bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB116: Prostaglandin F2 Receptor Negative Regulator (PTGFRN) is a novel target to inhibit tumor growth via antibody drug conjugate
Authors: Marquez Jorge , Dong Jianping , Dong Chun , Serrero Ginette 
Published: July 2021

Abstract
Introduction: Antibody-drug conjugates (ADC) are effective antibody-based therapeutics for a growing number of cancers, particularly hematopoietic and lymphoid tumors. There is need to identify new targets for ADCs, particularly for cancers with unmet needs. Methods: Our strategy has been to develop hybridoma libraries developed against cancer cells surface proteins and select antibody able to bind and internalize in cancer cell lines. Selected antibody can then be used for identification of the cancer cell surface target by immunoprecipitation (IP) and mass spectrometric analysis (Mass-spec), followed by target validation. After target validation, binding and target positivity can be tested by flow cytometry and western blot analysis on several cancer cell lines. The in vitro and in vivo efficacy of the antibody conjugated to a cytotoxic payload as ADC can then be evaluated with the target positive cancer cell lines.Results: Using the strategy described above, we have selected a monoclonal antibody named 33B7 able to bind and internalize in several cancer cell lines. The cell surface target binding 33B7 was identified by IP/Mass-spec as Prostaglandin F2 Receptor Negative Regulator (PTGFRN), a transmembrane protein in the Tetraspanin family. This target was then validated by showing that cells transfected with PTGFRN cDNA bound and internalized the antibody. Screening by Flow bidning and by western blot identified several human cancer cells lines expressing PTGFRN. In vitro treatment of these cell lines with the 33B7-saporin ADC inhibited their proliferation in a dose-dependent fashion. 33B7 conjugated to saporin was also able to block tumor growth in vivo in mouse xenografts when compared to a control ADC. Conclusion: These findings show that screening antibody libraries for internalizing antibodies in cancer cell lines is a good approach to identify new cancer targets for ADC development. These results suggest PTGFRN is a possible therapeutic target via antibody-based approach for certain cancers. The elucidation of PTGFRN role in cancer cells, particularly in possibly mediating metastasis is presently being carried out.
Citation Format: Jorge Marquez, Jianping Dong, Chun Dong, Ginette Serrero. Prostaglandin F2 Receptor Negative Regulator (PTGFRN) is a novel target to inhibit tumor growth via antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB116.
Abstract LB122: The complete estrogen receptor antagonist (CERAN) OP-1250 shrinks ER+ brain metastases in an intracranial xenograft tumor model expressing mutant ESR1
Authors: Hodges-Gallagher Leslie , Parisian Alison D. , Sun Richard , Myles David C. , Klein Pamela M. , Harmon Cyrus L. , Kushner Peter J. 
Published: July 2021

Abstract
Estrogen receptor-positive (ER+) breast cancer can undergo metastatic spread to the brain, which occurs in up to 15% of HER2-/ER+ metastatic breast cancer patients. Although endocrine therapy is not explicitly approved for brain metastasis and clinical trials are lacking, anecdotal reports of clinical responses by endocrine agents motivate further investigation. One such agent is the ER antagonist tamoxifen, which has previously been shown to reach high levels in brain tissue and ER+ brain metastases in patients with breast cancer*. We previously reported that OP-1250, a novel, oral complete ER antagonist (CERAN), penetrates the brain and is efficacious at shrinking tumors in a xenograft brain metastasis model in which patient derived human ER+ tumors were intracranially transplanted into immunocompromised mice**. Here we compare the ability of OP-1250 to shrink brain tumors in this model with tamoxifen and other agents. Whereas tamoxifen indeed had therapeutic effects in this brain xenograft model, the effect was not as profound as that of OP-1250, which was able to completely clear the tumors in many animals, as determined by MRI.
* Lien et al. Distribution of tamoxifen and metabolites into brain tissue and brain metastases in breast cancer patients. Br. J. Cancer, 1991, 63, 641-645.**Hodges-Gallagher, et al. OP-1250 a complete estrogen receptor antagonist that penetrates the brain and prevents lethality from an intracranial xenograft tumors expressing mutant ESR1, abstract, AACR 2020
Citation Format: Leslie Hodges-Gallagher, Alison D. Parisian, Richard Sun, David C. Myles, Pamela M. Klein, Cyrus L. Harmon, Peter J. Kushner. The complete estrogen receptor antagonist (CERAN) OP-1250 shrinks ER+ brain metastases in an intracranial xenograft tumor model expressing mutant ESR1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB122.
Abstract LB158: Implications of Targeting Novel Pathways in Exhausted T Cells for Immuno-Oncology Therapeutic Intervention
Authors: McPherson Rhoanne , Acklam Francis , Hay Joanne , Barbour Mark , Grant Courtney , Singh Preeti , Gambardella Adriana , Rzepecka Justyna , Anderton Stephen , Gooding Hayley 
Published: July 2021

Abstract
The induction of CD8+ T cell exhaustion, driven by the tumor microenvironment, is thought to be a major mechanism by which tumors can escape immune surveillance and are able to persist and progress. T cell exhaustion is typically characterized by the expression of co-inhibitory markers such as PD-1, LAG-3 and TIM-3 and a reduced capacity for pro-inflammatory cytokine production. Whilst treatment with therapeutics targeted at checkpoint inhibitors, such as Nivolumab (anti-PD-1), have shown great promise in the treatment of a subset of individuals and tumor types, resistance to these approaches is prevalent. As such, novel approaches are required in order to provide alternative options for the rescue of T cell exhaustion and cancer treatment.
Here we describe the characteristics of an in vitro human T cell exhaustion assay whereby in vitro stimulated T cells phenotypically and functionally recapitulate the exhausted T cells found within the tumor microenvironment and where exhaustion can be partially rescued by treatment with anti-PD-1. Furthermore, we demonstrate the effect of treatment with an inhibitor of a novel target identified in exhausted T cells on T cell function; both through analysis of pro-inflammatory cytokine production and the ability to kill tumor cells. These assays and approaches enable investigation into the ability of compounds to influence reversal of T cell exhaustion where anti-PD-1 treatment does not fully reverse the exhausted phenotype and offers the ability to test combination therapy approaches.
Citation Format: Rhoanne McPherson, Francis Acklam, Joanne Hay, Mark Barbour, Courtney Grant, Preeti Singh, Adriana Gambardella, Justyna Rzepecka, Stephen Anderton, Hayley Gooding. Implications of Targeting Novel Pathways in Exhausted T Cells for Immuno-Oncology Therapeutic Intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB158.
Abstract LB176: Anti-4-1BB x PD-1, a bispecific anti-cancer therapeutics
Authors: Kwon Byoung S. , Lee Hanna , Park Jin Sung , Oh Yeonji , Han SeungHee , Choi Jin Kyung , Hwang Bora , Im Sun Woo , Lee Seunghyun , Jeh HoonSung 
Published: July 2021

Abstract
4-1BB and PD-1 are both T cell costimulatory receptors/immune checkpoint regulators. 4-1BB/4-1BBL provides stimulatory signals while PD-1/PD-L1, suppressive ones to T lymphocytes. Various forms of agonists to 4-1BB or blockers to PD-1 have shown a potent anti-cancer activity by modulating mainly CD8+ T cells. Thus, synergistic or additive anti-cancer effect may be achieved by combining the agonists to 4-1BB and blockers to PD-1. We have tested various combinations of antibodies and proteins with consideration of overall size of the therapeutic candidates. The best anti-cancer activities were obtained by combination of an agonistic anti-4-1BB antibody and soluble PD-1 that binds to PD-L1 with high affinity. To obtain molecularly-evolved PD-1 we first used the 3D complex between PD-1 and PD-L1 to select the major contributing PD-1 amino acids, a library targeting selected amino acids and random mutations were constructed and screened using yeast surface display. The affinity-matured resulting PD-1 is called euPD-1. We finally constructed EU505 that composed of a scFv of anti-4-1BB and euPD-1. Through cell binding and dual antigen assays, we confirmed that EU505 binds both targets independently at the same time. The result of 4-1BB bioassays, a biologically relevant MOA-based assay, showed that potent PD-L1-dependent T cell activation with EU505. In-vitro killing assays showed that EU505 selectively activated T cells which in turn killed high PD-L1-expressing cells, but not low-PD-L1-expressing ones. EU505 demonstrated much stronger tumor-killing effect compared with each component alone when we tested against human PD-L1-expressing tumor cells in a 4-1BB Knock-in mouse model. Furthermore, it was observed that number of effector CD8+ T cells increased in the peripheral blood upon EU505 injection and consequently tumor size was reduced. EU505, a promising anti-cancer drug, appears to enhance CD8+ T cell infiltration and activate T cells in situ at the tumor sites by binding two different targets of 4-1BB and PD-L1 simultaneously.
Citation Format: Byoung S. Kwon, Hanna Lee, Jin Sung Park, Yeonji Oh, SeungHee Han, Jin Kyung Choi, Bora Hwang, Sun Woo Im, Seunghyun Lee, HoonSung Jeh. Anti-4-1BB x PD-1, a bispecific anti-cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB176.
Abstract LB177: Targeting SIRPα with APX701, a Novel Myeloid Checkpoint Inhibitor
Authors: Alvarado Ryan , Krishnan Sushma , Srivastava Minu K. , Tan Christine , Huang George , Jalgaonkar Swati , Bahjat Frances R. , Filbert Erin L. , Yang Xiaodong 
Published: July 2021

Abstract
Therapeutically targeting tumor myeloid cells has emerged as a complementary strategy to existing cancer immunotherapy approaches. The interaction of tumor-expressed CD47 with SIRPα (Signal Regulatory Protein-α, SIRPA) on macrophages, dendritic cells, and neutrophils inhibit key immune effector mechanisms. Targeting the SIRPα-CD47 axis represents a novel approach to enhance anti-tumor immunity by augmenting or reactivating critical tumor clearance mechanisms. While agents that target CD47 have shown promise in clinical trials, they present hematological toxicities and antigen sink issues that narrow their therapeutic application. Our approach targets SIRPα to focus on relevant mechanisms related to myeloid cell activation and increase of tumor cell phagocytosis while simultaneously avoiding the undesired effects of targeting CD47. Furthermore, SIRPγ, a close relative of SIRPα, is expressed on T cells and potentially co-stimulates T cell proliferation and is required for trans-endothelial T cell migration. We sought to develop an anti-SIRPα therapeutic that does not cross-react with SIRPγ and avoids potentially deleterious effects on T cell functions. Here, we describe APX701, a novel anti-SIRPα antibody generated using Apexigen's APXiMAB™ proprietary antibody discovery platform, and its differentiated properties as compared to other approaches targeting the SIRPα-CD47 interaction. APX701 binds to human SIRPα at a unique epitope with high affinity (Kd = 0.95nM) and with no detectable binding to SIRPγ expressed on primary human T cells. APX701 strongly binds to the major SIRPα variants—V1 and V2—and potently blocks their interaction with CD47, thereby allowing therapeutic targeting of SIRPα in a majority of patients. APX701 reverses SIRPα-mediated suppression of macrophage phagocytosis, resulting in potent destruction of a variety of tumor cells both as a single agent and in combination with anti-TAA (tumor associated antigen) antibodies including cetuximab, rituximab, and trastuzumab. Moreover, targeting SIRPα with APX701 does not interfere with T cell function, an effect previously observed following anti-CD47 treatment. Together, these data demonstrate the unique binding profile of APX701 and its ability to potently reactivate myeloid cell-mediated anti-tumor immunity. Our data support the development of APX701, a promising myeloid checkpoint inhibitor, for the treatment of cancer.
Citation Format: Ryan Alvarado, Sushma Krishnan, Minu K. Srivastava, Christine Tan, George Huang, Swati Jalgaonkar, Frances R. Bahjat, Erin L. Filbert, Xiaodong Yang. Targeting SIRPα with APX701, a Novel Myeloid Checkpoint Inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB177.
Abstract LB183: Erythritol acts as tumor enhancer and suppressor depending on concentrations in brain tumor cell lines
Authors: Nassani Rayan , AlAmri Hassan , Alrfaei Bahauddeen M. 
Published: July 2021

Abstract
Erythritol (ERT) is a simple four-carbon sugar alcohol, that is produced endogenously via pentose phosphate pathway from glucose in all human cells mainly erythrocytes with a plasma level of ∼9.8 μM. It can be obtained exogenously from diets as an FDA-artificial sweetener. It possesses hydroxyl groups that are responsible for hydroxyl radical scavenging effect (antioxidant property). Recent studies have pointed out an ERT protection based on concentration dependant effect on endothelial cells. The protection includes surviving death under high glucose conditions in diabetic patients. In addition, ERT has been reported in pre-diagnostic serum samples of glioblastoma patients, which was elevated. It was not known whether ERT elevation was defensive or harmful. We studied the cytotoxic activity of ERT on brain tumor cell lines (U87, Daoy) using metabolic activity assay (MTT) with different erythritol concentrations. We observed that on high concentrations (2.87 M, 1.43 M, 0.72 M), there was a significant growth inhibition (P&lt;0.05). On the other hand, lower concentrations (0.36 M, 8 mM, 4 mM, 2 mM, 0.8 mM, 36 µM, 8.2 µM, 4.1µM, 8.2nM), showed growth enhancement. ERT is known with its antioxidant effect in a concentration dependent manner. Therefore, we studied the antioxidant activity of ERT using ROS-Glo H2O2 Assay. We observed that on the high concentrations of ERT there was a significant decrease in hydrogen peroxide concentration to less than 50%, this suggests that ERT has antioxidant effect against hydrogen peroxide. In contrast, low ERT concentrations (around physiological level) showed significant enhancement to tumor growth (P&lt;0.05). In conclusion, we found that erythritol plays an important role in brain cancer development and hydrogen peroxide regulation through a concentration dependant manner. Since ERT is found normally in human plasma, controlling ERT concentration will grant ERT the ability to work as therapeutic enhancer for brain cancer treatment or even a biomarker for prognosis.
Citation Format: Rayan Nassani, Hassan AlAmri, Bahauddeen M. Alrfaei. Erythritol acts as tumor enhancer and suppressor depending on concentrations in brain tumor cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB183.
Abstract LB196: Comparison of whole exome sequencing and targeted sequencing in patients with advanced bladder cancer
Authors: Chawla Neal Shiv , Zengin Zeynep , Govindarajan Ameish , Pal Sumanta K. 
Published: July 2021

Abstract
Background: Next generation sequencing (NGS) to identify genomic alterations (GAs) in tumor samples are increasingly used in clinical practice. Targeted sequencing (TS) or whole exome sequencing (WES) are used by various commercially available platforms. Differing methods often result in poor inter-reproducibility, even when testing the same tissue. Bladder cancer has substantial genetic heterogeneity as compared to many other malignancies. The purpose of this study is to compare WES and TS in bladder cancer. Methods: Patients with advanced bladder cancer who had undergone tissue WES (GEM ExTra®) or TS (FoundationOne CDx® [FMI]) in the course of routine clinical care were assessed. Genes with at least one detected GA were selected, with others excluded. All detected GAs were classified as being detected on TS only, WES only, concordant (detected on both platforms), or partially concordant (different GAs detected within the same gene). Variants of uncertain significance were excluded for this study. Results: In our series, 25 patients had WES and 42 patients had TS - 14 patients (21%) had both tests performed. A total of 88 genes were detected to have at least one GA across all samples. Of all detected GAs, 66/162 (41%) were concordant, with 45/162 (28%) and 51/162 (31%) of GAs detected exclusively by WES and TS, respectively. The genes with the highest proportion of concordance when detected, were TERT (70%), TP53 (85%) and ARIDA1A (50%). SOX4 and E2F3 were detected on WES only, while RBM and CHEK2 were detected on TS only. Notably, six TP53 GAs were detected exclusively on TS. TP53, TERT, MLL2/KMT2D, ERBB2 were each partially concordant on one occasion. The difference in the rate of concordant GAs in samples from the same collection site and date (41%), as compared to those in which both differed (35%) were not statistically significant (p=0.54). Conclusions: Although the majority of GAs identified were concordant, each platform exclusively identified GAs with varying clinical significance. SOX4 and E2F3 mutation, shown to correlate with invasive potential in bladder cancer, were detected exclusively on WES. In contrast, RBM and CHEK2 (of known significance in melanoma and breast cancer) were found exclusively on TS. Larger series are needed to further establish the concordance of these approaches.
Citation Format: Neal Shiv Chawla, Zeynep Zengin, Ameish Govindarajan, Sumanta K. Pal. Comparison of whole exome sequencing and targeted sequencing in patients with advanced bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB196.
Abstract LB198: Inhibition of the RAC Activator VAV3 by the small molecule IODVA1 impedes RAC signaling & overcomes resistance to tyrosine kinase inhibition in lymphoblastic leukemia
Authors: Nassar Nicolas N. , Hegde Shailaja , Wunderlich Kark , Lin Yuan , Ahmadian Reza , Seibel William , Zheng Yi , Mizukawa Benjamin E. , Vinnedge Lisa Privette , Cancelas Jose A. 
Published: July 2021

Abstract
Aberrant activation of RHO guanine nucleotide exchange factors (RhoGEFs) is a chief mechanism driving abnormal activation of their RhoGTPase targets in transformation and tumorigenesis. Consequently, a small molecule inhibitor of RhoGEF activities can be used as an anti-cancer drug. Herein, we used cellular, mouse, and humanized models of RAC-dependent BCR-ABL1-driven and Ph-like lymphoblastic leukemia to identify VAV3, a tyrosine phosphorylation-dependent RacGEF, as the target of the small molecule IODVA1. We show that IODVA1 binds tightly to VAV3, inhibits RAC activation and signaling, and increases pro-apoptotic activity in BCR-ABL1-transformed cells only. Consistent with this mechanism of action, both VAV3-deficient leukemic cells and mouse models of BCR-ABL1 leukemia do not respond to IODVA1. IODVA1 eradicates leukemic propagating activity of TKI-resistant BCR-ABL1(T315I) B-ALL cells after treatment withdrawal by decreasing RAC signaling in vivo. Importantly, IODVA1 is superior to standard of care dasatinib and ponatinib at prolonging the survival of PDX models of relapsed pediatric Ph+ and TKI-resistant Ph+ B-ALL with commonly found genetic mutations especially after treatment withdrawal. Cells representing pediatric ALL patients with diverse genetic lesions are highly sensitive to IODVA1 ex vivo and this sensitivity is VAV3-dependent. IODVA1 thus spearheads a novel class of drugs that inhibits a RacGEF and holds promise as an anti-tumor therapeutic agent.
Citation Format: Nicolas N. Nassar, Shailaja Hegde, Kark Wunderlich, Yuan Lin, Reza Ahmadian, William Seibel, Yi Zheng, Benjamin E. Mizukawa, Lisa Privette Vinnedge, Jose A. Cancelas. Inhibition of the RAC Activator VAV3 by the small molecule IODVA1 impedes RAC signaling & overcomes resistance to tyrosine kinase inhibition in lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB198.
Abstract LB200: A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adeno carcinoma
Authors: Gopalan Vishaka , Singh Arashdeep , Rashidi Farid , Wang Li , Ruppin Eytan , Arda Efsun , Hannenhalli Sridhar 
Published: July 2021

Abstract
The stochasticity of transcription leads to phenotypic variation within a clonal population. This means that within a healthy tissue, a fraction of cells could assume an “edge” transcriptional state that is primed for a transition toward malignancy. We find such an edge transcriptional state amongst acinar cells in a publicly available PDAC single-cell RNA-seq dataset. These acinar edge cells (AE) cells have transcriptomes that are highly diverged from a typical normal acinar cell, and show transcriptional similarities to pancreatic ductal adenocarcinoma (PDAC).
The AE state can be found in several single-cell datasets from healthy human pancreatic tissue. The AE state is not mutationally-driven as AE cells in healthy tissues do not possess any known oncogenic driver mutations, nor are they clonally derived. The transition from a non-edge acinar to an AE state recapitulates key aspects of pancreatic biology; genes associated with this transition are enriched for known markers of acinar de-differentiation and acinar-ductal metaplasia. Further, the AE state represents a partial reversion to a SOX9+PTF1A+ multi-potent embryonic pancreatic progenitor state, likely through the activation of KLF5, HES1 and RBPJ targets. Remarkably, the promoters of genes upregulated in the AE state are significantly hypomethylated in PDAC relative to normal pancreas, while the genes up-regulated in the AE state are up-regulated in PDAC samples in the Cancer Genome Atlas (TCGA) database. It is thus likely that transcriptomic changes in the edge state are fixed epigenetically during tumor initiation and progression. A gene signature derived from the AE cells shows strong association with survival among PDAC patients. Remarkably, we also find that the fraction of AE cells in the healthy pancreas increases with age, which points to a strong non-genetic and transcriptomic component to the known increase in PDAC risk with age.
We also observed edge-like transcriptomic heterogeneity among alveolar, ciliated and club cells in the human lung, and amongst hepatocytes in liver tissues. This suggests that, across tissues, gene expression heterogeneity can lead to sub-populations of healthy cells across tissues existing in pre-malignant states.
Citation Format: Vishaka Gopalan, Arashdeep Singh, Farid Rashidi, Li Wang, Eytan Ruppin, Efsun Arda, Sridhar Hannenhalli. A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adeno carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB200.