tbuckley/cabot-search huggingface dataset:
Abstract 1872: A next generation treatment for Nectin-4 positive cancers - Preclinical characterization of LY4052031, an anti-Nectin-4 antibody, conjugated to a novel camptothecin payload
Authors: Divya Sagar, Mohan Srinivasan, Kevin Lindquist, Qianxu Guo, Wailin Wong, Maria B. Lebron, Rose Marie Sattler, Jieyu Zhou, Whitney Helms, Jeffrey Boyles, Petra Verdino, Xuan Zhao, Yvonne Mak, Joshua Park, Rikke Holmgaard, Kyla Driscoll, Omar Duramad, Kristin Bedard
Journal: Cancer Research (2024)

Abstract Nectin-4 is an immunoglobulin-like antigen overexpressed in a variety of cancers including bladder, breast, NSCLC, and gastric. Normal tissues including skin, salivary glands, bladder and esophagus express only low to medium levels of Nectin-4 making the protein an attractive target for cancer therapies. The approval of enfortumab vedotin-ejfv, an anti-Nectin-4 based antibody-drug conjugate (ADC) with a microtubule inhibitor payload, either as a single agent or in combination with pembrolizumab has been a significant advancement in the treatment of metastatic urothelial cancer. We have developed a novel anti-Nectin-4 ADC with a novel topoisomerase I (TOPO 1) inhibitor drug payload. Topoisomerase inhibitor payload-based ADCs offer potential advantages compared to microtubule payload-based ADCs including a different toxicity profile and the differentiated susceptibility to resistance mechanisms, such as P-gp mediated drug efflux. LY4052031 is a fully human monoclonal anti-Nectin-4 antibody conjugated to a novel TOPO 1 inhibitor by a cleavable peptide linker at a homogeneous drug antibody ratio (DAR) of 8:1. In vitro, both LY4052031 and its unconjugated parental antibody specifically bind to Nectin-4 expressing cell lines and are quickly and efficiently internalized. LY4052031 demonstrated potent cytotoxicity on tumor cells with high and low Nectin-4 expression. Additionally, bystander activity exerted by LY4052031 on antigen negative cells co-cultured with antigen positive cells was greater than that observed with the clinical benchmark enfortumab vedotin-ejfv. In vivo studies in xenografts expressing low to high levels of Nectin-4 showed significant tumor growth inhibition following treatment with LY4052031 as monotherapy. Overall, LY4052031 exhibits specificity, selectivity, potency, and effectiveness as a next generation therapy to treat Nectin-4 positive tumors. An IND submission is planned for 2024. Citation Format: Divya Sagar, Mohan Srinivasan, Kevin Lindquist, Qianxu Guo, Wailin Wong, Maria B. Lebron, Rose Marie Sattler, Jieyu Zhou, Whitney Helms, Jeffrey Boyles, Petra Verdino, Xuan Zhao, Yvonne Mak, Joshua Park, Rikke Holmgaard, Kyla Driscoll, Omar Duramad, Kristin Bedard. A next generation treatment for Nectin-4 positive cancers - Preclinical characterization of LY4052031, an anti-Nectin-4 antibody, conjugated to a novel camptothecin payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1872.
Abstract 2648: CD155 regulates cell growth and immune evasion in diffuse midline glioma
Authors: Theophilos Tzaridis, Tanja Eisemann, Augusto Faria Andrade, Jennifer L. Hope, Oren Becher, Nada Jabado, Linda M. Bradley, Peter Adams, Robert Wechsler-Reya
Journal: Cancer Research (2024)

Abstract There is an unmet need for effective treatment strategies for diffuse midline glioma (DMG), a devastating brain tumour arising in children and young adults. While immunotherapy is emerging as a powerful approach for treatment of other cancers, clinical trials with immune checkpoint inhibitors have failed to show a survival benefit for DMG patients. In this study, we analysed the expression of known immune checkpoint molecules on the surface of human and murine DMG cells by flow cytometry and identified CD155 and B7-H3 as the most highly expressed checkpoint molecules, with minimal expression of others, including PD-L1 and PD-L2. These findings were confirmed in primary patient samples from pediatric brain tumours (gliomas, medulloblastomas and ependymomas). To test whether CD155 regulates susceptibility to CD8+ T cell killing, we cultured murine DMG cells expressing ovalbumin (OVA) with CD8+ T cells from OT-I mice, which express T cell receptors specific for OVA. shRNA mediated silencing of CD155 led to a strong increase in T cell-mediated killing. In vivo, adoptive transfer of OT-I T cells into OVA-positive DMG-bearing immuno-compromised mice resulted in delayed tumour growth, and this effect was enhanced when tumours lacked CD155. Strikingly, CD155-deficient DMG cells failed to grow at all in immuno-competent mice, and depletion of CD8 T cells allowed these tumours to grow, highlighting a role for CD8 T cells in rejection of CD155-deficient cells. In addition to its effects on susceptibility to T cells, CD155 also exerted cell-autonomous effects on tumour cells: silencing of CD155 led to induction of apoptosis of DMG cells in vitro and to delayed tumour growth in vivo, even in immune-compromised mice. These studies demonstrate that CD155 functions as an immune checkpoint and as a regulator of tumour cell survival in DMG, and suggest that targeting CD155 could be a valuable double-pronged therapeutic strategy for this devastating disease. Citation Format: Theophilos Tzaridis, Tanja Eisemann, Augusto Faria Andrade, Jennifer L. Hope, Oren Becher, Nada Jabado, Linda M. Bradley, Peter Adams, Robert Wechsler-Reya. CD155 regulates cell growth and immune evasion in diffuse midline glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2648.
Abstract 2070: Engineered Inhalation nanoparticle formulation for lung cancer
Authors: Rahul Tiwari, Eswara N. Ghali, Neeraj Chauhan, Vivek Kashyap, Subhash C. Chauhan, Murali M. Yallapu
Journal: Cancer Research (2024)

Abstract Background: Lung cancer is a predominant cause of cancer-related morbidity and mortality across the world including in the United States. Treatment modalities for lung cancer include surgery, chemotherapy, radiotherapy, and/or targeted therapies depending on the cancer stage. Despite the survival benefits of chemotherapy, its value is offset by severe systemic side effects such as renal and/or hepatic toxicity or insufficient amounts of drug reaching to the target site. Such pitfalls can be handled by inhalable therapy which avoids first-pass metabolism and increases patients' compliance. In this study, we have investigated the inhalable therapy of cross-linked tannic acid-based nanoparticles (CTA NPs) into cancer cells and determined the synergistic effect of gambogic acid (GA) and gemcitabine (Gem). Methods: The CTA NPs formulations were characterized for particle size, chemical composition, and drug loading efficiency using various physicochemical methods (FT-IR, DSC, SEM, and TGA). Cellular uptake of CTA NPs was evaluated in lung cancer cell lines (A549 and NCI-H1299) using fluorescence microscopy and flow cytometry analysis. Further, the therapeutic efficacy of GA-Gem encapsulated CTA NPs (G-G CTA NPs) formulation was determined by various in vitro assays (CCK-8, mucoadhesion Boyden chamber, and apoptosis assays). The molecular effects of G-G CTA NPs formulation were also observed in lung cancer cell lines. Results: Our novel CTA NPs formulation provided an average size of 110 nm in dynamic light scattering with a sustained release of the drug(s). CTA NPs formulation showed a remarkable mucoadhesion and mucopenetration penetration potential in-vitro model(s). Cellular uptake studies show that CTA NPs formulation allows for effective endosomal release into the cytosol. Additionally, the G-G CTA NPs formulation showed superior in vitro anti-cancer activity in lung cancer cells (A549 and NCI-H1299) compared to free drugs. Conclusions: Taken together, our results demonstrate that G-G CTA NPs formulation exhibits superior anti-cancer potential than free drug against lung cancer and could be a novel therapeutic modality for the management of lung cancer. Citation Format: Rahul Tiwari, Eswara N. Ghali, Neeraj Chauhan, Vivek Kashyap, Subhash C. Chauhan, Murali M. Yallapu. Engineered Inhalation nanoparticle formulation for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2070.
Abstract 7065: AMBRA1 coordinates mitochondrial function to regulate cancer stemness and tumorigenesis in hepatocellular carcinoma
Authors: Yan Liu, Yunong Xie, Yimiao He, Stephanie Ma, Man Tong
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer, with emerging evidence highlighting the role of cancer stem cells (CSCs) in its progression. AMBRA1 has been implicated to exert both tumor-promoting and tumor-suppressive roles through regulating cell cycle and mitophagy in various solid tumors. However, the functional roles of AMBRA1 in modulating cancer stemness and tumorigenesis in HCC remain elusive. Initial analysis of The Cancer Genome Atlas data revealed a significant inverse correlation between AMBRA1 expression and stemness indices (TSS) in HCC patients, with low AMBRA1 levels associated with an upregulated oxidative phosphorylation (OXPHOS) gene signature. To elucidate the functional consequences of AMBRA1 modulation in liver tumor development and stemness maintenance, we exploited both hydrodynamic mouse models and human HCC cell lines. Our findings indicate that hepatic AMBRA1 deletion enhances cancer stemness and tumorigenesis both in vivo and in vitro. Moreover, HCC cells with reduced AMBRA1 expression demonstrated heightened mitochondrial activity, characterized by increased oxygen consumption, respiration, mitochondrial membrane potential, and intracellular ATP levels. Apart from OXPHOS, we also observed a concomitant up-regulation and enrichment of MYC targets in TSS-high and AMBRA1-low HCC patients, pointing towards a deregulated c-MYC signaling to promote cancer stemness under AMBRA1 regulation in HCC. Collectively, our results demonstrate that AMBRA1 loss enhances mitochondrial function to support hepatic tumorigenesis in HCC. Citation Format: Yan Liu, Yunong Xie, Yimiao He, Stephanie Ma, Man Tong. AMBRA1 coordinates mitochondrial function to regulate cancer stemness and tumorigenesis in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7065.
Abstract 5975: Characterization and pharmacokinetics of ligand traps targeting the human epidermal growth factor receptor (HER) family
Authors: Daniel C. Maneval, Cindy Yang, Cynthia Trevisiol, H. Michael Shepard, Pei Jin
Journal: Cancer Research (2024)

Abstract Antibodies targeting HER receptors have led to successful therapeutics for multiple human malignancies. Targeting the family of HER ligands provides an alternative strategy to inhibit signaling and subsequent proliferation of cancer cells. We have engineered ligand traps that bind the growth factors activating the HER family and have characterized a series of molecules (EN2000-Fc) using Surface Plasmon Resonance (SPR). Five distinct molecules were further evaluated for improved in vivo pharmacokinetics in mice that express human neonatal Fc receptor (FcRn). Mutations in the IgG Fc known to extend the in-vivo half-life of monoclonal antibodies were incorporated into the parental EN2000-Fc to generate 3 more distinct pan HER ligand traps. In addition, an EN2000-Fc variant with a full-length hinge was engineered, which is 5-amino-acid longer N-terminally than the parental molecule. These five molecules were synthesized (&amp;gt; 300 mg of each), purified (&amp;gt;98%), and characterized for in vitro and in vivo testing. Two variants were compared by evaluating the ligand binding affinity to 11 HER ligands using SPR. Both molecules showed comparable affinity against all ligands tested, confirming reproducibility of the pan HER ligand trap engineering technology. Among the ligands, HB-EGF had the highest affinity. High binding affinities to EGF, NRG1, NRG2, betacellulin and TGFα were also measured. The serum pharmacokinetics of the different ligand traps were compared in 6- to 8-week-old female C57BL/6 mice engineered to express human FcRn. Ligand traps were administered by single tail vein injection, and serum samples collected over a 28-day interval were analyzed by ELISA. Ligand traps with engineered Fc-mutations had 3- to 4-fold greater systemic exposure (area-under-the-curve) compared to ligand traps with the parental sequence, demonstrating improved in vivo characteristics of selected engineered fusion proteins. These results provide useful information for product candidate selection and for further preclinical development of a ligand trap targeting HER family receptors. Citation Format: Daniel C. Maneval, Cindy Yang, Cynthia Trevisiol, H. Michael Shepard, Pei Jin. Characterization and pharmacokinetics of ligand traps targeting the human epidermal growth factor receptor (HER) family [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5975.
Abstract 6055: COOTO-Me (10e) acts as a molecular glue to target NCOR/HDAC3 degradation
Authors: Ping Gong, Min Huang, Xin Li, Haoling Wang, Samuel Waxman, Linxiang Zhao, Yongkui Jing
Journal: Cancer Research (2024)

Abstract Histone deacetylase 3 (HDAC3) is overexpressed in cancer cells and functions as transcription repression complex with nuclear receptor corepressor (NCOR) to inhibit gene transcription. The pan-HDAC inhibitors have been approved for T-cell lymphoma with evident side effects. The selective HDAC3 inhibitors needs to be developed. Proteolysis-targeting chimera (PROTAC) approach is taken to design HDAC3 degraders with unsolved bioavailability obstacle. We screened small molecules with HDAC3 degradation ability and found two small molecules derived from glycyrrhetinic acid, methyl 2-cyano-3-oxo-18β-olean-1,9(11), 12-trien-30-oate (COOTO, 10e) and methyl 2-cyano-3,12-dioxo-18β-olean-1,9(11)-dien-30-oate (CDODO-Me, 10d), selectively decreased HDAC3 protein with increased acetylation of Histone 3. We explored the mechanism of HDAC3 degradation and found that 10e interrupted the interaction of HDAC3 with NCOR and induced degradation of both HDAC3 and NCOR protein. Biotin labeled 10e shows binding to both HDAC3 and NCOR directly as well as to E3 ligases SIAH2 and ITCH. Mass spectrometry analysis profiling reveals covalent interactions of 10e with multiple cysteine sites of SIAH2 in the binding regions for NCOR and HDAC3. Silencing SIAH2 blocks degradation of HDAC3. N-Acetylcysteine and GSH block the binding of 10e to HDAC3, NCOR and SIAH2. In addition, 10e decreased the levels of c-FLIP protein and increased the levels of NOXA protein leading to apoptosis induction. These data suggest that 10e functions as a molecular glue to attract SIAH2 to HDAC3 and NCOR to cause degradation through covalent binding. Citation Format: Ping Gong, Min Huang, Xin Li, Haoling Wang, Samuel Waxman, Linxiang Zhao, Yongkui Jing. COOTO-Me (10e) acts as a molecular glue to target NCOR/HDAC3 degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6055.
Abstract 6078: Circulating tumor cell-based early detection of breast cancer
Authors: Justin M. Drake, Kaylee J. Kamalanathan, Catalina Galeano-Garces, Nathaniel Bristow, Nicholas Heller, Mahdi Ahmadi, Olivia Hedeen, Alexa Hesch, Grant Schaap, Joel Hapke, Jeff Miller, Ivo Babris, Tuan Le, Tony Clacko, Jiarong Hong, Badri Konety, Jayant Parthasarathy
Journal: Cancer Research (2024)

Abstract Although mammograms have been a useful tool since the first half of the 20th century and have an acceptable sensitivity (87%) in the general population, that drops to &amp;lt;50% in women with dense breasts making it an ineffective screening tool in this population. Cell free DNA (cfDNA) has proven to be an inadequate alternative in this population, and while MRI is acceptable, it is expensive. Astrin Biosciences has developed a blood-based assay that detects circulating tumor cells (CTCs) at a high sensitivity to serve as an alternative screening method to mammography in breast cancer early detection, specifically in women with high-density breasts. Astrin’s technology integrates holographic imaging, machine learning, and microfluidics to identify CTCs in the blood stream. Omics analysis can then be performed on the collected cells to further differentiate patients with cancer from matched healthy controls. Astrin has initiated a small cohort study to investigate the sensitivity and specificity of CTC detection in women with early-stage breast cancer. Astrin’s small cohort study, including patients with ductal carcinoma in situ, stage 1, and stage 2 breast cancer patients, demonstrated &amp;gt; 85% sensitivity and specificity. A large cohort study is being conducted to validate these preliminary results. The small cohort study demonstrates the ability of Astrin Bioscience’s platform to detect cancer cells at an early stage, particularly in breast cancer. This technology will drastically increase the effectiveness of breast cancer screening modalities available to patients. Additionally, since it is a blood-based assay, it can be performed at shorter intervals in high-risk populations than mammograms which require a full patient appointment. Citation Format: Justin M. Drake, Kaylee J. Kamalanathan, Catalina Galeano-Garces, Nathaniel Bristow, Nicholas Heller, Mahdi Ahmadi, Olivia Hedeen, Alexa Hesch, Grant Schaap, Joel Hapke, Jeff Miller, Ivo Babris, Tuan Le, Tony Clacko, Jiarong Hong, Badri Konety, Jayant Parthasarathy. Circulating tumor cell-based early detection of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6078.
Abstract 6085: Leveraging targeted epigenetic and genetic detection for cost-effective cancer classification
Authors: Robert Crawford, Ben Krajacich, Ermira Lleshi, Aurel Negrea, Lisabet Andreasen, Jens Fullgrabe, Jack Monahan, David Morley, Fabio Puddu, Donna McDade Walker, Semyon Kruglyak, Páidí Creed
Journal: Cancer Research (2024)

Abstract The combinatorial power of genetics and epigenetics is vital to understanding biology in healthy and cancerous states. Utilizing a recent novel approach, we enable the simultaneous identification of modified cytosine and the canonical bases A, C, T &amp; G in an enzymatic single-workflow solution. Generating this information across the whole genome provides a much-improved understanding of genetic and epigenetic changes, but can require a large amount of sequencing, particularly when exploring at depth. Enrichment protocols such as target enrichment enable deep interrogation of target areas whilst maintaining cost effectiveness. Target enrichment panels enable the selective isolation of sequences of interest through target hybridization. Using commercially available panels combined with the novel enzymatic single-workflow solution we show uniform performance across a range of input amounts with reduced sequencing requirements. Samples used were cell free DNA (cfDNA) from patient samples with either Stage I or IV Colorectal Cancer and reportedly healthy controls and were targeted using pan-cancer and methylome panels. Widespread differences such as hypermethylation are clearly observed in late-stage cancer vs early-stage or healthy controls demonstrating utility of the approach for applications such as liquid biopsy. Refining genetic and epigenetic investigations to a narrower region of interest can improve detection of low prevalence disease associated biomarkers at significant sequencing depth and lower sequencing costs. Citation Format: Robert Crawford, Ben Krajacich, Ermira Lleshi, Aurel Negrea, Lisabet Andreasen, Jens Fullgrabe, Jack Monahan, David Morley, Fabio Puddu, Donna McDade Walker, Semyon Kruglyak, Páidí Creed. Leveraging targeted epigenetic and genetic detection for cost-effective cancer classification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6085.
Abstract 1128: Association between gut microbial change and acute gastrointestinal toxicity in patients with prostate cancer undergoing definitive radiation therapy
Authors: Bum-Sup Jang, Dong Soo Lee
Journal: Cancer Research (2024)

Abstract Purpose: This prospective cohort study investigated the association between gut microbial changes and acute gastrointestinal toxicities in prostate cancer patients undergoing definitive radiation therapy (RT). Methods: Seventy-nine fecal samples were analyzed. Stool samples were collected at the following timepoints: pre-RT (prRT), 2 weeks after the start of RT (RT-2w), 5 weeks after the start of RT (RT-5w), 1 month after completion of RT (poRT-1m), and 3 months after completion of RT (poRT-3m). We computed the microbial community polarization index (MCPI) as an indicator of RT-induced dysbiosis. Results: Patients experiencing toxicity had lower alpha diversity, especially at RT-2w (P=0.037) and RT-5w (P=0.003). Compared to patients without toxicity, the MCPI in those experiencing toxicities was significantly elevated (P=0.019). In terms of predicted metabolic pathways, we found linearly decreasing pathways including carbon fixation pathways in prokaryotes (P=0.035) and the bacterial secretion system (P=0.005), in patients who experienced toxicities. Conclusions: We showed RT-induced dysbiosis among patients who experienced toxicities. Reduced diversity and elevated RT-related MCPI could be helpfully used for developing individualized RT approaches. Citation Format: Bum-Sup Jang, Dong Soo Lee. Association between gut microbial change and acute gastrointestinal toxicity in patients with prostate cancer undergoing definitive radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1128.