler, Anže Lovše, Klemen Žiberna, Miha Štajdohar, Luka Ausec, Janez Kokošar, Daniel Pointing, Aditya Pai, Rafael Rosengarten, Mark Uhlik. ResponderID™ KRAS: Biology-driven machine learning to personalize KRAS inhibitor therapeutics [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 6446.
Abstract 6478: Intracranial neoplasms: Disparities in access to care
Authors: Hsiung Jayla , Taneja Kamil , Ladehoff Lauren , Patel Karan , Toloza Eric 
Published: March 2024

Abstract
Purpose: Excision of intracranial neoplasms is a life-saving procedure. However, there is not much research that has demonstrated how demographic variables interact with a patient’s access to healthcare for intracranial neoplasms.
Methods: The Nationwide Inpatient Sample was queried from 2018 to 2020 to identify patients with an intracranial neoplasm. Multivariable logistic regression with patient- and hospital-level characteristics as covariates was used to identify factors associated with receiving an intracranial tumor excision.
Results: From 2018 to 2020, there were 97,795 hospital encounters with a primary diagnosis of an intracranial neoplasm. Of these patients, 64.6% underwent a tumor excision procedure during their hospital visit. The average age of all patients with intracranial neoplasm was 58.90.2 years. Most intracranial neoplasm patients were male (59.0%), White (73.8%), Medicare beneficiaries (45.1%), and of the highest income quartile (26.4%). These patients commonly presented to hospitals in the West (35.0%), with a medium number of beds (36.4%), and to rural hospitals (39.1%). The most common locations of these neoplasms were the frontal (18.9%), temporal (12.0%), and parietal (7.5%) lobes. Neoplasms in more than one location in the brain occurred in 5.8% of patients. Multivariable logistic regression identified the following factors as significantly associated with a decreased odds ratio (OR) of receiving an excision surgery: identifying as Black (OR=0.63; p&lt;0.001), Hispanic (OR=0.82; p=0.001), or Asian or Pacific Islander (OR=0.78; p=0.009) and being a Medicaid Beneficiary (OR=0.84; p=0.008). Presenting to a hospital in the South (OR=1.30; p&lt;0.001) or in the West (OR=1.38; p&lt;0.001) were associated with higher chances of having a surgical excision.
Conclusion: There are very substantial differences in access to care for brain cancer patients. Race and insurance status are related to a patient’s chance of receiving tumor excision therapy.
Citation Format: Jayla Hsiung, Kamil Taneja, Lauren Ladehoff, Karan Patel, Eric Toloza. Intracranial neoplasms: Disparities in access to care [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 6478.
Abstract 651: 3D-bioprinted cancer models for target discovery, drug development, and personalized therapy
Authors: Satchi-Fainaro Ronit , Krinsky Anne , Katyal Anshika , Avramoff Opal , Yeini Eilam , Neufeld Lena , Halparin Sharon , Frommer-Shapira Ronnie 
Published: March 2024

Abstract
Many drugs show promising results in laboratory research, but eventually fail in clinical trials. We hypothesize that one main reason for this translational gap is that the cancer models used are inadequate. Most models lack the complex tumor-stromal cell interactions with their microenvironment which are required for tumor progression. Conventional 2D cultures, where cells grow on rigid plastic plates mainly as mono-cultures of a single type of cells, are not able to recapitulate the complex settings of such interactions. Therefore, there is a need to develop a 3D model that better mimics the tumor microenvironment. Hence, we developed a vascularized, hydrogel-based 3D-bioprinted tumor model consisting of patient-derived tumor and microenvironmental cells. Our 3D-bioprinted models are based on a library of hydrogels that we developed as scaffolds for different tumor types, designed according to the mechanical properties of the tissue/organ of origin. The patient-derived models consist of cells from a biopsy, constructed based on CT/MRI scans, and include functional vessels that allow serum and peripheral blood mononuclear cells (PBMC) to flow when connected to a pump. Using this unique model platform, we identified P-selectin as a novel immune checkpoint in the brain regulating cancer-microglia-tumor-associated macrophages (TAMs) interactions. Moreover, we are currently validating our 3D platform for its ability to mimic patient-specific tumors and their microenvironment in order to predict patient response to different treatments (such as chemotherapy, immunotherapy, and targeted therapies). Hence, we are currently conducting an 80-patient “basket” clinical trial testing different treatments on patient samples to validate the ability of our model to predict patient outcomes covering 7 different cancer types. These unique 3D-bioprinted models have the potential to facilitate target discovery and drug development, as well as to serve as a reliable system for precision medicine.
Citation Format: Ronit Satchi-Fainaro, Anne Krinsky, Anshika Katyal, Opal Avramoff, Eilam Yeini, Lena Neufeld, Sharon Halparin, Ronnie Frommer-Shapira. 3D-bioprinted cancer models for target discovery, drug development, and personalized therapy [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 651.
Abstract 6547: Dysregulated FGFR3 signaling alters immune landscape in bladder cancer and presents therapeutic possibilities
Authors: Bergman Daniel R. , Trujillo Erica , Li Lie , Pearson Alexander T. , Sweis Randy , Jackson Trachette L. 
Published: March 2024

Abstract
Bladder cancer is an increasingly prevalent global disease that continues to cause morbidity and mortality despite recent advances in treatment. Immune checkpoint inhibitors (ICI) and FGFR-targeted therapeutics have had limited success in bladder cancer when used as monotherapy. Emerging data suggests that the combination of these two therapies could lead to improved clinical outcomes. The optimal strategy for combining these agents remains uncertain. Mathematical models, and more specifically agent-based models (ABMs), have shown recent successes in uncovering the multiscale dynamics that shape the trajectory of cancer. They have enabled the optimization of treatment methods and identification of novel therapeutic strategies. To assess the combined effects of anti-PD-1 antibodies and anti-FGFR3 small molecule inhibitors (SMI) on tumor growth and the immune response, we built an ABM that captures key facets of tumor heterogeneity and CD8+ T cell compartments, their spatial interactions, and their response to therapeutic pressures. With our model, we quantify how tumor antigenicity and FGFR3 activating mutations impact disease trajectory and response to anti-PD-1 antibodies and anti-FGFR3 SMI. We find that even a small population of weakly antigenic tumor cells bearing an FGFR3 mutation can render the tumor resistant to combination therapy. However, highly antigenic tumors can overcome therapeutic resistance mediated by FGFR3 mutation. The optimal therapy depends on the strength of the FGFR3 signaling pathway. Under certain conditions, ICI alone is optimal; in others, ICI followed by anti-FGFR3 therapy is best. These results point to the need to quantify FGFR3 signaling and the fitness advantage conferred on bladder cancer cells harboring this mutation. Employing this ABM modeling approach may enable rationally designed treatment plans to improve clinical outcomes.
Citation Format: Daniel R. Bergman, Erica Trujillo, Lie Li, Alexander T. Pearson, Randy Sweis, Trachette L. Jackson. Dysregulated FGFR3 signaling alters immune landscape in bladder cancer and presents therapeutic possibilities [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 6547.