bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1869: Preclinical evaluation of mosunetuzumab for the treatment of relapsed/refractory chronic lymphocytic leukemia
Authors: Barrett Kathy , Lu Kai , Jin Hyun Yong , Millen Rosie , Lefebure Marcus , Jiang Yanwen 
Published: April 2023

Abstract
Background: CD20 x CD3 T-cell engaging bispecific antibodies, such as Mosunetuzumab (Mosun), have shown promising efficacy in Non-Hodgkin’s lymphoma. However, their role in treating chronic lymphocytic leukemia (CLL) is still uncertain. CLL, a clonal disease of mature B cells, is associated with high B/T cell ratios and diminished T cell activation and function, including the inability to form strong immunosynapses (Ramsay et al, J Clinical Investigation, 2008). Herein, we explore whether Mosun could overcome these barriers and elicit strong T-cell mediated B-cell killing in CLL samples.
Methods: PBMCs from CLL patients and healthy donors were exposed to a titration of Mosun for 48 and 72 hours and analyzed for B cell death with flow cytometry. Markers of T cell activation and exhaustion were quantified in CD4 and CD8T cells and within their CD45RA/CCR7 subsets. The concentrations of secreted cytokines were measured by ELISA. To study the impact of high B/T ratio on B cell killing, B cells were isolated from healthy donor PBMC and added back to autologous PBMC to attain B/T ratios seen in CLL patient samples.
Results: After 48 hours with 0.04ug/ml Mosun, the percentage of dead B cells in healthy-donor samples (n=9) exceeded that in CLL samples (n=7) by four-fold (54.2 + 17.9 vs: 12.9 + 17.5%, p=0.0004). Under the same conditions, significantly more T cells expressed activation markers in healthy donors than in CLL patients, with 58.8 +17.1% of healthy donor CD8T cells expressing both CD69 and CD25 compared to and 31.4 +21.4% of CLL CD8T cells (p=0.013). The mean concentration of Granzyme B secreted by healthy donor samples upon Mosun treatment was over ten times higher than by CLL patient samples. Reconstitution of a healthy donor sample to a B/T ratio of 10 resulted in decreased B cell killing (29.7% dead B cells vs: 70.5% in un-reconstituted) without affecting T cell activation (62.9% CD69+CD25+ CD8T cells versus 56.2% in un-reconstituted).
Conclusions: Although single-agent Mosun treatment can activate T-cells in CLL patient samples and result in B-cell death, the response is suboptimal due to a number of factors, including deficient T cell activation and high B/T ratio. Ongoing work is focusing on evaluating drug partners to debulk CLL B cells or prime CLL T cells for better B-cell killing by Mosun.
Citation Format: Kathy Barrett, Kai Lu, Hyun Yong Jin, Rosie Millen, Marcus Lefebure, Yanwen Jiang. Preclinical evaluation of mosunetuzumab for the treatment of relapsed/refractory chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1869.
Abstract 2265: STING pathway activation by ATR inhibition potentiates the antitumor immune response to anti-PD-L1 antibody in small cell lung cancer
Authors: Sen Triparna 
Published: April 2023

Abstract
Introduction: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a very poor prognosis and limited therapeutic options. Recent clinical trials of immune checkpoint blockade (ICB) combined with chemotherapy delivered only very modest benefit. Here, we identified that ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, is highly enriched in SCLC and inhibition of ATR induced DNA damage and apoptosis in multiple SCLC models.
Methods: In this study, we performed genetic and pharmacological inhibition of ATR in a panel of human and murine SCLC models. Furthermore, we investigated the effect of ATR inhibition either alone or in combination with PD-L1 blockade either as a first-line or a second-line treatment in multiple immunocompetent mouse models of SCLC. The downstream effects of ATR inhibition was assessed by single-cell RNA sequencing, multicolor flow cytometry, western blot analysis, IHC, and genomic analysis.
Results: In multiple immunocompetent SCLC mouse models, ATR inhibition (ATRi) remarkably enhanced the anti-tumor effect of PD-L1 blockade both as first- and second-line treatment regimen. Targeting ATR activated the cGAS/STING pathway, induced the expression of Type I and II interferon pathways, and caused significant infiltration of cytotoxic and memory/effector T-cells into tumors. Interestingly, ATRi also led to significant induction of MHC class I in SCLC in vitro and in vivo models. Analysis of pre- and post-treatment clinical samples from a proof-of-concept study of a first-in-class ATR inhibitor, M6620 (VX970, berzosertib), and TOP1 inhibitor topotecan, in patients with relapsed SCLCs validated the induction of MHC class I and interferon pathway genes, for the first time in this disease.
Conclusion: Our findings highlight ATRi as a potentially transformative vulnerability of SCLC, paving the way for combination clinical trials with anti-PD-L1. Given the increasing importance of immunotherapy for the management of SCLC and that ATR inhibitors are already in clinical trials, combining an ATR inhibitor with PD-L1 blockade may offer a particularly attractive strategy for the treatment of SCLC and contribute to the rapid translation of this combination into the clinic.
Citation Format: Triparna Sen. STING pathway activation by ATR inhibition potentiates the antitumor immune response to anti-PD-L1 antibody in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2265.
Abstract 2395: A bioluminescent probe for detection and imaging of heparanase enzymatic activity
Authors: Somers Johnathan , Schleyer Kelton , Liu Jun , Wang Zhishen , Kafle Arjun , Cui Lina 
Published: April 2023

Abstract
Cancers of all types have been shown to overexpress the carbohydrate-processing enzyme heparanase during angiogenesis and invasion, and this enzymatic activity correlates positively with tumor stage and the presence of metastases. While detection of heparanase enzymatic activity holds potential for cancer diagnosis and staging, no probe has been achieved for in vivo systems. We have recently developed fluorogenic heparanase probes for single-step detection of in vitro heparanase enzymatic activity, drastically simplifying the detection of heparanase activity. The modular chemistry allows us to extend the utility further to improve the sensitivity of in vitro heparanase activity detection and enable in vivo detection. Thus, we have developed a bioluminescent heparanase probe, which upon activation by heparanase produces a substrate of firefly luciferase, a standard reporter enzyme for in vivo monitoring of tumor progression. This probe will be validated in multi-well assays of heparanase activity, and applied in real-time correlation of heparanase activity and tumor progression in, fLuc+ tumors in animal models. These studies hold promise in enabling highly sensitive detection of heparanase activity both in vitro and in vivo, and in allowing future research of real-time monitoring of heparanase activity with the tumor progression.
Citation Format: Johnathan Somers, Kelton Schleyer, Jun Liu, Zhishen Wang, Arjun Kafle, Lina Cui. A bioluminescent probe for detection and imaging of heparanase enzymatic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2395.
Abstract 2586: OncogenicPIK3CA promotes hematopoietic reprogramming and cell transdifferentiation developing hematopoietic malignancy
Authors: Kozurek Emma , Dickerson Erin B. , Kim Jong Hyuk 
Published: April 2023

Abstract
PIK3CA mutation is one of the most common, recurrent genetic abbrations identified across multiple types of cancers. Such mutations sustain activation of PI3K/AKT/mTOR pathway, being considered reliable therapeutic targets; yet, the functional consequences still remain unclear. Angiosarcomas are a heterogenous group of soft-tissue sarcomas that form malignant endothelium with disorganized, irregular blood-filled vascular spaces, and a subset of the vascular tumors harbor PIK3CA mutations. In this study, we found that one of 11 canine angiosarcoma cells gave rise to vascular tumors in 3 of 3 mice in a series of xenograft experiments using a total of 86 immunodeficient BNX mice. Intriguingly, we also observed that xenografts developed lymphoproliferative tumors indicating a mouse B-cell origin in 3 of 4 mice from one case of canine patient-derived tumor xenografts: four tumor cases surgically implanted in a total of 16 BNX mice. Additionally, canine angiosarcoma cells induced splenomegaly with expansion of Ter-119+ erythroid progenitors in NSG mice. Canine angiosarcoma cells (two cell lines; DHSA-1426 and EFB) were capable of hematopoietic expansion and cell lineage differentiaton in vitro. Since PIK3CA mutations appear to promote cellular stemness and impairment of cell lineage differentiation, we determined if the mutations play a role in hematopoietic regulations of angiosarcoma cells. DHSA-1426 angiosarcoma cells were used to induce PIK3CA H1047R mutations using CRISPR/Cas9. We found that PIK3CA mutant angiosarcoma cells dysregulated AKT, ERK, and mTOR pathway with enrichement of inflammatory cytokines such as IL-6, IL-8, and MCP-1. Single cell RNA-seq data showed that PIK3CA mutant angiosarcoma cells established distinct single cell clusters representing immune reactions, cellular stemness, and lineage differentiation. Furthermore, PIK3CA mutant angiosarcoma cells developed malignant hematopoietic tumor in one of five BNX mice, while no evidence of hematopoietic tumor formation was found in mice transplanted with non-mutant cells. Altogether, our data suggest that angiosarcoma cells have the capacity to promote hematopoietic imbalance impacting on cellular ontogeny and lineage differentiation, potentially mediated by oncogenic PIK3CA. Our ongoing work is determining the mechanism of the cell fate decisions using bi-potential hematoendothelial progenitors derived from induced pluripotent stem cells harboring oncogenic PIK3CA.
Citation Format: Emma Kozurek, Erin B. Dickerson, Jong Hyuk Kim. OncogenicPIK3CA promotes hematopoietic reprogramming and cell transdifferentiation developing hematopoietic malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2586.
Abstract 2669: RRM2 inhibition synergizes with PARP inhibitor in ovarian cancer cells
Authors: Chen Chi-Wei 
Published: April 2023

Abstract
The use of Poly(ADP-ribose) polymerase inhibitors (PARPi) has been applied for the treatment of epithelial ovarian cancer (EOC) patients with homologous recombination (HR)-deficient disease, such as BRCA1/2 mutations. However, 40 - 70% of patients do not initially respond to PARPi in ovarian cancer with non-BRCA mutations, and acquired resistance has been demonstrated clinically. Ribonucleotide reductase (RNR, which consists of two RRM1 subunits and two RRM2 subunits) is the rate-limiting enzyme in the biosynthesis of dNTPs for DNA replication and DNA damage repair. As targeting RRM2 has been applied for many cancer therapies clinically or in clinical trials, this study hypothesizes that the inhibitory of RRM2 arguments PARPi potency against ovarian cancer. To this goal, this study evaluates the therapeutic effects of RRM2 inhibitor Osalmid (a resveratrol analog) alone or combined with PARPi by employing a panel of ovarian cancer cell lines using SRB assay. The effects on apoptosis and cell-cycle arrest were analyzed using flow cytometry. The cellular thermal shift assay was conducted to explore if Osalmid interacts with RRM2. DNA double strand break marker, ϒH2AX, was detected in compound-treated cells using Western blot. The results provide a new synthetic lethality by combining RRM2 inhibitor and PARPi. The combination induced apoptosis and caused the cell-cycle arrest. The results show that Osalmid binds to RRM2 directly. This study provides both a novel RRM2 inhibitor from a natural compound and a new understanding of the dNTP metabolic demands and may lead to urgently-needed strategies for the treatment of ovarian cancer.
Citation Format: Chi-Wei Chen. RRM2 inhibition synergizes with PARP inhibitor in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2669.
Abstract 2757: Combination of a fluorescent substrate-based MMP activity assay and hit pick reading/imaging procedure to screen for inhibitors of MT1-MMP activity and 3D glioma tumoroid invasion
Authors: Larson Brad , Fields Gregg , Knapinska Ania 
Published: April 2023

Abstract
Malignant and nonmalignant brain tumors are composed of a group of more than 100 different types. Malignant gliomas, including glioblastoma multiforme (GBM) and astrocytomas, are the most common primary brain tumors in the United States, and make up 78% of malignant brain tumors. Membrane type 1 matrix metalloproteinase (MT1-MMP) has been shown to be crucial for the progression, invasion, migration, and angiogenesis of tumors. Use of a FRET substrate to quantify MT1-MMP activity, where tumoroids are embedded in a collagen hydrogel, would simplify detection of potential protease inhibitors, while using an in vivo-like cell model. In the present study, multiple glioma cell lines were formed into tumor spheroids, followed by type I collagen addition. Many known MT1-MMP inhibitors were then added to the wells, to potentially inhibit invasion of the 3D cell models. The substrate and experimental setup were then combined with the joint reading and imaging process available in the Agilent BioTek Gen5 microplate reader and imager software, to create a hit pick screening method. During the procedure, all control and test wells were read, and the signal from cleaved substrate was quantified. Uninhibited invasion within positive control wells exhibited high fluorescence values. Therefore, a hit pick criterion was established such that any wells containing test molecules that were statistically lower than average in fluorescent signal from the corresponding positive control, which should exhibit inhibited invasion, were imaged. Wells that were not significantly lower were not imaged. The result was a screening method which increased efficiency by reducing image capture time and storage requirements.
Citation Format: Brad Larson, Gregg Fields, Ania Knapinska. Combination of a fluorescent substrate-based MMP activity assay and hit pick reading/imaging procedure to screen for inhibitors of MT1-MMP activity and 3D glioma tumoroid invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2757.
Abstract 276: Delineating the role of vesicular glutamate transporter SLC17A7 in osteosarcoma
Authors: Nerlakanti Niveditha , McGuire Jeremy , Bishop Ryan T. , Yu Diana , Reed Damon R. , Lynch Conor C. 
Published: April 2023

Abstract
Osteosarcoma (OS) frequently metastasizes to lung where it greatly contributes to patient mortality. Frustratingly, OS treatment options have remained static due to a paucity of strong pre-clinical evidence to motivate clinical trials. To identify therapeutic targets, we assessed a number of FDA approved therapies for their cytotoxic effects. We found that histone deacetylase (HDAC) inhibitors (panobinostat and romidepsin) limited OS viability at low nM and were highly effective for the treatment of lung metastatic disease in vivo. Although clinically approved, HDAC inhibitors have noted toxicities. Therefore, we next examined the potential mechanisms through which HDAC controlled OS growth. Gene expression analyses on romidepsin treated OS cells revealed key up and downregulated targets. We found that SLC17A7, a vesicular glutamate transporter, was highly and consistently induced in response to romidepsin (greater than 100 fold more than base line) across multiple OS cell lines. Functionally, SLC17A7 traps glutamate in cytoplasmic synaptic vesicles that are then released via exocytosis. Our data show that HDAC inhibition reduces glutamate secretion from OS cells while SLC17A7 overexpression significantly impaired OS viability. Further, we showed that the glutamate export inhibitor, riluzole, significantly impairs the OS growth in vitro and is highly effective for the treatment of lung metastatic OS in vivo. Taken together, we conclude that HDAC1/2 suppression of SLC17A7 ensures high cytoplasmic glutamate levels that can be leveraged for OS growth. We posit that targeting glutamate usage by OS cells using FDA approved inhibitors such as riluzole will be highly effective for the treatment of lung metastatic OS.
Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Ryan T. Bishop, Diana Yu, Damon R. Reed, Conor C. Lynch. Delineating the role of vesicular glutamate transporter SLC17A7 in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 276.
Abstract 3075: Enhanced efficacy of ARV-471, a novel PROTAC® estrogen receptor degrader, in combination with targeted agents in estrogen receptor-positive (ER+) breast cancer models
Authors: Teh Jessica , Bortolon Elizabeth , Pizzano Jennifer , Pannone Melissa , Landrette Sean , Gedrich Richard , Taylor Ian 
Published: April 2023

Abstract
ARV-471 is a selective, orally bioavailable PROteolysis-TArgeting Chimera (PROTAC®) small molecule that induces wild-type and mutant estrogen receptor (ER) alpha degradation via the ubiquitin-proteasome system. ARV-471 demonstrates superior ER degradation and antitumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER+ breast cancer patients. Dual pathway inhibition combining ER targeting agents with CDK4/6 or PIK3CA/mTOR pathway inhibitors is now a central strategy for treatment of advanced ER+ breast cancer. However, resistance to aromatase inhibitors resulting from ESR1 gene mutations, suboptimal ER degradation and the intramuscular route of administration of fulvestrant underscore a need for superior orally bioavailable endocrine therapy backbones for these combinations. Here, we assessed the effects of ARV-471 in combination with CDK4/6 or PIK3CA/mTOR pathway inhibitors in preclinical models of ER+ breast cancer. In vitro studies revealed evidence of synergistic interactions between ARV-471 and the CDK4/6 inhibitors abemaciclib and ribociclib, the mTOR inhibitor everolimus, or the PIK3CA inhibitors alpelisib and inavolisib in ER+ breast cancer cells. Evidence of synergistic effects between ARV-471 and everolimus was also observed in ER+ breast cancer cells expressing ER Y537S or D538G mutations. ARV-471 in combination with CDK4/6, PIK3CA or mTOR inhibitors led to tumor regressions in MCF7 xenografts when compared to single agents alone. ARV-471 also displayed greater anti-tumor activity in combination with abemaciclib, ribociclib or inavolisib than that observed with fulvestrant in combination with these agents. Taken together, these data suggest the potential utility of ARV-471 as a combination partner for clinically relevant targeted agents for treatment of early and late-stage ER+ disease.
Citation Format: Jessica Teh, Elizabeth Bortolon, Jennifer Pizzano, Melissa Pannone, Sean Landrette, Richard Gedrich, Ian Taylor. Enhanced efficacy of ARV-471, a novel PROTAC® estrogen receptor degrader, in combination with targeted agents in estrogen receptor-positive (ER+) breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3075.
Abstract 3243: Modulating the brain immune system to fight cancer in 3 dimensions
Authors: Yeini Eilam , Vaskovich-Koubi Daniella , Kleiner Ron , Florindo Helena F. , Satchi-Fainaro Ronit 
Published: April 2023

Abstract
Despite the remarkable efficiency of immune checkpoint modulators against primary and metastatic brain neoplasms, there is a low percentage of responders and clinical trials report severe immune-mediated side effects and disease relapse. An accumulated body of evidence show that non-tumor cells within the tumor microenvironment (TME), specifically the brain microenvironment (BME), including tumor vasculature and immune stromal cells, such as astrocytes, microglia and pericytes, dictate the overall therapeutic efficacy. We synthesized a biodegradable, off-the-shelf and cost-effective nano-sized polymeric platform that combines a cancer vaccine with the targeted inhibition of molecular and/or cellular immune suppressive players. These precision nano-sized medicines aim to re-educate and harness patient T-cell response against tumors, leading to an immunological memory able to control tumor relapse without any follow-up treatment. The design of these advanced peptide and RNA immunotherapeutics is guided by the identification of lead immune suppressor factors and tumor-specific antigens and proinflammatory cytokines using novel 3D bio-printed brain tumor-immune models developed in our lab. Using this unique model platform we identified P-selectin as a novel immune checkpoint in the brain regulating cancer cells-microglia and tumor-associated macrophages interactions. Combining a P-selectin inhibitor with our first nano-immunotherapy candidates sensitized brain malignancies mouse models to immune-checkpoint modulators, dramatically increasing disease-free survival rates.
Citation Format: Eilam Yeini, Daniella Vaskovich-Koubi, Ron Kleiner, Helena F. Florindo, Ronit Satchi-Fainaro. Modulating the brain immune system to fight cancer in 3 dimensions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3243.