bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5975: Characterization and pharmacokinetics of ligand traps targeting the human epidermal growth factor receptor (HER) family
Authors: Maneval Daniel C. , Yang Cindy , Trevisiol Cynthia , Shepard H. Michael , Jin Pei 
Published: March 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 (&gt; 300 mg of each), purified (&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 6020: GPC3-targeted radiopharmaceutical therapy for neuroendocrine prostate cancer
Authors: Clift Renee , Lin Fanching , Salvador Katrina , Guest Matt , Kim Daniel , Han Guangzhou , Li Gary 
Published: March 2024

Abstract
Introduction: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein with minimal expression in normal tissues. Besides hepatocellular carcinoma, upregulation of GPC3 protein has been observed in a significant subset of treatment-emergent neuroendocrine prostate cancer (NEPC), which accounts for to 30% of prostate cancer cases refractory to anti-androgen and other therapies. The differential expression of GPC3 between NEPC cells and normal tissues provides a theranostic opportunity for targeted radiopharmaceutical therapy (RPT).
Methods: The novel RPT agent RYZ-GPC3 comprises a small macrocyclic peptide binder with high affinity to GPC3 linked with a tetraxetan moiety capable of chelating a variety of radioisotopes. The expression of GPC3 in NEPC cells was assessed by flow cytometry and immunohistochemistry (IHC). The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR) and radioligand binding assays. In vivo biodistribution of [177Lu]Lu-RYZ-GPC3 and anti-tumor therapy with [177Lu]Lu-RYZ-GPC3 or [225Ac]Ac-RYZ-GPC3 were performed in NEPC xenografts.
Results: The novel agent is a highly potent and selective peptide binder to GPC3 of human, mouse and NHP origins, and is compatible with multiple radiometal isotopes. In vivo biodistribution study of [177Lu]Lu-RYZ-GPC3 in GPC3-positive NEPC xenografts showed sustained tumor uptake of 10.8, 12.6, 5.1, and 2.2 %ID/g at 2, 24, 72 and 168 hours post dose, respectively, with fast renal clearance. Minimal or no uptake was observed in other normal tissues. A single injection of [225Ac]Ac-RYZ-GPC3 (11.1 kBq) resulted in significant tumor growth inhibition (TGI 109%) with durable regression and prolonged survival. All treatments were well tolerated.
Conclusion: Preclinical in vitro and in vivo data demonstrated the potential of the novel binder as a theranostic agent for the treatment of patients with GPC3+ NEPC.
Citation Format: Renee Clift, Fanching Lin, Katrina Salvador, Matt Guest, Daniel Kim, Guangzhou Han, Gary Li. GPC3-targeted radiopharmaceutical therapy for neuroendocrine prostate 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 6020.
Abstract 6031: Fasting associated microbiota contributes to small intestinal radioprotection by modulating the epigenome
Authors: Barrodia Praveen , Arslan Emre , Jeter-Jones Sabrina , Jenq Robert R. , Rai Kunal , Piwnica-Worms Helen 
Published: March 2024

Abstract
Normal tissue toxicity often restricts the administration of effective radiation doses for optimal tumor cell elimination. We identified a novel host-protective effect conferred by short-term fasting when treating mice with high dose radiation. We showed that fasting mice for 24h induces epigenetic and transcriptional changes in small intestinal epithelial cells (siECs) and confers protection to small intestinal stem cells from high dose radiation. Here we report that fasting induces changes in the gut microbiome favoring bacteria producing metabolites, specifically short-chain fatty acids, that induce epigenetic changes in siECs. 16S rRNA sequencing of feces isolated from the small intestines of fed and fasted mice revealed a marked enrichment of Akkermansia muciniphila (AKK) in fasted relative to fed mice. Specific depletion of AKK through antibiotic treatment impaired the ability of fasting to provide organismal radioprotection whereas both organismal and OLFM4+ stem cell protection was restored in fasted animals upon reintroduction of AKK. AKK produces short chain fatty acids (SCFAs) including propionate which is able to induce histone modifications and our metabolomic analysis of feces isolated from the ileums of mice demonstrated a significant increase in propionic acid levels in fasted mice compared to fed mice. Importantly, we showed that AKK conditioned medium as well as its metabolite (propionate) are able to induce histone acetylation in Lgr5+ stem cell enriched epithelial spheroids cultured in vitro. We are currently employing high-dimensional analysis techniques, including single cell analysis, Cut&Tag and RNAseq to determine how the epigenetic and transcriptional changes induced by fasting provide organismal and SI radioprotection.
Citation Format: Praveen Barrodia, Emre Arslan, Sabrina Jeter-Jones, Robert R. Jenq, Kunal Rai, Helen Piwnica-Worms. Fasting associated microbiota contributes to small intestinal radioprotection by modulating the epigenome [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 6031.
Abstract 6035: Fluoride effects on thermal properties of irradiated dentin and enamel
Authors: Kulchar Rachel J. , Kakiuchi Yusuke , Sanchez-Gamarra Vania , Deng Jie , Mante Francis 
Published: March 2024

Abstract
Aim: Radiation therapy to treat oral cancer introduces various harms, including decreased hardness of dentin and enamel. Fluoride treatments, including silver diamine fluoride (SDF), have been used as a tool to combat these harms, but its influences on the thermal properties of dentin and enamel prior to and after radiation therapy are not well understood. Thus, this study analyzed how SDF influences the thermal stability of dentin and enamel that has been exposed to radiation therapy intended for head and neck cancer patients.
Methods: Forty human posterior teeth were collected, cleaned of debris and soft tissue, and then mounted into acrylic resin molds. The teeth were divided into two equal groups, with one group being the control (no treatment) and the other group receiving SDF treatment. Using an X-Rad 320ix biological irradiator, all teeth were subjected to two grays of radiation therapy every day for six weeks. Afterwards, the dentin and enamel were pulverized a SPEX freezer mill. Samples were heated in a NETZSCH Thermal Analysis instrument, and the amount of carbon dioxide and water released was determined. All teeth were heated to 1429 °C from room temperature.
Results: The SDF-treated dentin released the most carbon dioxide (49,611.82 ppm/mg), followed by irradiated dentin (47,672.76 ppm/mg) and untreated dentin (45,249.66 ppm/mg). In contrast, the SDF-treated enamel released less carbon dioxide (7,367.62 ppm/mg) than the control enamel (8,172.01 ppm/mg). The pattern of release of water was different from that of carbon dioxide. The control dentin group released the most water (45.56 ppt/mg), followed by the SDF-treated (39.72 ppt/mg) and irradiated dentin (23.51 ppt/mg). Similarly, the control enamel also released the highest amount of water (0.83 ppt/mg), as well as the highest amount of carbon dioxide. The SDF-treated enamel released around 65% of the water compared to the control enamel group (0.54 ppt/mg). Furthermore, the irradiated dentin had the largest heat reversal temperatures for carbon dioxide (85.19 °C) and water (86.57 °C).
Conclusions: The impacts of SDF treatment and radiation vary between dentin and enamel. Comparatively, dentin has a higher content of combustible material than enamel. Radiation treatment reduces the water content of both enamel and dentin, which may make teeth more susceptible to fracture. Therefore, regular dental check-ups and frequent fluoride treatment to increase the strength of the teeth are recommended for patients undergoing radiation therapy.
Citation Format: Rachel J. Kulchar, Yusuke Kakiuchi, Vania Sanchez-Gamarra, Jie Deng, Francis Mante. Fluoride effects on thermal properties of irradiated dentin and enamel [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 6035.
Abstract 6054: UPPGRADER: a bioinformatics-based novel E3 ligase discovery platform
Authors: Ha Kyungsik , Song Woojeung , Choi Woochang , Lee Gi Bbeum , Ryu Soohee , Lee Jun Kyu , Lee Hwajin 
Published: March 2024

Abstract
In Target Protein Degradation (TPD) field, conventional E3 ligases utilized in the clinic are limited to CRBN and VHL, which opens the need for exploration of novel E3 ligases for the advancement of TPD. To address this, we have developed a proprietary platform, UPPGRADER, for systematic discovery of novel E3 ligases based on -omics data including single cell RNA sequencing (scRNA-seq) and whole genome sequencing (WGS), in conjunction with proteomics data and bioinformatics tools.UPPGRADER enables systematic analyses on alterations occurred in all genomic areas including E3 ligase genes and potential target genes. For example, analyzing Pan-Cancer Analysis of Whole Genomes (PCAWG) data identified amino acid changes into Cysteine or Lysine, which can be targeted by covalent binders with cancer specificity. Through such analysis, we discovered several novel E3 ligases, including but not limited to FBXW7, with the categorization of the findings based on specific cancer types.At the single cell expression level, UPPGRADER provides the capability to assess gene expression levels of E3 ligases and target proteins by proprietary measurements based on gene detection rate. This system also allows assessment of E3 ligase-Target gene co-expression per single cell. In colorectal cancer, UPPGRADER has shown that the co-expression of E3 ligase FBXW7 and well-known colorectal cancer target (KRAS) increases from 1% (4 out of 334) in normal epithelial cells to 17% (2,967 out of 17,458) in cancerous epithelial cells, highlighting a significant change in their simultaneous expression patterns during cancer progression.UPPGRADER also identified E3 ligase X which showed high co-expression level with KRAS gene alongside universal expression properties and high cancer cell dependencies. For E3 ligase X, we developed novel small molecule binders (nM binding affinity) with bioavailability &gt; 20% in animal pharmacokinetics. Bifunctional degraders utilizing these binders displayed BRD4 degradation in more than 20 cell lines with double to triple digit nM DC50 and DC90 values. Other targets (AURKA, CRBN and others) were potently degraded with anticipated mechanism of action (assessed by E3 ligase KO cell line and proteasomal inhibitors).To conclude, UPPGRADER is a comprehensive bioinformatics tool for discovering novel E3 ligases with biological validations. Through recent explosion of scRNA-seq and WGS datasets in different diseases and mechanism-based identification of additional molecular targets, UPPGRADER is poised to advance the field of TPD.
Citation Format: Kyungsik Ha, Woojeung Song, Woochang Choi, Gi Bbeum Lee, Soohee Ryu, Jun Kyu Lee, Hwajin Lee. UPPGRADER: a bioinformatics-based novel E3 ligase discovery platform [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 6054.
Abstract 6064: Discovery of potent and selective EP300 degraders with anti-cancer activity
Authors: Zimmerman Mark , Adam Ammar , Ahmad Hafiz , Adams Benjamin , Adhikari Ketaki , Austin Wesley , Bullock Breanna , Bernardo Julie Di , Dixon Thomas , Daniels Danette , Dominici Claudia , Elliot GiNell , Ethell Brian , Gervais Anais , Hossain Md Imran , Huang David , Lahr Dave , Lin Mei Yun , Mayhew David , Mizeracka Karolina , Negretti Solymar , Nguyen Tyler , Prifti Olga , Sappal Darshan , Schiller Shawn , Sherbanee Brenna , Terry David , Ucisik Nihan , Wittenborn Elizabeth , Zhou Qianhe , La Bonte Laura 
Published: March 2024

Abstract
E1A binding protein (EP300) and CREB binding protein (CBP) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcriptional co-activators. Dysregulation of one or both proteins has been implicated in various cancers, and functional genomic screens have demonstrated a bidirectional synthetic lethal relationship between the two genes in tumor cells. Due to the high homology between EP300 and CBP, identifying chemical matter that selectively targets EP300 or CBP has proven challenging. Here, we describe a potent, highly selective heterobifunctional degrader of EP300 with biological activity in CBP-deficient and EP300-dependent tumor cells. Targeted degradation of EP300 protein resulted in a stronger suppression of cell growth and survival than targeting the bromodomain or HAT activity of EP300/CBP with small molecule inhibitors. Anti-proliferative effects have been demonstrated in multiple cancer types, including malignant lymphomas and castration-resistant prostate tumors, highlighting the essential role of EP300 in mediating oncogenic transcription required for tumor cell growth and survival. Degradation of EP300 in vivo attenuated androgen-driven transcription and inhibited tumor growth in VCAP (AR+) prostate tumor xenografts. Importantly, no evidence of overt toxicity or thrombocytopenia was observed at therapeutically efficacious doses. These findings indicate that selective targeting of EP300 with targeted protein degradation is a safe and effective treatment strategy for advanced tumors.
Citation Format: Mark Zimmerman, Ammar Adam, Hafiz Ahmad, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie Di Bernardo, Thomas Dixon, Danette Daniels, Claudia Dominici, GiNell Elliot, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, Dave Lahr, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Darshan Sappal, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Qianhe Zhou, Laura La Bonte. Discovery of potent and selective EP300 degraders with anti-cancer activity [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 6064.
Abstract 6082: Rapid on-site nucleic acid detection using CRISPR and digital signal processing for portable and integrated cervical cancer screening in low resource settings
Authors: Lee Chang Yeol , Kim Hyunho , Lee Hanna , Randall Thomas , Ly Amy , Lee Hakho , Castro Cesar M. 
Published: March 2024

Abstract
Addressing the global disparity in cancer care necessitates the development of rapid and affordable nucleic acid (NA) testing technologies. This need is particularly critical for cervical cancer. Molecular detection of human papillomavirus (HPV) has emerged as a highly accurate screening method, surpassing traditional Pap smears. However, implementing this transition in low- and middle-income countries has been challenging due to the high costs and centralized facilities required for current NA tests. Here, we present CreDiT (CRISPR Enhanced Digital Testing), an advanced diagnostic system for rapid, on-site NA detection. CreDiT integrates two major technical breakthroughs: i) a one-pot CRISPR strategy that simultaneously amplifies both target NAs and analytical signals, and ii) a robust fluorescent detection method based on digital communication (encoding/decoding) technology. These innovations enhance CreDiT's practical utility, offering a rapid assay (&lt;35 minutes) that integrates NA extraction and detection in a single streamlined workflow. Furthermore, CreDiT's straightforward probe design enables easy incorporation of new NA targets, while its compact device provides robust signal detection. We adapted CreDiT for point-of-care HPV screening by designing probes for high-risk HPV genes (HPV16, HPV18, HPV45, HPV31, HPV33, HPV58) and oncoprotein mRNAs (E6, E7, p16INK4a) and developing a portable CreDiT device capable of processing 12 samples. CreDiT demonstrated sensitive detection of cell-derived HPV DNA targets down to single copies and accurately identified HPV types in every clinical cervical brushing specimen (n = 121) we tested. This technology has the potential to facilitate prompt and reliable triaging of high-risk HPV, overcoming pathology bottlenecks and circumventing geographical and socioeconomic barriers to effective cervical cancer screening in resource-limited regions. This work has spearheaded recent screening research efforts in Uganda and Ghana.
Citation Format: Chang Yeol Lee, Hyunho Kim, Hanna Lee, Thomas Randall, Amy Ly, Hakho Lee, Cesar M. Castro. Rapid on-site nucleic acid detection using CRISPR and digital signal processing for portable and integrated cervical cancer screening in low resource settings [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 6082.
Abstract 6096: Targeting premalignant lung cancer to intercept progression to invasive disease
Authors: Martin Mitchell , He Yongfeng , Bhinder Bhavneet , Yoffe Liron , Zhong Sijin Luo , Singh Arshdeep , Elemento Olivier , Jiang Shaoyi , Altorki Nasser , Mittal Vivek 
Published: March 2024

Abstract
Increased implementation of low dose CT-guided screens in the clinic has led to the identification of premalignant lung nodules (ground glass opacity, GGO) which progress to invasive adenocarcinoma1,2. Using integrated genomic analysis of a cohort of &gt;300 patients with premalignant lesions, we constructed the first high-resolution landscape of composition, lineage/functional states, developmental trajectories, and multicellular crosstalk networks, which revealed potential targets for therapeutic intervention. We uncovered that early lesions exhibit marked immune-suppressive phenotypes characterized by increased T lymphocyte exhaustion to cytotoxic scores, decrease in NKT cells, elevated Tregs, increased myeloid suppressor activity, accumulation of immunosuppressive myeloid cells activation of unfolded protein response (UPR) sensor IRE1α that activates the multitasking transcription factor XBP1 known to drive malignant progression. Targeting IRE1α endoribouclease with a small molecule drug limited disease progression with marked immunomodulation in our newly developed Kras and EGFR driven mouse models, which mirror progression of human precursor lesions to invasive disease. As an immunoprevention approach, we have generated LNP-mRNA vaccines targeting top two shared neoantigens in premalignant lesions, which have shown marked immunogenicity and efficacy in early disease. Our work provides the molecular foundation for precision oncology strategies to intercept transition of preinvasive to invasive adenocarcinoma. 1. Altorki, N.K., et al. Nat Rev Cancer, 2019. 2. Altorki, N.K., et al. Cell Rep, 2022.
Citation Format: Mitchell Martin, Yongfeng He, Bhavneet Bhinder, Liron Yoffe, Sijin Luo Zhong, Arshdeep Singh, Olivier Elemento, Shaoyi Jiang, Nasser Altorki, Vivek Mittal. Targeting premalignant lung cancer to intercept progression to invasive disease [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 6096.