bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5775: Structure and dynamics of the major PDGFR-β oncogene promoter G-quadruplex and insights into its cellular regulation
Authors: Han Yichen , Dickerhoff Jonathan , Yang Danzhou 
Published: March 2024

Abstract
Overexpression of the receptor tyrosine kinase PDGFR-β promotes cancer growth and metastasis. PDGFR-β is a validated cancer target but PDGFR-β kinase inhibitors suffer from lack of selectivity and side effects. G-quadruplexes are an exciting class of non-B DNA secondary structures with functional importance. The G-quadruplex formed in the PDGFR-β promoter is a transcription repressor and targetable by small molecules. Therefore, the PDGFR-β promoter G-quadruplex is an attractive molecular target for anticancer drugs. Structural information of the PDGFR-β promoter G-quadruplex is crucial for understanding its cellular function and rational drug design. Herein, we used nuclear magnetic resonance (NMR) spectroscopy and biophysical methods to determine the structure and dynamics of the major G-quadruplex formed in the human PDGFR-β promoter. Unlike canonical G-quadruplexes formed by four runs of three continuous guanines (G), the major PDGFR-β G-quadruplex adopts a novel broken-strand structure where a two-G segment is continued by a non-adjacent guanine. The broken-strand G-quadruplex has a vacancy-G-tetrad (vG4) which is filled-in intramolecularly by a distal guanine. Interestingly, we discovered that the major PDGFR-β G-quadruplex is a novel mixture of two equilibrating broken-strand G-quadruplexes. Both structures adopt overall parallel-stranded folding with all 1-nt chain-reversal loops. However, a different 3’-filled-in guanine is delivered by a lateral loop, which forms structurally similar hairpin with a unique capping G-G base-pair. The formation of the equilibrating broken-strand G-quadruplexes and unique capping structures are both specific to the PDGFR-β promoter sequence. Intriguingly, the observed dynamic equilibrium between the two co-existing structures with different intramolecular fill-in guanines indicates a novel vG4 intermediate, which could be filled-in by cellular guanine metabolites such as cGMP. Therefore, our study provides critical insights into how the dynamics of the major PDGFR-β G-quadruplex lead to vG4 formation and potential regulation of gene transcription by cellular guanine metabolites. The determined molecular structures of the novel broken-strand G-quadruplexes provide a structural basis for rational design of small molecules to specifically target the major PDGFR-β promoter G-quadruplex for cancer therapeutics.
Citation Format: Yichen Han, Jonathan Dickerhoff, Danzhou Yang. Structure and dynamics of the major PDGFR-β oncogene promoter G-quadruplex and insights into its cellular regulation [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 5775.
Abstract 5793: Functional DKK1 antibodies binding to cysteine-rich domain 1 or 2 of hDKK1 demonstrate antagonistic activities on tumor suppression or TCF/LEF signaling
Authors: Wang Linya , Han Zhen , Yang Marisa , Hernandez Ana G. Lujan , Prabhu Vishwas , Hu Cameron F. , Htoy Tammy , Villalta Mouna , Yuan Tom Z. , Giang Hoa , Sato Aaron 
Published: March 2024

Abstract
Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the β-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. DKK1 has been shown to be a potent inhibitor of Wnt signaling via competing Wnt binding to LRP5/6. DKK1 is tumorigenic in multiple cancer types and also immunosuppressive via MDSCs and NK cells. Emerging evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. With Twist’s precision DNA writing technologies, we have created phage display libraries with diversity greater than 1 × 1010, and utilized machine learning model for optimal discovery. In this study, we discovered anti-DKK1 antibodies bind to different cysteine-rich domain (CRD) of hDKK1 by epitope binning and mapping, and block the binding of DKK1 to the receptor. Binding of the antibodies to different CRDs of hDKK1 lead to different activation effect. The in vitro functional assays showed that the interaction of Wnt to its receptor was restored in the presence of anti-DKK1 antibodies binding to DKK1 CRD2, resulting in TCF/LEF signaling upregulation. Moreover, anti-DKK1 antibodies binding to DKK1 CRD1 induced immune cell activation and led to tumor cell cytotoxicity. In vivo study indicated anti-DKK1 antibody lead is potent in tumor regression. Our anti-DKK1 lead shows promising efficacy in cancer immunotherapy without influencing Wnt canonical pathway.
Citation Format: Linya Wang, Zhen Han, Marisa Yang, Ana G. Lujan Hernandez, Vishwas Prabhu, Cameron F. Hu, Tammy Htoy, Mouna Villalta, Tom Z. Yuan, Hoa Giang, Aaron Sato. Functional DKK1 antibodies binding to cysteine-rich domain 1 or 2 of hDKK1 demonstrate antagonistic activities on tumor suppression or TCF/LEF signaling [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 5793.
Abstract 5807: Bicycle Toxin Conjugates®for the treatment of solid tumors
Authors: Walsh Stephen J. , Lahdenranta Johanna , Huxley Philip , Mudd Gemma , Bennett Gavin , Brown Amy , an Rietschoten Katerine , Chen Liuhong , Scott Heather , Ivanova-Berndt Gabriella , Dzionek Katarzyna , Rigby Mike , Burenkova Olga , Jeffrey Phil , Beswick Paul , Skynner Michael , Keen Nicholas 
Published: March 2024

Abstract
Bicycle Therapeutics is developing a unique class of chemically synthesized medicines. Based on its proprietary bicycle peptide (Bicycle®) phage display platform, Bicycles are a unique class of highly constrained peptides, which have demonstrated utility in the targeted delivery of different classes of payloads (for example cytotoxic agents, radioisotopes, immune modulators) into tumors. Bicycles are currently being explored in the clinic as Bicycle Toxin Conjugates® (BTCs) for targeted delivery of cytotoxic payloads into tumors. BTCs consist of a bicyclic peptide that is conjugated to a cytotoxic payload via a cleavable linker, which allows payload release in the tumor microenvironment or within the tumor cell. BTCs were developed to address the shortcomings of antibody drug conjugates (ADCs) in several ways. First, the small size of BTCs (∼4 kDa) compared to large biologic entities such as monoclonal antibody (mAb)-based conjugates (∼150 kDa) allows rapid distribution to tissues and extensive tumor penetration, which enables rapid delivery of payload into the tumor. Second, the peptidic nature of BTCs results in relatively short, yet tunable, duration of systemic exposure and liver-sparing renal elimination. These properties limit the body’s exposure to payload and should therefore minimize damage to normal tissue. In this body of work, we used in vitro cytotoxicity and cell uptake assays and mouse and rat cell line derived xenograft models for 1) cytotoxicity and anti-tumor activity evaluation, and 2) Bicycle and toxin uptake and biodistribution evaluation. Here, we show that BTCs targeting a number of different tumor antigens can deliver toxins to tumor tissue producing durable responses in a range of preclinical in vivo models, spanning several solid tumor indications.
Citation Format: Stephen J. Walsh, Johanna Lahdenranta, Philip Huxley, Gemma Mudd, Gavin Bennett, Amy Brown, Katerine an Rietschoten, Liuhong Chen, Heather Scott, Gabriella Ivanova-Berndt, Katarzyna Dzionek, Mike Rigby, Olga Burenkova, Phil Jeffrey, Paul Beswick, Michael Skynner, Nicholas Keen. Bicycle Toxin Conjugates®for the treatment of solid tumors [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 5807.
Abstract 584: Synergistic action of ATF6 and EZH2 in sensing metabolic stress to boost anti-tumor immunity
Authors: Edmondson Jacob L. , Reed Megan R. , Fil Daniel , Heflin Billie , Koss Brian , Tackett Alan J. 
Published: March 2024

Abstract
Although immune checkpoint blockade (ICB) marked a breakthrough in melanoma treatment, half of patients fail to respond, underscoring the crucial need for complementary adjuvant and neo-adjuvant therapies. Due to the low overall response rate and the stark contrast in outcomes between patients that respond and those that fail to respond, identifying the defining characteristics of immune checkpoint blockade (ICB) response is essential for enhancing the efficacy of melanoma treatments. To recapitulate and investigate the ICB-responsive phenotype in vitro, melanoma cells were metabolically adapted to an environment lacking glucose which successfully drove the dependence on oxidative metabolism and restored MHC-I expression, two established characteristics of ICB responsive tumors. Further, metabolic adaptations significantly enhance the tumor sensitivity to T-cell killing. Surprisingly even in JAK1 and IFNAR1 deficient cells, metabolic adaptation restored MHC I antigen presentation, indicating an interferon-independent mechanism of MHC-I regulation. Proteomic analysis of three metabolically conditioned melanoma cells lines (human and mouse) identified downregulation of the histone methyltransferase EZH2 and the activating transcription factor ATF6 as key corollaries of MHC-I expression. Interestingly, EZH2 and ATF6 activity were found to be inversely related in metabolically adapted cells and patient tumor samples. These studies mechanistically explore the epigenomic control of antigen presentation machinery and the transcriptional targets of ATF6 controlling sensitivity T cell killing. Here, through in vitro and in vivo studies, we demonstrate that constitutive activation of ATF6, and thereby activation of the adaptive unfolded protein response (UPR), sensitizes melanoma to immune control. These data suggest that EZH2 and ATF6 act synergistically to balance immune mediated killing during metabolic stress whereby loss of EZH2 increases MHC-I antigen presentation and activation of ATF6 sensitizes tumor cells to T cell-mediated control. Ongoing therapeutic studies combining EZH2 inhibition, ATF6 activation, and ICB in pre-clinical models further suggest targeting the synergy between EZH2 and ATF6 is a putative adjuvant or neo-adjuvant target to improve the clinical response of ICB.
Citation Format: Jacob L. Edmondson, Megan R. Reed, Daniel Fil, Billie Heflin, Brian Koss, Alan J. Tackett. Synergistic action of ATF6 and EZH2 in sensing metabolic stress to boost anti-tumor immunity [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 584.
Abstract 5850: Multiomics analysis unravels tumor metabolic reprogramming and potential resistance mechanism(s) to curative therapy in TNBC
Authors: Ren Zuen , Kurmi Kiran , Morris Robert , Joshi Shakchhi , Zaniewski Eric , Kreuzer Johannes , Gioia Gabrielle Elena , Bossuyt Veerle I. , Dontchos Brian N. , Wang Gary X. , Chou Shinn-Huey S. , Spring Laura M. , Haas Wilhelm , Haigis Marcia C. , Ellisen Leif W. 
Published: March 2024

Abstract
Drug resistance is the leading cause of treatment failure to completely eliminate viable tumor cells in ~40% of patients with triple negative breast cancer (TNBC). Making a major impact on the treatment and prognosis for TNBC patients requires a better understanding of drug resistance mechanism(s). Combining clinical data with high-throughput metabolomic and proteomic analyses, we probed the molecular basis for chemotherapy resistance in treatment-naive TNBC primary tumors, reflected by pathological complete response (pCR) and non-pCR after neoadjuvant chemotherapy (NAC). Metabolic profiling uncovered that glycolysis and oxidative phosphorylation (OXPHOS) co-exist in TNBC primary tumors compared to benign lesions regardless of pCR status, indicating metabolic reprogramming. However, non-pCR tumors were more enriched in OXPHOS and less in glycolysis relative to pCR tumors, pointing to the potential importance of OXPHOS in drug resistance. Moreover, parallel proteomic profiling of these same TNBC tumors supported the results from metabolic profiling, showing that OXPHOS was indeed highly enriched at the protein level, and may be regulated by SIRT5-mediated sirtuin signaling. In alignment with these findings, non-pCR tumors were abundantly enriched in immune-inhibitory metabolites that may be due to the products of SIRT5-mediated mitochondrial metabolism. Thus, these findings led me to hypothesize that SIRT5 may play an important role in chemoresistance through regulation of mitochondrial metabolism and ROS detoxification. Together, the metabolite resulted from SIRT5-mediated mitochondrial metabolism led to the suppression of immune cell infiltration in non-pCR tumors. Understanding SIRT5-mediated chemoresistance mechanism may uncover a metabolic and therapeutic vulnerability to resistant TNBCs.
Citation Format: Zuen Ren, Kiran Kurmi, Robert Morris, Shakchhi Joshi, Eric Zaniewski, Johannes Kreuzer, Gabrielle Elena Gioia, Veerle I. Bossuyt, Brian N. Dontchos, Gary X. Wang, Shinn-Huey S. Chou, Laura M. Spring, Wilhelm Haas, Marcia C. Haigis, Leif W. Ellisen. Multiomics analysis unravels tumor metabolic reprogramming and potential resistance mechanism(s) to curative therapy in TNBC [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 5850.
Abstract 5911: In vivo efficacy of a novel peptide-conjugated drug in patient-derived xenograft models of breast cancer
Authors: Elliott Mitchell J. , Mcguire Meghan , Silvester Jennifer , Tobin Chantal , Ghamrasni Samah El , Lui Francine , Zhai Andrew , Yoluk Ozge , Broom Aron , Stone Tracy , Butterfoss Glenn , Popa Serban , Lu Tianyu , Ing Chris , White David , Cescon David W. 
Published: March 2024

Abstract
Introduction: Antibody and peptide-conjugated drugs are rapidly entering the clinic for the treatment of patients with early and advanced breast cancer. These drugs are designed to achieve more targeted delivery of cytotoxic agents to tumor cells with robust clinical activity. ARB-1-6, a sortilin (SORT1) targeted peptide conjugated to the cytotoxic agent MMAE, has demonstrated pre-clinical activity and tolerability in cell line xenografts of breast cancer. To further characterize its spectrum of antitumor activity and biomarker correlates we evaluated ARB-1-6 in a collection of clinically and genomically annotated breast cancer patient-derived xenografts (PDX).
Methods: Breast cancer PDX models were generated and propagated under IRB approved protocols [14-8358]. ARB-1-6 was dosed in tumor-bearing SCID mice by tail vein injection at 3 mg/kg weekly x 4 doses. Tumor volume was measured twice weekly until day 35 or until models reached humane endpoints, after which tumors were collected. Animals were weighed regularly and assessed for treatment-related toxicity.
Results: 7 models (5 TN and 2 HR) have completed efficacy assessment to date. 3/7 models were derived from treatment naïve patients while 4/7 were derived from pre-treated patients (Table 1). Complete response (mRECIST) was seen in 5/7 (71.4%) models with stable disease occurring in 2/7 (28.6%). ARB-1-6 was well tolerated with no weight loss observed. Complete tumor regression was seen in a PDX derived from a patient with clinical resistance to a TROP2 antibody drug conjugate (ADC). Antitumor activity was observed in models with low SORT1 RNA expression; SORT1 IHC and other correlatives studies are underway.
Conclusion: ARB-1-6 demonstrates substantial preclinical activity in PDX models at doses that are well tolerated in mice. Treatment of additional models is ongoing. Full results and correlative analyses including relationships between antitumor activity and target protein expression will be presented.
PDX Model Characteristics and Patient Treatment PDX Subtype Pt. Treatment 1 TN AC-T 2 TN FEC-D, Gem+Carbo 3 TN AC-T 4 TN No 5 TN No 6 HR No 7 HR TC, ET, Cape, Gem+Cis, TROP2-ADC
Citation Format: Mitchell J. Elliott, Meghan Mcguire, Jennifer Silvester, Chantal Tobin, Samah El Ghamrasni, Francine Lui, Andrew Zhai, Ozge Yoluk, Aron Broom, Tracy Stone, Glenn Butterfoss, Serban Popa, Tianyu Lu, Chris Ing, David White, David W. Cescon. In vivo efficacy of a novel peptide-conjugated drug in patient-derived xenograft models 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 5911.
Abstract 5934: Ferroptosis induction therapy for castration resistant prostate cancer
Authors: Awolowo Mojisoluwa , Dike Precious Elechi , Odero-Marah Valerie 
Published: March 2024

Abstract
Prostate cancer (PCa) is the most common non-skin cancer in men, and second leading cause of death. The fundamental treatment for treating PCa is androgen deprivation therapy which is an effective form of treatment initially. Nevertheless, the disease reoccurs in most men; this is referred to as castration-resistant PCa (CRPC), for which the standard treatment is enzalutamide. However, some develop resistance to this enzalutamide anti-androgen agent. Ferroptosis is an iron-dependent lipid peroxidation form of regulated cell death being investigated as a novel potential therapy for PCa using ferroptosis inducers such as RSL3; they have shown promise in selectively triggering cell death in cancer cells while sparing healthy tissues. We hypothesize that RSL3- induced ferroptosis will overcome enzalutamide resistance in PCa cells. To test this, we utilized C4-2B MDVR cells which represents a cell model for aggressive PCa that metastasized to the bone and is resistant to both castration therapy and the enzalutamide drug treatment. C42B-MDVR cells were treated with increasing concentrations of RSL3 followed by analysis of cell viability with MTS assay. A dose dependent reduction in cell viability was observed which was reversed by ferroptosis inhibitor, ferrostatin-1. Western blot analysis revealed a decreased expression of the antioxidant enzyme glutathione peroxidase 4 (GPX4) with ferroptosis induction indicating a mechanism of the RSL3-induced cell death. The limitations to our research are that the research was performed in vitro and have not been tested on mouse models to visualize the effects of the treatments in animals. In conclusion, ferroptosis inducer RSL3 decreases GPX4 expression and decreases proliferation of PCa cells while ferrostatin-1 reverses the effects of the RSL3 treatment. Thus, ferroptosis inducers present a potential novel therapeutic approach for CRPC patients who have developed resistance to conventional androgen therapies. NIH NIGMS RISE 5R25GM058904, NIH/NIMHD U54MD007590; U54MD013376
Citation Format: Mojisoluwa Awolowo, Precious Elechi Dike, Valerie Odero-Marah. Ferroptosis induction therapy for castration resistant 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 5934.
Abstract 5971: F3 targeted near-infrared photoimmunotherapy: The ideal therapeutic approach for numerous malignancies
Authors: Takao Seiichiro , Furusawa Aki , Fukushima Hiroshi , Okuyama Shuhei , Kano Makoto , Yamamoto Hiroshi , Choyke Peter L. , Kobayashi Hisataka 
Published: March 2024

Abstract
Introduction: F3 is a cell surface protein that plays a role in blood clotting, but recent research has revealed its implication in cancer proliferation, metastasis, angiogenesis, and immune escape. TCGA cohort analysis has shown that elevated F3 is a common feature of many cancers, and generally correlates with poor patient survival. Therefore, the potential of F3 as a therapeutic target in cancer is worth exploring. Tisotsumab-vedotin, an antibody-drug conjugate (ADC) that targets F3, was approved by the FDA for cervical cancer and is undergoing clinical trials in some solid cancers. However, ADCs may give rise to concerns about drag resistance following cellular internalization. Herein, we developed and tested an F3 targeted near-infrared photoimmunotherapy (NIR-PIT) to overcome some of these resistance mechanisms.
Methods: We created a conjugate of tisotumab as an F3 antibody and IR700. The efficacy of F3-targeted NIR-PIT was investigated using multiple cancer cell lines (A431; epidermoid carcinoma, HPAF-II; pancreatic adenocarcinoma, HSC-2; oral carcinoma, HT-1376luc; bladder carcinoma, MDAMB231; breast adenocarcinoma, and SKOV-3; ovarian serous cystadenocarcinoma) in vitro. In vivo, the efficacy of F3-targeted NIR-PIT was evaluated in HPAF-II tumor using xenograft mouse models. In addition, the pathological change after NIR-PIT was also evaluated in A431, HPAF-II, HSC-2, HT-1376luc, MDAMB231, and SKOV-3 tumors.
Results: These cell lines showed F3 expression in vitro and in vivo. Additionally, F3 expression was specific to cancer cells in HPAF-II tumor model. In vitro, F3-targeted NIR-PIT damaged the multiple cell lines in an NIR light dose-dependent manner. In vivo, F3-targeted NIR-PIT suppressed tumor growth and improved survival rates compared to the untreated group. Pathologically, A431, HPAF-II, HSC-2, HT1376-luc, MDAMB231 and SKOV-3 tumors after NIR-PIT contain large numbers of necrotic cells that are shown typically less dark nuclei and eosinophilic cytoplasm with some vacuolar degeneration than untreated tumors.
Conclusions: F3-targeted NIR-PIT holds the efficacy against multiple cancers expressing F3, regardless of the specific cancer type. Therefore, this modality exhibits significant promise as a potential NIR-PIT option.
Citation Format: Seiichiro Takao, Aki Furusawa, Hiroshi Fukushima, Shuhei Okuyama, Makoto Kano, Hiroshi Yamamoto, Peter L. Choyke, Hisataka Kobayashi. F3 targeted near-infrared photoimmunotherapy: The ideal therapeutic approach for numerous malignancies [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 5971.