bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5492: Activity of RP7214, a novel, selective, and potent small molecule inhibitor of DHODH, in AML
Authors: Viswanadha Srikant , Eleswarapu Satyanarayana , Vakkalanka Swaroop 
Published: June 2022

Abstract
Background: Dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme in pyrimidine synthesis, is overexpressed in certain cancers and impedes tumor cell proliferation via cell cycle arrest. RP7214 is a novel and potent DHODH inhibitor that inhibited DHODH activity in enzyme and PHA induced HWB/PBMC proliferation with IC50 and EC50 values of 7.8 & 2.5/0.60 nM respectively. Herein, we describe the efficacy of RP7214 as a single agent and in combination with standard of care drugs in preclinical models of AML
Methods: Cell viability of AML cell lines (U937, HL-60, THP-1, and KG-1) following incubation with RP7214 as a single agent or in combination with Azacytidine or Venetolcax for 72 h was determined in an MTT-based assay. Cell surface expression of CD11b in THP-1 and human primary bone marrow AML mononuclear cells in presence of RP7214 was evaluated by flow cytometry. Apoptosis was evaluated following incubation of cell lines with compound for 48 or 72 h, subsequent staining with Annexin-V-PE and 7-AAD, and analysis by flow cytometry. Anti-tumor potential of RP7214 as single agent was tested in subcutaneous MV-4-11 human leukemia xenograft model.
Results: RP7214 inhibited AML cell proliferation in all the four cell lines tested with GI50 ranging from 2.4 to 7.6 µM. Expression of the CD11b marker on THP-1 cell surface was enhanced by 40% following incubation with 5 µM compound; effect of which was reduced to 15% in the presence of 300 µM Uridine. Incubation of primary human bone marrow AML mononuclear cells with 10 µM of RP7214 increased the CD11b+ cells by &gt; 15 %. Combination of 3 µM-RP7214 and 1 µM-Azacytidine inhibited cell proliferation by &gt; 25% (P &lt; 0.05) compared to single agents in MV-4-11 cells. Similarly, combination of 3 µM-RP7214 with 3 nM Venetoclax demonstrated 15% (P &lt; 0.05) inhibition of cell growth compared to single agents in MV-4-11 cell line. RP7214 at 3, 10, and 30 mg/kg BID demonstrated significant anti-tumor activities in both tumor size and tumor weight in subcutaneous MV-4-11 human leukemia xenograft model.
Conclusions: Results demonstrate the utility of RP7214 as a single agent and in combination with standard of care drugs in inducing apoptosis and promoting differentiation to fully mature cells in AML. A Phase 2a trial in AML patients is planned.
Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Swaroop Vakkalanka. Activity of RP7214, a novel, selective, and potent small molecule inhibitor of DHODH, in AML [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 5492.
Abstract 5493: Activity of RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, in solid tumors
Authors: Viswanadha Srikant , Eleswarapu Satyanarayana , Rasamsetti Kondababu , Polimati Haritha , Veeraraghavan Sridhar , Vakkalanka Swaroop 
Published: June 2022

Abstract
Introduction: The Poly (ADP-ribose) polymerase (PARP) family plays an important role in the regulation of transcription, apoptosis and DNA damage response. Several PARP inhibitors have been approved for the treatment of BRCA-mutated ovarian, breast and pancreatic cancer. Through ‘synthetic lethality’, the applicability PARP inhibitors can be expanded to cancers beyond the well-defined BRCA defects either as monotherapy or in combination with established therapy across various solid tumor types. Herein, we describe the efficacy of RP12146 as a single agent and in combination with approved therapies in preclinical models of solid tumors.
Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 as a single agent or in combination with approved agents in various solid tumor cell lines. Apoptosis was evaluated following incubation of cell lines with compound for 48 or 72 h, subsequent staining with Annexin-V-PE and 7-AAD, and analysis by flow cytometry. Anti-tumor potential of RP12146 as a single agent or in combination with chemotherapeutic agents was tested in OVCAR-3 and NCI-H69 Xenografts. Expression of downstream PAR, PARP-trapping, and cleaved PARP expression were determined in cell lines and xenograft tumor samples by Western blotting. Plasma and tumor concentration of RP12146 in NCI-H69 xenograft samples were also determined.
Results: RP12146 demonstrated equipotent inhibition of PARP1 (0.6 nM) and PARP2 (0.5 nM) with several fold selectivity over the other members of the PARP family. Compound caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 µM to 9.6 µM. Combination of RP12146 with Temozolomide, Topotecan, Lurbinectedin, and Abemaciclib demonstrated either additive or synergistic effects manifested by an inhibition in growth of solid tumor cell lines. RP12146 exhibited anti-tumor potential with TGI of 28% and 21.8% as a single agent in OVCAR-3 and NCI-H69 Xenograft model respectively. In NCI-H69 xenograft model, RP12146 in combination with cisplatin exhibited TGI of 69.3 %.
Conclusion: Data demonstrate the therapeutic potential of RP12146 as single agent and in combination in solid tumors. RP12146 is currently being evaluated in Phase 1 clinical trials in patients with locally advanced or metastatic solid tumors (NCT05002868).
Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Haritha Polimati, Sridhar Veeraraghavan, Swaroop Vakkalanka. Activity of RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, in 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 5493.
Abstract 5548: PB101 simultaneously targets tumor angiogenesis and immunity and enhances the efficacy of PD-L1 immune checkpoint blockade
Authors: Yang Hannah , Lee Seung Joon , Yang Hyun-Gul , Lee Won Suk , Cheon Jaekyung , Kang Beodeul , Kim Sung-Eun , Lim Hyeseong , Chon Hong Jae , Kim Chan 
Published: June 2022

Abstract
Introduction: Tumor vasculature plays an important role in promoting tumor progression and immune evasion. Previously, we developed PB101, a novel glycosylated decoy receptor that can neutralize VEGF-A, VEGF-B, and PlGF, and demonstrated that it potently inhibits tumor angiogenesis, thereby retarding tumor growth and metastasis. However, its impact on tumor microenvironment (TME), especially anti-cancer immunity, has not been fully elucidated. Here, we investigated distinct modes of immune modulation by PB101 compared with other anti-angiogenic agents, and evaluated its immunotherapeutic potential when combined with immune checkpoint inhibitors (ICIs).
Methods: MC38 colon or Hepa-V liver cancer-bearing mice were treated with PB101 or other anti-angiogenic agents with or without various ICIs. The TME was evaluated by histologic, flow cytometric, and Nanostring immune profiling analyses.
Results: PB101 markedly suppressed MC38 colon and Hepa-V liver cancer growth in vivo. It simultaneously inhibited both VEGF and PlGF signaling within the TME, thus suppressing tumor angiogenesis. PB101 also induced extensive immune remodeling of the TME. PB101 enhanced intratumoral dendritic cells, but reduced M2-like tumor-associated macrophages. Moreover, PB101 resulted in high influx of activated CD8+, but not CD4+, T cells into the TME. PB101 exhibited the most prominent immune-modulating effect compared with other vascular targeting agents. When combined with various ICIs, PB101 had the greatest synergism with anti-PD-L1 antibody, inducing complete tumor regression and long-term survival. Furthermore, PB101-based combination immunotherapy induced a durable and protective immunity against subcutaneous tumor re-challenge and hematogenous lung metastasis.
Conclusion: PB101 elicited strong anti-tumor immunity more effectively than other anti-angiogenic agents. PB101 can strengthen the immunotherapeutic efficacy of PD-L1 inhibitor by establishing a potent and durable immune memory. The combination of PB101 and PD-LI needs to be further validated in clinical trials.
Citation Format: Hannah Yang, Seung Joon Lee, Hyun-Gul Yang, Won Suk Lee, Jaekyung Cheon, Beodeul Kang, Sung-Eun Kim, Hyeseong Lim, Hong Jae Chon, Chan Kim. PB101 simultaneously targets tumor angiogenesis and immunity and enhances the efficacy of PD-L1 immune checkpoint blockade [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 5548.
Abstract 5564: QLS31901, a novel bifunctional anti-PD-L1/TGF-β fusion protein for treatment of solid tumors
Authors: Jiang Jiahua , Han Cuicui , Chen Qi , Wu Yun , Yan Xiaodan , Cao Ping 
Published: June 2022

Abstract
Immunosuppressive pathway blocking antibodies (e.g., anti-programmed death ligand 1 [PD-L1] antibodies) are effective and feasible cancer therapy, but some patients have poor individual drug responses to this class of drugs. Simultaneous targeting other immunosuppressive pathways is therefore a novel method to enhance the efficacy. While the antitumor activity of bifunctional anti-PD-L1/transforming growth factor-β (TGF-β) fusion protein bintrafusp alfa (M7824) in preclinical studies is well known, clinical studies to date with M7824 have led to limited success. QLS31901 is another bifunctional fusion protein composed of the truncated extracellular domain of the TGF-β receptor II fused to the C-terminus of humanized anti-PD-L1 heavy chain (αPD-L1) with function as a “trap” for all three TGF-β isoforms and the blockage of PD-L1 immunosuppressive pathway. The present study demonstrated its superior antitumor activity over M7824 in a humanized MDA-MB-231 model. Furthermore, toxicology studies of QLS31901 only showed a transient interleukin 6 elevation. There were no other cytokine release and organ toxicity in cynomolgus monkeys. Overall, these data provided a rationale for an expansion cohort study of QLS31901 for the treatment of patients with solid tumors and dual blockade of TGF-β as well as PD-L1 with QLS31901 may be a promising therapy.
Citation Format: Jiahua Jiang, Cuicui Han, Qi Chen, Yun Wu, Xiaodan Yan, Ping Cao. QLS31901, a novel bifunctional anti-PD-L1/TGF-β fusion protein for treatment of 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 5564.
Abstract 5575: Pre-clinical validation of a LGR5-targeting CAR-T against colorectal cancer
Authors: Bandara Veronika , Mills Stuart , Thompson Emma , Tan Lih , Gundsambuu Batjargal , Napoli Silvana , Foeng Jade , McPeake Dylan , Coombs Justin , Cowin Allison , Bonder Claudine , Sadlon Timothy , McColl Shaun , Barry Simon 
Published: June 2022

Abstract
Chimeric antigen receptor T cells (CAR-T) have demonstrated robust clinical activity against B-cell malignancies, and rapid translation to approval for use in man has inspired the search for CAR-T cells against solid tumors. Cancer stem cells are a small population of cells within a tumor that have the capacity to self-renew, differentiate, and initiate new tumors. Cancer stem cells are known to be resistant to chemotherapy and radiotherapy and are enriched in residual disease which allows relapse. Targeting cancer stem cells will reduce the tumors’ ability to generate new cells resulting in tumor remission. We have tested a novel CAR-T cell that has the potential to target cancer stem cells. Leucine-rich G protein-coupled receptor 5 (LGR5) expression is restricted to stem cell populations in multiple tissues in adults. In addition, LGR5 is a marker of cancer stem cells and LGR5+ cells are implicated in tumor progression and metastasis. We designed six lentiviral CAR-T constructs targeting the extra cellar domain of LGR5 with differing linker lengths and binding domain orientation, and tested gene delivery to purified human CD3 T cells and in vitro cytotoxicity. All constructs were expressed robustly (&gt;90%), and four of six LGR5-targeting CAR-T cells showed significant antigen-specific cytotoxicity against colorectal cancer cell lines in vitro. We confirmed the on-target specificity of the LGR5 targeting CAR-T using a cell line over-expressing the LGR5 protein and antibody competition assays, which blocked cytotoxicity. Using optimized gene delivery and CAR-T manufacturing protocols, we generated pre-clinical scale batches of the four lead constructs to evaluate their potency in a pre-clinical colorectal cancer xenograft mouse model. Post expansion our cell products expressed markers of self-renewing naïve-like and central memory phenotype and three out of four LGR5-targeting CAR-T cells were able to significantly inhibit the growth of human colorectal tumors. These results suggest a CAR-T targeting LGR5 may provide long-term protection against tumor growth. Our data positions LGR5-targeting CAR-T therapy as a viable therapeutic for human metastatic colorectal cancer types with minimal off-target effects, which we now aim to test in human clinical trials.
Citation Format: Veronika Bandara, Stuart Mills, Emma Thompson, Lih Tan, Batjargal Gundsambuu, Silvana Napoli, Jade Foeng, Dylan McPeake, Justin Coombs, Allison Cowin, Claudine Bonder, Timothy Sadlon, Shaun McColl, Simon Barry. Pre-clinical validation of a LGR5-targeting CAR-T against colorectal 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 5575.
Abstract 5581: A genetically modified tumor-infiltrating lymphocytes product (GT202) exhibits enhanced persistence and anti-tumor efficacy against solid tumor in vivo
Authors: Sun Jingwei , Jin Jiahui , Tan Yongchao , Chen Lingyun , Wang Quanwei , Liu Yarong 
Published: June 2022

Abstract
Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated significant clinical benefits for patients with solid tumors. However, the toxicities related to high-dose IL-2 that is required to support TIL survival and the exhaustion status of the final TIL product after rapid expansion in culture largely limits the clinical application and long-term efficacy of TIL therapy. Grit Biotechnology designed a genetically engineered TIL product (GT202) to express a membrane-bound cytokine that is critical for T cell activation and effector function, leading to enhanced cytotoxicity as well as persistence in vitro and in vivo. Multiple designs of the transmembrane domain of GT202 were compared and the best design was selected based on stable and efficient expression of GT202 on the membrane of TILs. GT202 demonstrated significantly increased cytotoxicity and cytokine production when cocultured with tumor cells in vitro than conventional TILs and better tumor control ability during a serial killing assay. In the meanwhile, GT202 TILs showed enhanced long-term survival and better preservation of TCR clonality without IL-2 in vitro, as well as persisted longer in multiple tissues without IL-2 over conventional TILs + IL-2 in NGS mice. Notably, GT202 TILs achieved better anti-tumor efficacy with low IL-2 in NSG mice inoculated with HLA-matched tumor cells than conventional TILs, corelated with their better infiltration and proliferation in spleen and tumor. In summary, GT202 demonstrated enhanced anti-tumor efficacy and persistence as well as decreased IL-2 dependency in vitro and in vivo. Currently, an investigator-initiated trial of GT202 is ongoing in China.
Citation Format: Jingwei Sun, Jiahui Jin, Yongchao Tan, Lingyun Chen, Quanwei Wang, Yarong Liu. A genetically modified tumor-infiltrating lymphocytes product (GT202) exhibits enhanced persistence and anti-tumor efficacy against solid tumor in vivo [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 5581.
Abstract 5619: Co-occurrence ofLactobacillusandCandida sp.in periodontal disease severity suggests cancer-related dysbiosis
Authors: Acosta-Pagán Kimil T. , Godoy-Vitorino Filipa , Bolaños-Rosero Bejamín , Ortíz Ana P. , Oramas-Sepúlveda Carla , Pérez Cynthia M. , Vivaldi-Oliver José A. , Pérez-Santiago Josué , Castañeda-Avila Maira 
Published: June 2022

Abstract
Introduction: Microbiota plays an essential role in the oral cavity and oral dysbiosis, leading to inflammatory diseases such as periodontitis. Periodontal disease is associated with a two-fold increase in the risk of oral cancer; thus, evaluating polymicrobial associations across a gradient of periodontitis will help understand the microbial processes that could influence cancer development. We aimed to study the association of oral bacteria and fungi linked to high-risk behavior and periodontal disease.
Methods: This cross-sectional study recruited individuals aged 21 to 49 from sexually transmitted infection clinics in Puerto Rico. A total of 88 participants underwent a full-mouth periodontal examination following the NHANES protocol. Periodontal severity was defined according to the CDC/AAP. Saliva was collected for genomic DNA extraction, and downstream 16S V4 and ITS-2 genes were amplified, sequenced, and analyzed with standard bioinformatics pipelines.
Results: Nearly 29% of individuals had some degree of periodontal disease. Bacterial community analyses revealed differences in both composition and diversity as the periodontal disease progressed. The predominance of Prevotella and Veillonella in the salivary microbiota was attributed to periodontal conditions with low levels of Lactobacillus in patients with severe disease. In contrast, the predominance of Neisseria was related to healthy participants. Fungal communities changed in composition with disease severity, including the dominance of Candida tropicalis. Co-occurrence analyses revealed that Lactobacillus co-occurred with Candida dubliniensis, C. tropicalis, and Saccharomyces cerevisiae in individuals with periodontal disease.
Conclusion: Co-occurrence patterns of bacteria and fungi changed from participants with no disease to periodontal severity. Lactobacillus has been identified in caries, xerostomia, and saliva of HPV-positive head and neck cancer patients. This study is the first to report the co-occurrence of this Lactobacillus with oral candidiasis in periodontal severity. We expect that these biofilms induce inflammation in periodontal pockets while also making them more resistant to treatments.
Citation Format: Kimil T. Acosta-Pagán, Filipa Godoy-Vitorino, Bejamín Bolaños-Rosero, Ana P. Ortíz, Carla Oramas-Sepúlveda, Cynthia M. Pérez, José A. Vivaldi-Oliver, Josué Pérez-Santiago, Maira Castañeda-Avila. Co-occurrence ofLactobacillusandCandida sp.in periodontal disease severity suggests cancer-related dysbiosis [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 5619.
Abstract 5654: Degradation of Bcl-xL by DT2216 is lethal to T-cell acute lymphoblastic leukemia
Authors: Jaiswal Arunima S. , Williamson Elizabeth , Hromas Robert A. , Zhou Daohong 
Published: June 2022

Abstract
Cancer is a multistep process where genomic and epigenomic alterations results in abnormal cellular proliferation and dissemination. This unregulated cellular proliferation can be interrupted through intervention therapy. One such strategy utilizes proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional small molecular structures consisting of a ligand that binds to a target protein, and upon binding can recruit an E3 ligase which ubiquitinates the target protein, and eventually directs ubiquitinated protein for proteasomal degradation. This has been exploited as a revolutionary therapeutic strategy to degrade oncogenic and/or anti-apoptotic protein(s) that are overly expressed and offer a growth advantage in actively growing tumors. The accumulation of anti-apoptotic proteins creates resistance within the tumor against cancer treatments and preventative strategies in the clinical setting. In the present study, we used DT2216, a PROTAC that targets and promotes degradation of the anti-apoptotic protein Bcl-xL via the VHL (E3 ligase) pathway in T-cell acute lymphoblastic leukemia cells (T-ALL). Unlike other preclinical studies, like ABT263, DT2216 does not cause thrombocytopenia because VHL is poorly expressed in platelets. In our preclinical study, we treated thirteen human T-ALL cells with varying concentrations of DT2216 (0-1 µM) for 24 h and analyzed Bcl-xL expression by western blot analysis. Our data suggests that DT2216 results in the robust degradation of Bcl-xL in a dose-dependent manner at a minimal dose of 10 nM in eight of the cell lines studied (ALL-SIL, P12-Ichikawa, Jurkat, SUP-T1, HBP-ALL, HSB-2, PEER, and DND-41). Bcl-xL degradation triggers apoptosis, which was evident through the presence of cleaved products for Caspase-3 and PARP-1. We examined the expression of other anti-apoptotic proteins, Bcl-2 and Mcl-1 in response to DT2216 and neither protein was changed, which highlights DT2216’s specificity. We further evaluated the effect of DT2216 on the survival of T-ALL cells. Our data suggests that the IC50 for all the T-ALL cell lines ranges from 2-100 nM, with the exception of SUP-T1, which exhibited an IC50 above 1 µM. Our data suggests that DT2216 could serve as a viable, safe, and potent alternative or addition to traditional clinical treatments of T-ALL.
Citation Format: Arunima S. Jaiswal, Elizabeth Williamson, Robert A. Hromas, Daohong Zhou. Degradation of Bcl-xL by DT2216 is lethal to T-cell acute lymphoblastic leukemia [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 5654.