bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 343: New derivatives of 1,3-dioxoisoindoline: Potential breast cancer therapeutics that are S6K1 inhibitors
Authors: Kumar Satyendra , Komati Rajesh , Shaik Shahensha , Bratton Melyssa , Tran Linh , Sam Rion , Johnson-Henderson Elijah , Graham Breyanah , WIlliams Christopher , Sridhar Jayalakshmi 
Published: June 2022

Abstract
Currently, more than 3.8 million women in the United States are diagnosed with breast cancer which is the second leading cause of cancer-related death in women. The correlation of the ribosomal protein S6 kinase 1 (S6K1) activity and breast cancer is evident from the amplification of S6K1 localized chromosomal region 17q23 in 20% of primary breast cancers. S6K1 is a conserved serine/threonine protein kinase, is the principal kinase effector downstream of the PI3K/mTOR regulatory signaling pathway. Over-expression of S6K1 has been associated with cell transformation and elevated proliferation rates in tumors, poor prognosis and an increased risk of local recurrence. S6K1 has been found to play an important role in the progression of ER-positive (ER+) breast cancer, HER2 positive (HER2+) breast cancer and node-negative premenopausal breast cancer. Inhibition of this kinase can prove to be beneficial for the treatment of several types of breast cancer. Our group has identified new molecules that are derivatives of 6-amido-4-aminoisoindoline-1,3-dione core structure as S6K1 inhibitors with low micromolar inhibition potency (IC50 = 2-5 μM). These compounds also inhibited the growth of HER2+ (SKBR3 and HER2Δ16), ER+ and triple negative breast cancer cells (MDA-MB-231 and MDA-MB-468) with a range of EC50 values (2 - 2000 μM). The EC50 values of growth inhibition of these compounds varied by the type of breast cancer cells and were in direct correlation with the expression levels of S6K1 in those cell lines. These results clearly indicate that high efficacy S6K1 inhibitors can function as potential therapeutics for multiple types of breast cancer. Future work involves in-vivo studies to understand the efficacy and pharmacokinetics of the three compounds.
Citation Format: Satyendra Kumar, Rajesh Komati, Shahensha Shaik, Melyssa Bratton, Linh Tran, Rion Sam, Elijah Johnson-Henderson, Breyanah Graham, Christopher WIlliams, Jayalakshmi Sridhar. New derivatives of 1,3-dioxoisoindoline: Potential breast cancer therapeutics that are S6K1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 343.
Abstract 3432: A novel anti-CLDN6-CD137 bispecific antibody (NBL-028) for treating Claudin 6 positive solid tumors
Authors: Yu Raymond , Tong Yong , Lu Huarui , Danton Makenzie , Dillman Samantha , Dewe Joshua , Karchin Joshua , Patil Samruddhi , Lavery Danielle , Huang Haichun , Pei James , Liu Zhong , Li Han , Lei Ming 
Published: June 2022

Abstract
Claudin-6 is a tetraspan membrane protein associated with tight junction formation. Its expression in normal tissues is restricted to the fetal organs but is not detected in the adult tissues. Increased expression of CLDN6 has been shown in several human malignancies such as testicular, ovarian, uterine, liver and lung adenocarcinoma, and is associated with poor prognosis in these cancer patients. Therefore, CLDN6 is a promising tumor-associated antigen (TAA) for tumor-targeting therapeutics such as CART and T cell engaging bispecific antibodies. CD137 co-stimulation has been reported to lead to extended T-cell proliferation, reactivating anergic T cells, promoting memory T cell formation and maintenance. Activating CD137 with agonistic antibodies presents a great opportunity to improve the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or overcome resistance to ICIs. Additionally, a bispecific antibody that activates CD137 signaling only in the presence of TAA would help reduce the dose-dependent hepatotoxicity that was observed in clinical trials with monoclonal anti-CD137 agonistic antibody due to the activation of CD137 signaling in liver resident Kupffer cells. NBL-028 is a novel tetravalent bispecific antibody uniquely designed to activate the CD137 co-stimulatory pathway in the tumor microenvironment through the CLDN6-mediated clustering of CD137. NBL-028 binds to Claudin 6 with high affinity and specificity, activates CD137 in a CLDN6-dependent manner with fast-on and fast-off CD137 binding properties. NBL-028 demonstrated strong CLDN6-dependent T-cell activation and T-cell mediated cytotoxicity in vitro. NBL-028 elicits potent anti-tumor effects and immunological memory in mouse models without detectable liver damages or systemic toxicity. The tumor infiltrated Lymphocyte (TIL) analysis also demonstrated that NBL-028 treatment induced CD45+ immune cells infiltration, decreased Treg/CD8 ratio and increased M1/M2 like macrophage ratio. Furthermore, NBL-028 is designed upon a proprietary molecular scaffold with superior developability features, demonstrated by stability, yield and ease to purify. NBL-028 is currently at the stage of IND-enabling activities with the aim to enter clinical studies for treating Claudin 6 positive solid tumors in 1Q 2023.
Citation Format: Raymond Yu, Yong Tong, Huarui Lu, Makenzie Danton, Samantha Dillman, Joshua Dewe, Joshua Karchin, Samruddhi Patil, Danielle Lavery, Haichun Huang, James Pei, Zhong Liu, Han Li, Ming Lei. A novel anti-CLDN6-CD137 bispecific antibody (NBL-028) for treating Claudin 6 positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3432.
Abstract 3437: Characterization of a potent and selective A2aR monoclonal antibody antagonist for the treatment of cancer
Authors: Hu Changyun , Zhang Jiandong , Liu Shuying , Zhao Xinyan 
Published: June 2022

Abstract
Introduction: Adenosine-mediated suppression of anti-tumor immunity has been shown to be one of the mechanisms for immunosuppression and resistance to immune checkpoint blockade (ICB) therapies such as anti-PD-1 or anti-PD-L1 monoclonal antibodies (mAbs). Therapeutic candidates (biologics and small molecule inhibitors(SMIs)) targeting ectonucleotidases CD39 and CD73, enzymes responsible for hydrolyzing ATP to adenosine, and SMIs targeting adenosine receptors are currently under active preclinical and early clinical development. Here we present the characterization of a novel, selective anti-human A2aR antagonist mAb that showed high potency in inhibiting adenosine mediated immunosuppressive functions to enhance anti-tumor immunity.
Methods: A panel of mAbs binding to human adenosine receptor A2aR (hA2aR) were generated via hybridoma technology. The specificity and cross-reactivity were measured by FACS using human A1R, A2aR, A2bR, A3R or mouse A2aR over-expressing cells, as well as human and cynomolgus monkey PBMC. The cellular potency of these mAbs was assessed by measuring decreased cAMP levels in engineered HEK293 cells stably over-expressing hA2aR, a Gs protein coupled receptor (GPCR), upon stimulation with agonist NECA. The ability of lead candidate AT-004 to reverse adenosine-mediated immune suppression of human CD8 T-cells was determined using standard CD3/CD28 activation conditions. The in vivo efficacy of humanized AT-004 is being evaluated using ICB treatment resistant solid tumor mouse models.
Results: AT-004 represents a panel of novel, selective mAbs. These mAbs specifically bind to human A2aR, but not to family members including A1R, A2bR and A3R. Cross-reactivity to cynomolgus monkey PBMCs was also observed. AT-004 inhibited NECA-mediated A2aR activation with a potency over 100-fold higher than SMIs e.g. AZD4635. AT-004 significantly reversed the ability of adenosine to suppress CD8 T cell activation as indicated by restoration of cell surface marker expression and increased levels of cytokines such as IFN-γ in the supernatants.
Conclusions: AT-004 is a potent, selective and highly potent antagonist of A2aR receptor. Considering its potential safety advantage as an mAb comparing to most known A2aR SMI antagonists in that it does not cross the blood brain barrier, AT-004 maybe a promising novel therapeutic candidate for immunotherapy, vital for enhancing anti-tumor responses in solid tumors that show an incomplete response or resistance to anti-PD-1 or anti-PD-L1 mAb treatment due to elevated adenosine level in tumor microenvironment (TME).
Citation Format: Changyun Hu, Jiandong Zhang, Shuying Liu, Xinyan Zhao. Characterization of a potent and selective A2aR monoclonal antibody antagonist for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3437.
Abstract 3440: Novel in vitro TME platform for rapid cancer therapeutic and target discovery
Authors: Matre Polina R. , Choi Byung-Kwon , Delgado Oliver , Westwick John K. 
Published: June 2022

Abstract
The tumor microenvironment (TME) plays an important role in malignances as tumors react with a multitude of changes and microenvironmental cues. TME components modulate tumor profiles and treatment responses, thereby affecting sensitivity to anti-cancer agents. The limited clinical success of therapeutics, including immunotherapies, emphasizes an unmet need to identify new targets and develop preclinical platforms to accelerate anti-cancer drug discovery. Although in vitro methods are essential in early drug development, standard approaches, which do not capture the complexity of TME, have been historically favored for both discovery and evaluation of potential therapeutics.
Resonant's IMPACT TME platform couples proprietary high-fidelity TME models with deep data-driven analytics for rapid and cost-effective discovery of novel targets and antibody-based therapeutics. Target and candidate selection is based upon a biology-forward approach driven by live animal immune systems and functional screening prior to target identification. Identified candidates are then prioritized via integration of publicly available information with internal functional and multi-omic data. Resultant targets display attributes, such as tumor selectivity and immune-modulatory capabilities, that are amenable to several therapeutic modalities, including antibody-drug conjugates (ADCs) and bispecifics. To date, Resonant has interrogated a variety of solid tumor types and thousands of candidates resulting in an expanding library of actionable antibodies and targets. Representative examples of in vitro and in vivo efficacy of selected candidates derived from the IMPACT TME platform are presented, highlighting their individual potential and validating the Resonant approach. As technological advances transform the landscape of therapeutics, the need for novel targets is burgeoning, and Resonant’s TME-driven platform provides a valuable tool to meet these demands.
Citation Format: Polina R. Matre, Byung-Kwon Choi, Oliver Delgado, John K. Westwick. Novel in vitro TME platform for rapid cancer therapeutic and target discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3440.
Abstract 347: Comparative activity of MBQ-167 metabolites in metastatic breast cancer
Authors: Medina Julia I. , Hernández Eliud , Vlaar Cornelis , Dharmawardhane Suranganie 
Published: June 2022

Abstract
Metastasis continues to be the most difficult phase for cancer treatment due to few targeted therapy options. Therefore, we focus on targeting the Rho GTPases Rac1 and Cdc42, key drivers of the primary steps of metastasis: cell migration and invasion. We developed MBQ-167 as a small molecule dual inhibitor for Rac1 and Cdc42 activation with IC50s of 103 and 78 nM, respectively. In metastatic human breast cancer cells, MBQ-167 inhibits the Rac/Cdc42 downstream effector p21-activated kinase (PAK)/LIM kinase/Cofilin signaling, lamellipodia extension, and thus, cell polarity, and migration. In addition, in metastatic breast cancer cells, MBQ-167 inhibits cell proliferation and cell cycle progression to ultimately induce apoptosis via anoikis. MBQ-167 inhibits tumor growth and metastasis in experimental and spontaneous HER-positive and Triple negative breast cancer (TNBC) mouse models. MBQ-167 has 35% bioavailability and is not toxic in rodent or canine models up to 1000 mg/kg. Therefore, we are further developing MBQ-167 as a lead anti metastatic cancer compound. The objective in this study is to elucidate potential activity of MBQ-167 metabolites. Prior work has identified MBQ-167 metabolites via LC MS/MS from a mammalian liver microsome (rats and human) assay. Four of the MBQ-167 metabolites with the highest MS peak area, were analyzed in metastatic breast cancer cell lines, for cell viability via MTT assays and apoptosis via caspase 3/7 assays. We report that the metabolites M6, M7, M8, and M9 did not inhibit cell viability or induce apoptosis at 250 or 500 nM in HER2-type MDA-MB-435, and TNBC MDA-MB-231 and MDA-MB-468 breast cancer cell lines, compared to MBQ-167. We next analyzed whether these metabolites could inhibit the activation of Rac and Cdc42 by analyzing the phosphorylation status of its downstream effector p-21 activated kinase isoforms 1/2/3 (PAK1/2/3). When MBQ-167 and metabolites at 250nM were incubated for 24h in HER2-type MDA-MB-435 metastatic cancer cells, and the lysates western blotted with antibodies to total PAK1/2/3 or phospho-Pak1/2/3, we found a decrease in the phosphorylation levels of PAK in response to MBQ-167 and metabolite M6. However, since the peak area of M6 in the microsome assay is only 6% compared to MBQ-167, we conclude that MBQ-167 is the major active compound with anti-metastatic cancer properties.
Citation Format: Julia I. Medina, Eliud Hernández, Cornelis Vlaar, Suranganie Dharmawardhane. Comparative activity of MBQ-167 metabolites in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 347.
Abstract 3507: β-Hydroxy-β-methylbutyrate (HMB) sensitizes murine pancreatic ductal adenocarcinoma (PDAC) to immunotherapy
Authors: Etigunta Suhas K. , Coleman Michael F. , Liu Kristyn A. , Pfeil Alex J. , Cui Zhengrong , Hursting Stephen D. 
Published: June 2022

Abstract
Background: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. PDAC often presents at advanced tumor stages, resulting in poor survival rates. Immunotherapies such as inhibition of programmed death 1 (PD1) are effective in many cancers, but not in PDAC. HMB is a leucine metabolite that reduces PDAC progression and cachexia in association with enhanced antitumor immune responses. The purpose of this study was to determine if HMB treatment enhances immunotherapeutic response in PDAC.
Methods: C57BL/6J mice bearing subcutaneously transplanted PANC02 tumors were fed either a control (AIN93G) or HMB (1% w/w) supplemented diet. Once tumors were palpable, mice were randomized for treatment with vehicle or anti-PD1 immunotherapy (n=12-13/group). Tumors were harvested and global transcriptomic analysis was performed.
Results: Both HMB and anti-PD1 interventions alone were insufficient to reduce tumor growth. However, the combination of HMB and anti-PD1 resulted in significantly smaller tumors than the anti-PD1 alone group, indicating that HMB was able to stimulate PDAC response to ICI. Transcriptomic analysis revealed limited transcriptional effects attributable to immunosurveillance following treatment with either HMB or anti-PD1 alone; however, the combination produced a robust antitumor immune response. Digital cytometry analysis revealed altered immune cell composition in the tumor microenvironment.
Conclusion: The combination of HMB with anti-PD1 treatment elicited significant antitumor responses in a murine model of PDAC progression. Given that immunotherapy trials in PDAC have not yet proven effective, even when combined with cytotoxic chemotherapy, our preclinical findings support clinical evaluation of combined ICI and HMB regimens as a therapeutic strategy against PDAC.
Citation Format: Suhas K. Etigunta, Michael F. Coleman, Kristyn A. Liu, Alex J. Pfeil, Zhengrong Cui, Stephen D. Hursting. β-Hydroxy-β-methylbutyrate (HMB) sensitizes murine pancreatic ductal adenocarcinoma (PDAC) to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3507.
Abstract 3526: Host genetic susceptibility to gut microbiota-driven colorectal carcinogenesis
Authors: Vera-Urbina Ibis R. , Ayala Estefania , Rodriguez Ediel , Centeno-Girona Hilmaris , Casiano Leslie , Suarez Belisa , Cruz-Correa Marcia , Gonzalez-Pons Maria 
Published: June 2022

Abstract
Introduction: Colorectal cancer (CRC) is the 1st and 2nd leading cause of cancer death in men and women in Puerto Rico and the U.S., respectively. A dynamic balance between the host immune system and the gut bacterial communities is essential to protect colonic tissues against chronic inflammation, which may lead to CRC. The main goal of this study was to investigate if SNPs in the promoter regions of the IL-1β, IL-6 and IL-10, key cytokines that regulate gut inflammation, increase the risk for colorectal adenomas by enriching a subset of the toxin-producing gut microbiota (gene-environment interaction).
Methods: Using a case-control study design, associations between having pro-inflammatory SNPs and/or bacterial toxins in colonic mucosa or stool were assessed using odds ratios. TaqMan® SNP Genotyping Assays (ThermoFisher Scientific) for IL- 1β (rs1143627), IL-6 (rs1800795), and IL-10 (rs1800871) were performed according to the manufacturer’s recommendations. The presence of bacterial toxin genes (pks, TcPC, GelE, cnf-1, CDT, murB, and usp) in stool were determined using the QuantiTect SYBR Green PCR kit (QIAGEN).
Results: Our preliminary analyses showed that individuals with the IL-1β pro-inflammatory genotype were 1.5-times more likely to have colorectal adenomas (n=232; p=0.1). Detection of usp or pks in stool (n=147) was positively associated with having adenomas (OR=2.95; CI 95%= 0.92-9.45 and OR=2.91; CI 95%=0.58-14.50, respectively).
Conclusion: An evaluation of the association between having pro-inflammatory genotypes, the presence of bacterial toxin genes in stool, and colorectal adenomas using a larger sample size is warranted and currently underway. The integration of modifiable (e.g. gut bacterial toxins) and non-modifiable (e.g. host genetics) risk factors in a stratified model for CRC risk stratification and/or prevention may enhance current screening approaches.
Citation Format: Ibis R. Vera-Urbina, Estefania Ayala, Ediel Rodriguez, Hilmaris Centeno-Girona, Leslie Casiano, Belisa Suarez, Marcia Cruz-Correa, Maria Gonzalez-Pons. Host genetic susceptibility to gut microbiota-driven colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3526.
Abstract 3530: Microbial-Interleukin 17 receptor A (IL-17RA) signaling axis modulates tumor growth and microenvironment
Authors: Chandra Vidhi , Zhang Yu , Roux Olivereen Le , Petrosino Joseph , Kolls Jay , McAllister Florencia 
Published: June 2022

Abstract
Microbiota, both within the gut and the tumors, has emerged as a significant player influencing tumor growth and responses to therapies. Recent evidence links microbiota and pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer surrounded by a highly immuno-suppressive tumor microenvironment which limits efficacy of most available therapies. The immunosuppressive tumor microenvironment of PDAC is partially facilitated by a proinflammatory cytokine Interleukin 17 (IL-17). IL-17 can be stimulated by intestinal commensal bacteria under normal physiological conditions. It is critical for microbial defense as well as immunopathology. Both IL-17 neutralization and antibiotics reduce murine PDAC growth. While the vital role of microbiota in affecting tumor immunity has been identified, there is still a gap of knowledge as to how microbes may regulate pro-tumorigenic IL-17 signaling. We wanted to investigate the systemic and local role of IL-17 in regulating the microbial-tumor immune axis. For this purpose, we genetically deleted the IL-17 receptor A (IL-17RA) in different compartments and evaluated tumor growth. We found that IL-17RA signaling was important for maintaining microbial homeostasis and its disruption resulted in differential tumor growth. Absence of IL-17RA signaling in the gut lead to local inflammation as well as systemic immune effects. Our data suggests that modulation of IL-17 signaling could serve as a therapeutic intervention to alter microbial mediated tumor effects. The significance of these findings may extend to other cancers as well.
Citation Format: Vidhi Chandra, Yu Zhang, Olivereen Le Roux, Joseph Petrosino, Jay Kolls, Florencia McAllister. Microbial-Interleukin 17 receptor A (IL-17RA) signaling axis modulates tumor growth and microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3530.
Abstract 3536: Modulating T cell tumor infiltration by modulating T cell migration
Authors: Johnston Adrian , Du Frisco , Wan Zeqi , Lee Cameron , Lim Yeongseo , Bessiake Michelle , Nair Praful , Wu Pei-Hsun , Wirtz Denis 
Published: June 2022

Abstract
Traditional assessments of T cells killing cancer cells are routinely done in two-dimensional cell culture wells and plates. The general methods comprise developing a cancer cell monolayer then overlaying it with T cells, or, worse, pre-mixing cancer cells with T cells before placing the mixture into culture wells/dishes. Such methods obviously force cancer cell-T cell interactions. This is not physiological, since T cells must migrate to tumors for cancer cell killing to even occur. Migration is a little-explored, yet central parameter ignored in 2D killing assays. There is no tumor cell killing by T cells if there is no T cell migration, biased or unbiased. Our work making use of novel 3D multi-compartments organoids systems identifies key molecules regulating pathways for T cell migration in 3D. We are currently testing molecules currently FDA-approved or in clinical trials that block or enhance T cell killing of cancer cells by blocking or enhancing T cell migration through a first-of-its-kind 3D killing assay that we developed.
Citation Format: Adrian Johnston, Frisco Du, Zeqi Wan, Cameron Lee, Yeongseo Lim, Michelle Bessiake, Praful Nair, Pei-Hsun Wu, Denis Wirtz. Modulating T cell tumor infiltration by modulating T cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3536.