bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB386: Weakly-supervised prediction of tumor infiltrating lymphocytes per high power field from colorectal cancer histopathology slides using regression transformers
Authors: Nahhas Omar S. El , Bonner Joseph D. , Greenson Joel K. , Schmolze Daniel B. , Shaktah Lawrence , Salazar Jonathan , Reynaga Lorena , Lindsey Sidney , Lu Jenny , Moreno Victor , Schmit Stephanie L. , Tsai Ya-Yu , Hamilton Stanley R. , Rennert Gad , Kather Jakob N. , Gruber Stephen B. 
Published: April 2024

Abstract
Tumor infiltrating lymphocytes (TILs)-based biomarkers have emerged as a robust method for predicting treatment efficacy and outcome in colorectal cancer (CRC). However, the quantification of TILs remains a strenuous task for pathologists and is susceptible to inter-pathologist variations. Deep learning (DL) can predict cancer biomarkers directly from routine hematoxylin and eosin (H&E) pathology slides, enabling the automated and consistent quantification of TILs for clinical decision-making. Our study focuses on the prediction of TILs per high-power field (HPF) on two large cohorts of CRC patients. We developed a weakly-supervised, transformer-based deep regression model to predict TILs per HPF from routine H&E-stained histology slides. We trained the model using 5-fold cross-validation on a large cohort of CRC patients (n=1,738), and validated its performance on an external cohort of CRC patients (n=223). The model was evaluated using the Pearson’s correlation coefficient r. Moreover, pathologist-determined TILs per HPF was categorized into low (&lt;2) and high (≥2), enabling evaluation via the area under the receiver operating characteristic curve (AUROC). Our model achieved a significant correlation coefficient of 0.60 (p&lt;0.0001) for the predicted TILs per HPF in the holdout test sets of the internal cohort, and a significant correlation coefficient of 0.57 (p&lt;0.0001) on the external validation cohort. Using the thresholds for low and high TILs per HPF, we found that the model accurately predicted the presence of high TILs per HPF in both the internal and external test cohorts, yielding AUROCs of 0.76 and 0.81, respectively. These findings underscore the efficacy of our deep learning model in predicting TILs per HPF from routine pathology slides. This approach holds promise for cost-effective, efficient and uniform quantification of TILs per HPF in CRC, potentially across various cancer types.
Citation Format: Omar S. El Nahhas, Joseph D. Bonner, Joel K. Greenson, Daniel B. Schmolze, Lawrence Shaktah, Jonathan Salazar, Lorena Reynaga, Sidney Lindsey, Jenny Lu, Victor Moreno, Stephanie L. Schmit, Ya-Yu Tsai, Stanley R. Hamilton, Gad Rennert, Jakob N. Kather, Stephen B. Gruber. Weakly-supervised prediction of tumor infiltrating lymphocytes per high power field from colorectal cancer histopathology slides using regression transformers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB386.
Abstract LB410: Contrasting roles of different mismatch repair proteins in basal like breast cancer
Authors: Tithi Tanzia Islam , Mo Jiao , Zhang Weizhou 
Published: April 2024

Abstract
The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely unknown. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutSα). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2-deletion leading to reduced metastasis and MLH1-deletion to enhanced liver or lung metastasis. Mechanistically, MSH2-deletion induces the expression of a panel of chemokines in BLBC via epigenetic and/or transcriptional regulation, which leads to an immune reactive tumor microenvironment (TME) and elevated immune cell infiltrations. MLH1 is not correlated with chemokine expression and/or immune cell infiltration in BLBC, but its deletion results in strong accumulation of neutrophils that are known for metastasis promotion. Our study supports the differential functions of MSH2 and MLH1 in BLBC progression and metastasis, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism.
Citation Format: Tanzia Islam Tithi, Jiao Mo, Weizhou Zhang. Contrasting roles of different mismatch repair proteins in basal like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB410.
Abstract LB411: Investigating the dependency of androgen receptor-positive prostate cancer on class I myosins
Authors: Kadam Anoushka , Kumar Shivani , Vakkala Varsha , Kumar Rajendra , De Marzo Angelo M. , Pearce Edward J. , Sena Laura A. 
Published: April 2024

Abstract
Prostate adenocarcinoma is characterized by high expression and activity of the androgen receptor (AR). AR is a nuclear hormone receptor that stimulates anabolic cell metabolism. We hypothesized that the high activity of AR in prostate cancer creates unique dependencies on cellular machinery to support this high rate of anabolism. We observed that androgen treatment of patients with metastatic castration-resistant prostate cancer resulted in increased abundance of MYO1E, a class I myosin that facilitates intracellular vesicular trafficking, in tumor biopsies. Similarly, MYO1E protein increased in AR+ prostate cancer cell lines upon treatment with androgens. Notably, a specific small molecule inhibitor of MYO1E, pentachloropseudilin (PClP), induced cell death of AR-positive prostate cancer cell lines with an IC50 of 2-4uM, but was non-toxic to AR-negative prostate cancer cell lines. Expression of AR in these AR-negative lines conferred sensitivity to PClP, while deletion of AR in an AR-positive line conferred resistance to PClP, indicating that AR expression was required and sufficient for sensitivity of prostate cancer cell lines to PClP. Previous studies have suggested that AR globally increases protein synthesis and proteotoxic stress, and we asked whether this may create a dependency on MYO1E for secretion of protein-containing vesicles to manage proteotoxic stress. Initial experiments suggest that AR increases global rates of protein synthesis, as assessed by puromycin-incorporation assays, and inhibition of MYO1E increases phosphorylation of EIF2A, suggestive of activation of the integrated stress response. Further experiments will determine the essential function of MYO1E in AR-positive prostate cancer. Altogether our studies suggest that the class I myosin MYO1E is an essential protein in AR-positive cell lines and may represent a novel drug target for prostate adenocarcinoma.
Citation Format: Anoushka Kadam, Shivani Kumar, Varsha Vakkala, Rajendra Kumar, Angelo M. De Marzo, Edward J. Pearce, Laura A. Sena. Investigating the dependency of androgen receptor-positive prostate cancer on class I myosins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB411.
Abstract LB446: Decoding the mechanism of metastasis: A novel CAF-therapy that blocks the tumor microenvironment and reverses metastatic traits in all solid tumors
Authors: Prieto Benjamin , Núñez Muriel , Cerdfa Valentina I. , Cerda-Infante Javier 
Published: April 2024

Abstract
Progression and metastatic spreading of cancer cells are modulated by the carcinoma-associated fibroblasts (CAFs) within the primary tumor microenvironment in solid tumors. However, the mechanisms through which CAFs exert their pro-metastatic effects on cancer cells remain unknown. In this study, we have developed a small molecule that blocks Neuropilin-1 signaling in metastatic CAFs (mCAFs), reversing the mechanisms that promote metastasis in prostate, breast, colorectal and pancreatic cancer. To address these critical needs, in this study, we sought to assess the potential role of proteoglican neuropilin 1 (PG-NRP1) signaling in the maintenance of the activated CAF phenotype.
Our results by gene expression profile, qPCR, WB, and ELISA indicate that CAFs isolated from primary tumors of metastatic patients (mCAFs) are functionally different from CAFs isolated from primary tumors of non-metastatic patients, promoting metastasis traits of cancer cells. Among the most prominent differences is an increased PG-NRP1 expression.
siRNA studies demonstrated that the knockdown of NRP-1 in mCAFs showed the reversion of the activated phenotype, evaluated by the activation markers a-SMA, Tenascin C, and Fibronectin. Furthermore, conditioned media from PG-NRP1-siRNA-mCAFs failed to increase cancer cells' metastasis traits (migration and invasion) in vitro and tumor progression in vivo. Furthermore, we engineered a small molecule designed to bind PG-NRP1 in mCAFs. Our findings, demonstrate in vitro and in vivo models that the inhibition of PG-NRP1 impedes tumor growth and metastatic dissemination of cancer cells in spontaneous metastasis assay.
We designed and validated, using in vivo models, an inhibitor that blocks NRP1-mCAF. Our research demonstrates that blocking PG-NRP1 in mCAF, with a small molecule, is a transversal therapeutic strategy to prevent progression and metastatic spread in solid cancer tumors.
Citation Format: Benjamin Prieto, Muriel Núñez, Valentina I. Cerdfa, Javier Cerda-Infante. Decoding the mechanism of metastasis: A novel CAF-therapy that blocks the tumor microenvironment and reverses metastatic traits in all solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB446.
Abstract ND01: ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing tumors
Authors: Stone Jennifer , Fish Kamonwan Pear , Ashok Devika , McKay Laura , Akhand Saeed , Zhao Weilong , Wu Si , Makkouk Amani , Cosgrove Cormac , Ellis Paul , Peetz David , Shee Stephanie , Peterson Richard , Anderson Shelby , Chervin Adam , Stevenson Claudina , Uziel Tamar , Reilly Edward 
Published: April 2024

Abstract
Natural killer (NK) cell redirecting therapies are emerging as promising “off the shelf” treatments for cancer without the safety issues associated with T cell directed therapies. ABBV-303 is a novel c-Met targeted multispecific NK cell engager based on Dragonfly Therapeutics’ TriNKET® technology. ABBV-303 includes three functional arms: (1) a c-Met binding scFv based on ABT-700, common to c-Met-targeting antibody-drug conjugates ABBV-400 and Teliso-V; (2) a Fab arm that binds NKG2D, a stimulatory receptor expressed by NK cells and activated CD8+ T cells; and (3) a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. ABBV-303 binding to NKG2D and CD16a results in redirection of both innate (NK cells) and adaptive (CD8+ T cells) immune cells to lyse c-Met expressing tumor cells. Treatment of peripheral blood mononuclear cells (PBMCs) from healthy donors and cancer patients with ABBV-303 in the presence of c-Met+ tumor cells stimulates NK and CD8+ T cells as demonstrated by modulation of activation-associated surface proteins and release of soluble factors. ABBV-303 drives sub-nanomolar redirected killing potency against tumor cells expressing a broad range of c-Met. Additionally, anti-tumor activity of ABBV-303 has been demonstrated against established xenografts in CD34 humanized NSG mice. NK and CD8+ T cell activity in response to ABBV-303 has been observed in c-Met-expressing fresh patient tumor explants. A benign safety profile was observed in non-human primates through three repeat doses up to 150 mg/kg given every two weeks, with antibody-like exposures and a serum half-life around 8 days. Based on these findings, the First in Human ABBV-303 study will initiate in 1H 2024 in solid tumors as a monotherapy and in combination with an anti-PD-1 checkpoint inhibitor.
All authors are current employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Citation Format: Jennifer Stone, Kamonwan Pear Fish, Devika Ashok, Laura McKay, Saeed Akhand, Weilong Zhao, Si Wu, Amani Makkouk, Cormac Cosgrove, Paul Ellis, David Peetz, Stephanie Shee, Richard Peterson II, Shelby Anderson, Adam Chervin, Claudina Stevenson, Tamar Uziel, Edward Reilly. ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND01.
Abstract ND05: The discovery of ARV-393, a potent, orally bioavailable BCL6 targeting PROTAC® for the treatment of Non-Hodgkin’s Lymphoma
Authors: Sherman Dan 
Published: April 2024

Abstract
Discovery of ARV-393, a potent, orally bioavailable BCL6 targeting PROTAC® for the treatment of Non-Hodgkin’s Lymphoma (NHL)Dan Sherman, Sheryl M. Gough, Lynn DeCarr, Sarah Eaton, Mark Bookbinder, Jennifer Pizzano, Elizabeth Bortolon, John Corradi, Rashaun Wilson, Daniel Rogoz, Ram Lingamaneni, Wei Zhang, Michelle Zhang, Xin Chen, Gan Wang, Hanqing Dong, Michael Berlin, Keith R. Hornberger, Lawrence Snyder, Achal Pashine and Ian Taylor.
Arvinas, Inc., 5 Science Park, New Haven, CT, USA.
Approximately 18,000 cases of Diffuse large B-cell lymphomas (DLBCL) are diagnosed worldwide per year making this cancer the most prevalent (30%) of the non-Hodgkin’s Lymphomas (NHL). Despite the success of R-CHOP treatment, approximately 40% of patients are refractory or relapse. While much progress has been made with CAR-Ts and bi-specific antibodies following frontline therapy in recent years, there remains a need for an orally bioavailable small-molecule that targets molecular drivers of NHL. The BCL6 transcription factor has long been known as an oncogenic driver of B-cell malignancy. The BCL6 gene has been found to be translocated and/or mutated resulting in deregulation of its expression, predominantly in DLBCL and Burkitt’s lymphoma (BL). The deregulated expression and scaffolding role of BCL6 in the transcriptional repressor complex make it an ideal target for the PROteolysis Targeting Chimera (PROTAC®) technology with one BCL6 degrader recently entering Phase 1 trials. We undertook a medicinal chemistry campaign to identify a BCL6-targeting PROTAC®. This effort identified ARV-393, an orally bioavailable PROTAC® that recruits BCL6 and the E3 ligase cereblon to rapidly degrade BCL6 via the cell’s natural ubiquitin proteasome system. ARV-393 is potent, demonstrating DC50 and GI50 values &lt;1 nM in numerous DLBCL and BL cell lines. This agent demonstrates deep BCL6 degradation in vitro and in vivo, resulting in excellent TGI in several tumor xenograft models supporting a first-in-human trial in 1H 2024. We will present the chemical structure of ARV-393 and selected pre-clinical data.
Citation Format: Dan Sherman. The discovery of ARV-393, a potent, orally bioavailable BCL6 targeting PROTAC® for the treatment of Non-Hodgkin’s Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND05.
Abstract PL04-03: Metastasis aggressiveness: A function of metabolite signaling
Authors: Fendt Sarah-Maria 
Published: April 2024

Abstract
Metastasis formation is the leading cause of death in cancer patients. Yet, the molecular mechanisms responsible for the aggressiveness of metastases remain largely unknown. We used experimental metastasis mouse models and samples from patients with breast cancer to study metastases aggressiveness. We discovered that the aggressiveness of cancer cells in lung metastases was driven by an alternative translational program that was regulated by metabolite signaling. Strikingly, the identified molecular mechanism could be disrupted by repurposing a clinical approved inhibitor, which resulted in reduced metastasis formation in mouse models. Thus, this research highlights that dissecting and targeting cancer cell aggressiveness may provide therapeutic options against metastasis formation.
Citation Format: Sarah-Maria Fendt. Metastasis aggressiveness: A function of metabolite signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr PL04-03.
Abstract SY02-03: Stochastic modeling of clonal evolution in carcinogenesis
Authors: Curtius Kit 
Published: April 2024

Abstract
In order to develop strategies that can detect cancer earlier, we need to better understand the dynamics of cancer evolution during the human lifetime. Starting from gestation, this includes measuring both the timing of early somatic mutations that lead to clonal mosaicism as well as the growth rates of mutated clones that carry higher potential for malignant transformation. Continuous observation of this evolving clonal composition across a lifetime is not feasible, therefore mathematical models are needed to integrate data from longitudinal and cross-sectional samples and infer these dynamics. Stochastic models of clonal evolution offer such a framework and provide a means for predicting individual clone trajectories into the future. Furthermore, if measurements of evolution are to be utilized clinically for early detection and patient risk stratification, faster methods to apply these models to data are required. To this end, we derived methods using coalescent theory for single-cell DNA sequencing data that enable instantaneous estimation of the growth rate of a clone along with its confidence intervals. Our tool is available in an open source R package, cloneRate, and provides the first method for constructing valid confidence intervals of growth rates analytically without having to rely on Bayesian inference techniques and complex simulations. When applying our methods to recent datasets derived from normal and neoplastic human blood cells, we quantified increased fitness effects of multi-hit driver mutations and found that higher initial clone growth rates led to decreased time to cancer diagnosis in patients. We can also use these models to estimate other important biological parameters that are difficult to measure in vivo such as bounds for total number of hematopoietic stem cells and expansion rates in early development. Ultimately, the ability to easily and quickly parameterize clonal dynamics in individual patients will benefit future early detection efforts and screening strategies for many cancer types.
Citation Format: Kit Curtius. Stochastic modeling of clonal evolution in carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY02-03.
Abstract SY05-03: Circular extrachromosomal DNA promotes tumor heterogeneity and enhancer rewiring
Authors: Chavez Lukas 
Published: April 2024

Abstract
Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent ‘enhancer rewiring’ events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.
Citation Format: Lukas Chavez. Circular extrachromosomal DNA promotes tumor heterogeneity and enhancer rewiring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY05-03.
Abstract SY22-01: A strategy to intervene mitotic kinases to induce mitotic catastrophe in cancer cells
Authors: Takahashi Motoko , Jo Minji , Kamakura Nana , Liu Chang , Kato Utako , Hirota Toru 
Published: April 2024

Abstract
Chromosomal instability (CIN) is an outstanding feature of cancer, which relates to intratumor heterogeneity, therapeutic resistance, and poor prognosis. While cancer cells can proliferate with CIN, experimentally induced aneuploidy is known to suppress cell growth, leading to the idea that extreme ploidy changes are detrimental to cancer cells. One of the major etiologies of CIN is abnormal kinetochore microtubule attachments, followed by chromosome missegregation. To avoid this, cells have evolved a robust system including two molecular networks for stabilizing and destabilizing microtubule attachments. Two mitotic kinases are involved in this system which have opposite but balanced mode of actions. We previously found that a wide range of cancer cells are defective for destabilization and results in an elevated rate of missegregation. In this study, we aimed to manipulate this kinase balance and found that weighing the balance to stabilizers can cause catastrophic chromosome segregation in mitosis, and such effect could be induced predominantly in cancer cells. These findings prompted us to undertake a screen for small molecules targeting the balanced activity of mitotic kinases.
Citation Format: Motoko Takahashi, Minji Jo, Nana Kamakura, Chang Liu, Utako Kato, Toru Hirota. A strategy to intervene mitotic kinases to induce mitotic catastrophe in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY22-01.