bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 6159: Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease
Authors: Ahmed Md Shakir Uddin , Dorsey Tiffany , Ambs Stefan
Published: March 2024

Prostate cancer is a leading cause of cancer-related deaths among men in the United States and affects African American (AA) men more so than other men. We and others previously described a distinct tumor immunobiology in AA prostate cancer patients. Furthermore, we discovered a serum proteome-defined suppression of tumor immunity signature that is prevalent among these patients and associated with lethal prostate cancer. In the current study, we sought to investigate the composition of circulating peripheral blood mononuclear cells (PBMCs) in AA and European American (EA) prostate cancer patients and their association with patient group and lethal prostate cancer. We obtained high-quality RNA-sequencing data for 277336 single cells representing circulating PBMCs from 59 AA and EA men. In the analysis, being an AA patients associated with an increased abundance of exhausted T cells, higher numbers of plasma B cells and CD16+ monocytes. Gene signatures indicative of T cell exhaustion and Treg activity were generally elevated in AA PBMCs while T cell effector function features were decreased. Within the overall cell population, interferon gene signatures were robustly elevated in AA than EA patients. This gene signature pattern that we observed in AA patients also associated with lethal prostate cancer, namely the T cell exhaustion, Treg activity and elevated interferon signaling gene signatures, may contribute to immune dysfunction and immune injury; pointing to potential clinical implications. Lastly, the interferon-induced transmembrane protein (IFITM3), interferon alpha inducible protein (IFI6), cysteine rich protein-1 (CRIP1), and the RAC family small GTPase2 (RAC2) were notably upregulated in AA patient-derived immune cells. In summary, we show that circulating immune cell populations and the associated gene signatures differ between men of African and European descent. Those elevated in AA patients correlated with lethal prostate cancer.

Citation Format: Md Shakir Uddin Ahmed, Tiffany Dorsey, Stefan Ambs. Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease [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 6159.
Abstract 6262: Optimal cut-off age for AJCC staging system in Middle Eastern patients with differentiated thyroid cancer
Authors: Parvathareddy Sandeep K. , Siraj Abdul K. , Annaiyappanaidu Padmanaban , Ahmed Saeeda O. , Siraj Nabil , Qadri Zeeshan , Azam Saud , Al-Kuraya Khawla S.
Published: March 2024

Background: Differentiated Thyroid Cancer (DTC) has an indolent nature and generally has favorable prognosis. AJCC TNM classification is the most adopted system to evaluate the biological behavior of DTC. Age cut-off of 55 years has been included in the eighth edition of TNM staging system since it led to better prediction of disease specific survival (DSS) of patients with DTC. However, optimal age cut-off in DTC patients from Middle Eastern ethnicity has not been fully explored. We evaluated the optimal age cut-off for the TNM staging system to predict DSS in Middle Eastern patients with DTC.

Methods: We retrospectively analyzed a large cohort of 1721 adult DTC patients who underwent surgery between 1990 to 2018. The optimal age cut-off value was determined using several age cut-offs (between 20 and 85 years) to assess DSS. Harrel’s C-Index, Akaike information criterion (AIC) and Bayesian Information Criterion (BIC) were used to assess the statistical model performance of the TNM staging system (eighth edition), with different age cut-offs for prediction of DSS. The proportion of variation explained (PVE) was also calculated to compare predictability of DSS in patients with DTC.

Results: The median age of patients at diagnosis was 39.9 years (IQR 31.0 - 51.7 years) and 75.5% (1299/1721) were female. Median follow up was 9.3 years and 10 years DSS was 97.1%. For DTC overall, an age cut-off of 50 years had the best statistical model performance. On receiver operating characteristic curve analysis, the optimal age cut-off for prediction of DSS was 50.5 years (area under the curve = 0.872, p < 0.0001).

Conclusion: In this large cohort of Middle Eastern DTC patients, an age cut-off of 50 years was more appropriate for TNM staging to achieve better predictability for DSS. Therefore, implementation of different age cut-off for DTC in Middle Eastern patients could improve the predictive value for TNM staging system, and allow for better therapeutic and surveillance approach for these patients.

Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Nabil Siraj, Zeeshan Qadri, Saud Azam, Khawla S. Al-Kuraya. Optimal cut-off age for AJCC staging system in Middle Eastern patients with differentiated thyroid 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 6262.
Abstract 6269: Assessment of new generation endocrine therapies for the treatment of breast to bone metastasis
Authors: Zboril Emily Kate , Altman Julia E. , Hairr Nicole S. , Myrick Rachel K. , Olex Amy L. , Dozmorov Mikhail G. , Harrell J. Chuck
Published: March 2024

Estrogen receptor (ER) signaling is the main driver of tumorigenesis in ER+ breast cancers by inducing proliferation and survival through genomic and non-genomic means, therefore inhibition of ER signaling has been a mainstay of treatment for decades. Roughly 30 percent of patients will develop treatment-refractory recurrence or metastasis within their lifetime, which may include metastasis to the bone, lung, liver, and brain. Although advances in treatment approaches have prolonged average progression free survival, metastatic breast cancer remains incurable. A new endocrine therapy, Elacestrant, has been approved by the FDA for the treatment of ER+, ESR1-mutant advanced or metastatic breast cancer. The mechanism of action of Elacestrant involves both degradation of ER and modulation of ER signaling through non-degradative means. The central hypothesis of this study was that Elacestrant may prolong progression free survival in animal models of breast to bone metastasis, because modulation of ER in the bone would decrease the incidence of osteoporosis which is induced by other endocrine therapies. However, we discovered that prolonged Elacestrant treatment induces destruction of the trabecular bone structure and increased adipocyte mass within the bone, consistent with an osteoporotic phenotype. Ongoing studies will seek to determine if other endocrine therapies will provide better protection to the bone architecture while reducing metastatic burden in animal models. Additionally, we will evaluate organotropic efficacy of new endocrine therapies on multi-organ metastasis to determine if utility is contingent upon the metastatic site.

Citation Format: Emily Kate Zboril, Julia E. Altman, Nicole S. Hairr, Rachel K. Myrick, Amy L. Olex, Mikhail G. Dozmorov, J. Chuck Harrell. Assessment of new generation endocrine therapies for the treatment of breast to bone metastasis [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 6269.
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

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

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

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

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

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

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<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<0.001) or in the West (OR=1.38; p<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

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

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.
Abstract 6619: Dynamic prediction with repeated mammogram images improves 5-year breast cancer risk performance
Authors: Colditz Graham A. , Tamimi Rulla M. , Rosner Bernard , Jiang Shu
Published: March 2024

Background: Increasing use of digital screening mammography opens potential to add individualized dynamic measures of breast image history to predict future breast cancer risk. Current prediction models use a single mammogram measure, usually breast density, at one point in time, to add to prediction models based on established risk factors. Our previous work has shown that change in each breast over time is related to risk of diagnosis with breast cancer.

Methods: We apply a dynamic prediction model that includes full field digital mammogram in each breast to predict future 5-year risk. Data from Joanne Knight Breast Health Cohort (JKBHC) serve as training population with 290 pathology-confirmed breast cancer cases and 658 controls sampled with a total number of 8,712 craniocaudal (CC) view mammograms for analysis. Nurses’ Health Study 2 (NHS2) serves as the external validation with 188 cases and 462 controls sampled with a total number of 3,712 CC-views. The dynamic risk prediction model aims to estimate the probability of future breast cancer risk conditional on the past history of the longitudinal mammograms. We train the model on the JKBH cohort, retaining 20% for testing and 15% for validation. We report a time dependent AUC when evaluating model performance.

Results: The mean age of women was 56.6 years at entry to cohort; 81.3% were white. Adding trajectory of mammogram images in each breast to a model improved performance. The mean number of mammograms conditional on 5 years of observation in JKBHC was 3.36 (1.49) and in NHS2 2.36 (1.53). We obtained a 5-year dynamic AUC of 0.81 (0.05) in the JKBHC internal validation and 0.77 (0.06) in the NHS2 external validation. Model performance was comparable in pre- and postmenopausal women. Because breasts with high mammographic density hinder detection of tumors we stratify analyses by dense and non-dense at baseline. Among women with dense breasts at baseline (BIRADS C and D), we observe a dynamic 5-year risk AUC = 0.77. In the subgroup with less dense breasts (BIRADS A and B) we observe AUC = 0.74.

Conclusions: With this approach we can accommodate the irregularly observed time-varying images and project only partial information prior to doing the prediction. Adding trajectory of mammogram history in each breast improves 5-year breast cancer risk prediction beyond models used in clinic today.

Citation Format: Graham A. Colditz, Rulla M. Tamimi, Bernard Rosner, Shu Jiang. Dynamic prediction with repeated mammogram images improves 5-year breast cancer risk performance [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 6619.
Abstract 6685: Control of melanoma development by B. rodentium in germ free mice
Authors: Olea Ximena Diaz , Beede Kristin , Osterman Andrei , Scott David , Petucci Christopher , Kelly Daniel , Ramer-Tait Amanda , Ronai Ze’ev A.
Published: March 2024

Growing evidence supports the importance of the gut microbiota in controlling tumor development, often via activation of anti-tumor immunity. Earlier studies from our laboratory identified 11 bacterial strains that were sufficient to inhibit melanoma development by inducing anti-tumor immunity in germ-free mice. Of these, three were predominant at the time of tumor collection. We thus set out to address whether fewer bacterial strains may be sufficient for melanoma growth inhibition. Here, we demonstrate that the administration of one bacterial strain, B. rodentium, was sufficient to attenuate melanoma growth in gnotobiotic mice. In all cases, gnotobiotic mice were also administered the altered Schadler flora (ASF), a mixture of 8 bacterial strains that are provided to establish minimal flora in these mice. RNAseq-based gene expression studies identified enrichment of immune-related genes, suggesting enhanced anti-tumor immunity. Metabolomic analysis identified reduced levels of tryptophane and isoleucine, which were implicated in control of immune system function. These findings point to a mechanism which may provide novel means to alter anti-tumor immunity and limit melanoma growth.

Citation Format: Ximena Diaz Olea, Kristin Beede, Andrei Osterman, David Scott, Christopher Petucci, Daniel Kelly, Amanda Ramer-Tait, Ze’ev A. Ronai. Control of melanoma development by B. rodentium in germ free mice [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 6685.
Abstract 6705: A novel tri-specific T cell engager targeting the intracellular oncoprotein WT1
Authors: Gao Shan , Yang Liu , Du Jun , Jiang Wenqing , Fang Lei
Published: March 2024

Background: Wilms' tumor gene 1 (WT1) is considered an oncogenic factor, with high expression observed in several hematological malignancies and solid tumors. However, its expression is rarely found in normal adult tissue. WT1 can be degraded by the proteasome, processed and presented on the cell surface as major histocompatibility complex (MHC) I epitopes and recognized by T cell receptors (TCR). Here, we described the development of WT1-TOPAbody, a novel tri-specific T cell engager (TCE), that activated T cells by both CD3 and 4-1BB signaling upon recognition of WT1 in the context of HLA-A02, leading to superior anti-tumor efficacy.

Materials and Methods: WT1-TOPAbody was evaluated for its antigen binding activity and target specificity by a series protein/peptide and cell-based assays. In vitro cytotoxicity and T cell activation mediated by WT1-TOPAbody was further assessed in a panel of WT1+ tumor cell lines in coculture with effector cells. Anti-tumor activity was investigated in a humanized syngeneic mice model bearing WT1/HLA-A02 expressing tumors. Safety assessment including cytokine release assay (CRA) and preliminary CMC developability was also performed.

Results: WT1-TOPAbody exhibited superior binding affinity to the WT1/HLA-A02 complex while displaying lower binding to off-target peptides and CD34+ HSC from healthy donor than clinical benchmark WT1-CD3 bispecific antibody, RG-6007. WT1-TOPAbody effectively induced tumor lysis in multiple WT1+ tumors including leukemia, ovarian, breast, and colon cancer cells. Moreover, serial killing of tumor cells were observed in WT1-TOPAbody treated T cells, accompanied by lower exhaustion markers expressed, suggesting a prolonged anti-tumor inhibition effect of WT1-TOPAbody. In a humanized CD3e/4-1BB/HLA-A2.1 mouse model, WT1-TOPAbody significantly inhibited tumor growth in a dose-dependent manner and the efficacy was superior than that of the benchmark. Additionally, IL-6 release was minimal in PBMC upon treatment of the antibody, indicating a reduced risk of inducing cytokine release syndrome (CRS). Drug developability assessment indicated that the leading WT1-TOPAbody was a reasonably developable molecule to be taken forward.

Conclusion: WT1-TOPAbody is a differentiated WT1/HLA-A02 targeted T cell engagers that displayed potent and durable anti-tumor activity. These results collectively support the potential of WT1-TOPAbody as a novel therapeutic agent against WT1/HLA-A02+ cancers and warrant its further development.

Citation Format: Shan Gao, Liu Yang, Jun Du, Wenqing Jiang, Lei Fang. A novel tri-specific T cell engager targeting the intracellular oncoprotein WT1 [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 6705.
Abstract 6717: Targeting mutant KRAS proteins with novel TCR-mimic fully human antibodies
Authors: Du Jun , Tang Wanbo , Jiao Xin , Zhao Limin , Du Pengfei , Zhang Yuqi , Bao Jian , Chen Han , Guo Chaoshe , An W. Frank
Published: March 2024

Mutated KRAS proteins are ideal cancer targets, as they are expressed frequently and specifically in certain solid tumors. A large proportion of human colorectal cancer and pancreatic ductal adenocarcinoma express the tumor driver KRAS gene mutations G12V/G12D, but drugs targeting G12V/G12D are not available, revealing a huge unmet clinical need. While small molecules often fail to target the KRAS mutation G12V/G12D, T cell receptor-mimic (TCR-mimic) antibodies can specifically recognize KRAS mutations presented by human leukocyte antigen (HLA), opening up possibilities for targeting such intracellular antigens.

Here, we discovered novel antibodies highly specific to G12V/HLA and G12D/HLA complexes by immunizing our proprietary RenTCR-mimicTM mice and using high-throughput Beacon-based screening. These TCR-mimic antibodies have higher affinities compared to endogenous TCRs, which may effectively reduce the possibility of tumor escape. Germline distribution analysis indicated their high sequence diversity, which suggests diverse epitope targeting. Although pancreatic cancer is extremely difficult to treat and has an extremely low KRAS mutant peptide-HLA complex density on the cell surface, our TCR-mimic antibodies exhibited potent in vitro tumor lysis activity when assembled into CD3 T cell engagers. Furthermore, these antibodies demonstrated convincing off-target safety. Together, our results indicate promising therapeutic potential of these KRAS mutation-targeted TCR-mimic antibodies for the treatment of solid tumors.

Citation Format: Jun Du, Wanbo Tang, Xin Jiao, Limin Zhao, Pengfei Du, Yuqi Zhang, Jian Bao, Han Chen, Chaoshe Guo, W. Frank An. Targeting mutant KRAS proteins with novel TCR-mimic fully human antibodies [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 6717.
Abstract 6724: Mechanistic validation of MAIT cell engagers in HUB patient-derived organoids (PDO) co-culture model
Authors: Abouleila Yasmine , Prigent Julie , Doorn Mayke , Germain Claire , Boj Sylvia , Plyte Simon , Verissimo Carla
Published: March 2024

In the field of cancer immunotherapy, bispecific antibodies have emerged as a promising approach for redirecting T-cells to target and combat tumors. However, their efficacy is limited to only a subset of patients. A major challenge that hinders the development of bispecific antibody targets is the lack of preclinical models that preserve patient-specific tumor antigens and recapitulate the complex interaction between the human immune system and tumor cells. HUB Organoids technology presents a valuable platform for novel immunotherapies testing and validation as they are directly derived from patient tumor tissues, accurately reflecting patient-specific tumor antigens. BIOMUNEX Pharmaceuticals has developed the BiXAb® technology platform, a computational modeling approach that rapidly generates bispecific antibodies from various monospecific monoclonal antibodies, eliminating the need for extensive engineering. This platform includes a bivalent T cell engager specifically targeting MAIT cells and human epithelial growth factor receptor (HER2), a tumor antigen highly expressed in some colorectal cancer (CRC) patients. This innovative approach forms an efficient immunological synapse, allowing exclusive redirection of MAIT cells to directly eliminate cancer cells. In a collaborative research initiative between HUB Organoids® and BIOMUNEX Pharmaceuticals, the mechanisms by which BiXAb® induce tumor cell killing were confirmed using CRC patient-derived organoids (HUB Organoids® or PDOs) co-cultured with allogenic MAIT cells in an in vitro model. The study results depicted BiXAb® induced MAIT-cell activation in a dose-dependent manner, as detected by FACS and ELISA. Furthermore, BiXAb®-mediated MAIT-cell-specific killing of CRC PDOs was observed in a HER2-dependent manner, determined using an image-based viability assay. In conclusion, the co-culture platform of CRC PDOs-MAIT cells described here effectively captured the activation and targeted killing of MAIT cells mediated by BiXAb®, underscoring the added value of this PDO-based co-culture platform in developing novel immunotherapies.

Citation Format: Yasmine Abouleila, Julie Prigent, Mayke Doorn, Claire Germain, Sylvia Boj, Simon Plyte, Carla Verissimo. Mechanistic validation of MAIT cell engagers in HUB patient-derived organoids (PDO) co-culture model [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 6724.
Abstract 674: Novel anti-cancer small molecule targeting the protein regulator of cytokinesis pathway
Authors: Peled Amnon , Abraham Michal , Wald Hanna , Rosenfeld Rakefet , Eizenberg Orly , Aharon Arnon
Published: March 2024

Aberrant migration and proliferation of cancer cells are the hallmark of metastatic tumors. Protein Regulator of Cytokinesis 1 (PRC1) is a scaffold protein that regulates metabolic pathways of cancer cell proliferation, survival, and metastasis. BKT300 is a small molecule (MW 399.33, C22H25NO6), that selectively inhibits the migration and survival of hematological and solid cancer cells. BKT300 inhibits, at high affinity, both actin and microtubule formation and organization leading to G2/M cell cycle arrest, mitotic catastrophe, and apoptosis through the caspase 3 pathway. These effects are selective to cancer cells and were not observed on normal cells. BKT300 was found to arrest PRC1 in a phosphorylated form at position T481, down regulates the expression of CDC25C and up regulate p21. Suppression of PRC1 using SiRNA ablation inhibited BKT300 induced apoptosis on several tumor cell lines and inhibited the effect of BKT300 on G2M cell cycle arrest. Furthermore, using Biacore SPR, microscale thermophoresis (MST), and ELISA assays we were able to demonstrate the direct binding of BKT300 to PRC1. Beyond its single agent activity, BKT300 was shown to synergize with standard of care (SoC) treatments, including anti PD-1 immunotherapy, BCL-2 inhibitor (Ventoclax), topoisomerase I inhibitor (Irinotecan) topoisomerase II inhibitor (Doxorubicin), anti-metabolite Fluorouracil (5-FU) and alkylating agent (Temozolomide). BKT300 has a remarkable safety profile when administered at high doses to mice rats, minipigs and non-human primates. Treatment with BKT300 showed almost no effects on hematopoiesis and biochemistry in doses far higher than the affective ones. The in-vivo activity of BKT300 was demonstrated in multiple Xenograft, Syngeneic and PDX models in mice. In-vivo treatment with BKT300 resulted in preventive (small tumors) as well as therapeutic (large tumors) activity in triple negative breast cancer (TNBC) xenograft, MDA-MB-453 and MDA-MB-468 models leading to over then 70%-90% reduction in tumor size following one to two treatments cycles. Similar results were obtained using PDX models derived from patients with Colon, Ovarian and Pancreatic cancer. BKT300 is a novel, first in class, targeted anti-cancer treatment that inhibits the activity of the scaffold protein PRC1. BKT300 is expected to provide a new treatment option to, the high unmet medical need of, advanced difficult to treat cancers, specifically ones that overexpress PRC1 and CDC25C.

Citation Format: Amnon Peled, Michal Abraham, Hanna Wald, Rakefet Rosenfeld, Orly Eizenberg, Arnon Aharon. Novel anti-cancer small molecule targeting the protein regulator of cytokinesis pathway [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 674.
Abstract 6865: Single cell analysis of melanoma reveals a prognostic myeloid cell associated with survival in melanoma with brain metastases
Authors: Ahmad M. Usman , Heo Leong , Nair Ramesh V. , Sharma Saurabh , Kirane Amanda
Published: March 2024

INTRODUCTION: The interface of the innate and adaptive immune system are a critical factor in tumor behavior and responses to immunotherapy with myeloid cell behavior varying widely between various biogeographies. We sought to elucidate myeloid sub-type differences to characterize biology and support therapeutic strategies.

METHODS: scRNA-seq of primary skin, acral, and metastatic melanoma were combined from 6 datasets with 126 patients for analysis. After integration, cells were analyzed with scCCESS, which uses an artificial neural network to reduce data and optimize k for k-means clusters. Myeloid clusters with analyzed with Recursive Partitioning Analysis (RPA), differential expressed gene (DEG) analysis, and pseudobulk comparison of RPA groups by gene expression.

RESULTS: 102,971 single cells from 126 patients were analyzed to generate a cluster of 15,303 myeloid cells further subjected to clustering generating 6 cell types. RPA analysis of 6 myeloid populations in 46 patients with melanoma brain metastases generated 3 nodes with differing median survival months (17 vs 41 vs 57, p=0.01). There was a trend towards more adjuvant immunotherapy (p=0.057) and targeted therapy (p=0.019) in the worst surviving group. Myeloid type 1 cells showed increased expression of CLEC10A and AXL genes compared to all other cells (adj p = 0.000). Pseudobulk comparison of patient groups of genes showed CLEC10A was significant between all groups (p<0.05).

CONCLUSIONS: Although there were no significant differences in neoadjuvant treatment, increased infiltration of CLEC10A myeloid cells showed improved survival in melanoma brain metastases. Targets of current therapies, such as AXL tyrosine kinase, have heterogenous presence across multiple cell types beyond tumors that may impact wide response variances, further study of these populations will have significant impact in both biomarker and therapeutics development.

Citation Format: M. Usman Ahmad, Leong Heo, Ramesh V. Nair, Saurabh Sharma, Amanda Kirane. Single cell analysis of melanoma reveals a prognostic myeloid cell associated with survival in melanoma with brain metastases [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 6865.