bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2287: Circulating extracellular vesicles from patients with advanced pancreatic cancer contain low levels of tumor-derived DNA
Authors: Lapin Morten , Tjensvoll Kjersti , Nedrebø Karoline , Taksdal Eline , Janssen Hans , Gilje Bjørnar , Nordgard Oddmund 
Published: June 2023

Abstract
Purpose: Extracellular vesicles (EVs) have been shown to contain nucleic acids, including DNA. Several studies have highlighted the potential of EV-derived DNA (evDNA) as a circulating biomarker, even demonstrating that evDNA can outperform circulating cell-free DNA (cfDNA) in terms of sensitivity. Here, we evaluated whether EVs could be a potential source of tumor-derived DNA in patients with advanced pancreatic cancer.
Methods: evDNA from both DNase-treated and untreated circulating EVs, enriched from patients with advanced pancreatic cancer (n=10), was analyzed by fluorometry and digital droplet PCR to determine the level of evDNA inside and outside (surface-bound) the EVs. To also determine if choice of methodology affected the results, EVs were isolated using four different small EV isolation methods (differential ultracentrifugation, size-exclusion chromatography, affinity purification and precipitation) and differential centrifugation for isolation of large EVs. Western blotting, dynamic light scattering and transmission electron microscopy confirmed the enrichment of EVs.
Results: Our results indicated that EVs enriched from patient blood samples contained significantly lower amounts of DNA compared to cfDNA (p &lt; 0.001); &gt;50-fold lower for untreated sEVs and &gt;1000-fold lower for DNase-treated EVs. Thus, most of the detected vesicle-associated DNA seemed to be located outside of the vesicles. Further, tumor-derived DNA in EVs was barely detectable and the tumor-derived fraction in all evDNA samples was similar to that of cfDNA.
Conclusion: Our results demonstrated that evDNA do not add any extra information compared with cfDNA as a source of tumor-derived DNA, at least not in patients with advanced pancreatic cancer.
Citation Format: Morten Lapin, Kjersti Tjensvoll, Karoline Nedrebø, Eline Taksdal, Hans Janssen, Bjørnar Gilje, Oddmund Nordgard. Circulating extracellular vesicles from patients with advanced pancreatic cancer contain low levels of tumor-derived DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2287.
Abstract 2656: Reversible chemical modification of antibodies: A complementary approach to tuning FcγR binding that maintains anti-tumor activity while mitigating peripheral immune activation
Authors: Moquist Philip N. , Leiske Chris I. , Bindman Noah A. , Zhang Xinqun , Duncan Nicole , Zeng Weiping , Wo Serena W. , Wong Abbie , Henderson Clark M. , Crowder Karalyne , Neff-LaFord Haley D. , Sussman Django , Gardai Shyra J. , Levengood Matthew R. 
Published: June 2023

Abstract
Modification of effector function has proven to be an effective modality for optimizing activity and tolerability of therapeutic antibodies. Currently available methods to modulate effector function include the introduction of point mutations in the Fc region and glycan engineering of the antibody. Here we present an alternative and complementary method of tuning effector function utilizing a conjugation-based approach. This methodology uses conjugation of polyethylene glycol (PEG) to native cysteines of an antibody to impair FcγR binding of antibodies to innate immune effector cells. Utilizing maleimide or disulfide conjugation techniques, attenuated effector function can be either permanent or restored over time through a de-conjugation process. Impacts of PEGylation on FcγR binding, signaling, and restoration of function were assessed in vitro and in vivo. As a proof-of-concept, the lead technology was applied to an agonist CD40 antibody, which resulted in significant reductions in systemic cytokine production in hCD40 mice and non-human primates, while demonstrating retained efficacy and improved pharmacokinetics. Additionally, we combined the conjugation technology with glycan engineering and FcγR enhancing point mutations to impart unique effector function profiles to clinical antibodies. This simple, modular approach can be rapidly applied to existing antibodies to reduce immune-driven toxicities, such as infusion reactions, and optimize effector function activity.
Citation Format: Philip N. Moquist, Chris I. Leiske, Noah A. Bindman, Xinqun Zhang, Nicole Duncan, Weiping Zeng, Serena W. Wo, Abbie Wong, Clark M. Henderson, Karalyne Crowder, Haley D. Neff-LaFord, Django Sussman, Shyra J. Gardai, Matthew R. Levengood. Reversible chemical modification of antibodies: A complementary approach to tuning FcγR binding that maintains anti-tumor activity while mitigating peripheral immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2656.
Abstract 2678: Combination therapy with cabozantinib and cannabidiol enhances the apoptotic cell death via phosphorylation ofTP53 regulated by ER-stress in hepatocellular carcinoma
Authors: Jeon Youngsic , Kim Taejung , Kwon Hyukjoon , Ham Jungyeob , Kim Young-Joo 
Published: June 2023

Abstract
Cannabidiol (CBD), a primary constituent of hemp and cannabis, has pharmacologically broad properties for a variety of diseases including cancer. Cabozantinib (CBZ), a potent multikinase inhibitor, has been approved for use in patients with advanced hepatocellular carcinoma (HCC). Recently, research is increasing for combination therapy using CBZ for better improved efficacy and safety for the patients. Here, we investigated the effect of the combination therapy with CBZ and CBD in HCC cells. CBD enhances the sensitivity of CBZ against HCC cells by increasing cytotoxicity and apoptosis. Especially, analysis of phospho-kinase array demonstrated that the apoptotic effect of combination treatment with CBZ and CBD was significantly related phosphorylation of TP53 regulated by endoplasmic reticulum stress (ER-stress) compared to other kinases. Inhibition of TP53 expression and ER-stress abolished the apoptotic effect of combination treatment with CBZ and CBD, revealing no expression changes in Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9. On the other hand, we found that the effect of combination treatment with CBZ and CBD was not associated with cannabinoid receptor 1 (CNR1) and CNR2 receptors signaling pathway. Our findings suggest that combination therapy with CBZ and CBD provides enhanced therapeutic efficacy against HCC.
Citation Format: Youngsic Jeon, Taejung Kim, Hyukjoon Kwon, Jungyeob Ham, Young-Joo Kim. Combination therapy with cabozantinib and cannabidiol enhances the apoptotic cell death via phosphorylation ofTP53 regulated by ER-stress in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2678.
Abstract 2858: Radiotherapy and NK cell-based immunotherapy: An evolutionary double-bind
Authors: Luddy Kimberly , West Jeffery , Robertson-Tessi Mark , Desai Bina , Bursell Taylor M. , Barrett Sarah , Brown Joel , O'Sullivan Jacintha , Gatenby Robert , Marignol Laure , Anderson Alexander R. , O'Farrelly Cliona 
Published: June 2023

Abstract
Evolution-informed therapies exploit the ecological and evolutionary consequences of drug resistance to inhibit the expansion of treatment resistant populations and prolong time to progression. One strategy, termed an evolutionary double-bind, uses an initial therapy to elicit a specific adaptive mechanism that is then selectively targeted by a follow-on therapy. Here we examine combining radiation therapy followed by immunotherapy as a double bind strategy. Radiotherapy (RT) induces lethal double-strand DNA breaks in tumor cells and radiosensitivity is governed by the cells’ DNA repair capabilities. Radioresistant cancer cells upregulate DNA damage response pathways. However, successful adaptations to RT and other DNA damaging agents can increase natural killer (NK) cell ligand expression on tumor cells increasing their vulnerability to the immune system.
We conducted a multidisciplinary investigation of this potential evolutionary double bind using an isogenic cell line model of radiation resistance derived from an androgen-independent human prostate carcinoma cell line (22Rv1). We demonstrate that RT-resistant cells maintain higher expression of NK cell ligands and have a 2-fold increase in sensitivity to NK cell mediated killing. Furthermore, we show that preferential targeting of the RT-resistant population by NK cells is preserved in competition assays with varying initial population frequencies. Scope of treatment responses are dependent on population frequencies in our in vitro analysis.
Mathematical modeling quantified three key elements of a double-bind: cost of resistance, inter-specific competition between RT-sensitive and RT-resistant lines, and preferential targeting of RT-resistant lines by NK cells. We conclude that RT followed by immunotherapy produces an evolutionary double bind that can be exploited in heterogenous tumors to limit RT resistance. Furthermore, model simulations predict that extinction of both populations is achievable by sequential RT and NK cell therapy.
Citation Format: Kimberly Luddy, Jeffery West, Mark Robertson-Tessi, Bina Desai, Taylor M. Bursell, Sarah Barrett, Joel Brown, Jacintha O'Sullivan, Robert Gatenby, Laure Marignol, Alexander R. Anderson, Cliona O'Farrelly. Radiotherapy and NK cell-based immunotherapy: An evolutionary double-bind [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2858.
Abstract 3088: Identification of a novel series of MTAP-selective PRMT5 inhibitors, and first disclosure of AZ-PRMT5i-1
Authors: Smith James M. , Barlaam Bernard , Beattie David , Cumming Iain , Robb Graeme , Wilson David , Gianni Davide , Srinivasan Bharath , Stubbs Chris , Debreczeni Judit , Vazquez-Chantada Mercedes , Chiarparin Elisabetta , Lynch James , Dean Emma 
Published: June 2023

Abstract
Background: PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. Despite this therapeutic potential, there is growing evidence that the first generation of clinical PRMT5 inhibitors may not be able to achieve high clinical efficacy due to PRMT5-driven (e.g. hematological) toxicities.
Aims: In order to pharmacologically exploit the MTAP ‘collateral vulnerability’ mechanism for the potential of increased therapeutic index and clinical efficacy, next-generation PRMT5 inhibitors are required to bind PRMT5 in a cooperative manner with natural metabolite methylthioadenosine (MTA). Whilst MTAP-selective PRMT5 inhibitors have recently been reported,1,2,3 there is continued interest in identifying new and structurally diverse in vivo-quality compounds to further investigate this therapeutic opportunity.
Results: To identify novel inhibitors of PRMT5 suitable for the MTAP line of sight, our hit finding strategy used a ‘biased’ biochemical high throughput screen of a 2.4M compounds collection. MTA-cooperative hits were validated using techniques including SPR and Xray crystallography. One series identified from this screen was extensively optimized using techniques including structure-based design to improve potency, MTAP selectivity and DMPK properties. Through these optimizations, we have identified AZ-PRMT5i-1, which shows potent in vitro cellular inhibition of PRMT5, over 50-fold MTAP selectivity margin, excellent selectivity against a broad panel of methyltransferases, and suitable oral PK properties.
Conclusion: AZ-PRMT5i-1 is a structurally novel and potent PRMT5 inhibitor with high MTAP-selectivity suitable for use in in vitro and in vivo PRMT5-driven models of cancer’.
Note: the structure of AZ-PRMT5i-1 will be disclosed at this meeting
PRMT5 Cell SDMA: IC50 nM (HCT116 MTAP KO/WT) SDMA MTAP selectivity (fold) LogD/Rat heps CLint/Caco2 intr. A-B HTS hit A 660/4300 6.5 2.1/34/1.6 AZ-PRMT5i-1 5.4/290 54 2.8/5.0/48
References:1. J. Med. Chem. 65, 1749-1766 (2022); 2. WO2021163344; 3. WO2022026892
Citation Format: James M. Smith, Bernard Barlaam, David Beattie, Iain Cumming, Graeme Robb, David Wilson, Davide Gianni, Bharath Srinivasan, Chris Stubbs, Judit Debreczeni, Mercedes Vazquez-Chantada, Elisabetta Chiarparin, James Lynch, Emma Dean. Identification of a novel series of MTAP-selective PRMT5 inhibitors, and first disclosure of AZ-PRMT5i-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3088.
Abstract 3101: Discovery of helical sulfonyl-γ-AApeptides targeting LC3 in cancer cells
Authors: Mahmoud Mentalla , Chen Jianyu , Cai Jianfeng , Xie Hao 
Published: June 2023

Abstract
Introduction: Autophagy pathway activation and upregulation is an important mechanism for cancer cell survival upon exposure to chemotherapeutic agents. LC3, a ubiquitin-like protein, plays a key role in the regulation of cargo selection and autophagosome formation. Given small molecule inhibitors have not been well developed to target LC3, we aim to design and synthesize an LC3 binder and evaluate its activity in the inhibition of autophagy pathway in cancer cells.
Methods: The crystal structure of LC3 and p62 complex (PDB: 2ZJD) was used to assist our design of helical sulfonyl-γ-AApeptides to the LC3 interacting region of p62. The peptidomimetics were synthesized on the solid phase and purified by HPLC. We used fluorescent polarization assay to assess the binding affinity of the peptidomimetics to LC3. We then utilized an LC3 HiBiT reporter cell line (U2OS) from Promega, which was engineered to have a fused human LC3-HiBiT with a HaloTag in between to study the effect of the lead LC3 binder on autophagic flux. In addition, confocal microscopy enabled direction visualization of the colocalization of FITC-labeled LC3 binder with LC3 and lysosome, respectively. Cytotoxicity of LC3 binder was evaluated in colorectal cancer cell line HCT116.
Results: We designed and synthesized 6 helical sulfonyl-γ-AApeptides (JC1-6) to target the binding interface of LC3 and p62. These peptidomimetic compounds were designed to retain essential LC3 and p62 interactions at the W and L regions and yet have different functional groups on the helical scaffold. Compounds JC1 and JC6 have binding affinity of Kd 280 nM and 150 nM with LC3, respectively. FITC-labelled JC6 was able to penetrate U2OS and HCT116 cells. It had intracytoplasmic colocalization with not only lysosomes but also LC3 aggregates. Direct visualization of intracytoplasmic LC3 aggregates showed that JC6 at 50 µM significantly inhibited the autophagic degradation of LC3 aggregates. This effect was augmented by the presence of 2 µM autophagy activator PP242. Lastly, JC6 demonstrated cytotoxicity with IC50 approximately 50 µM in HCT116 cells bearing baseline autophagy activation compared to lack of cytotoxicity in U2OS cells with no baseline autophagy activity.
Conclusion: We designed and synthesized novel helical sulfonyl-γ-AApeptide LC3 binders. With the ability of cellular penetration, they demonstrated inhibition of autophagic flux and preliminary cytotoxicity in cancer cells. Future studies may focus on structural activity relationship and further evaluation of its mechanisms of action in cancer cells.
Citation Format: Mentalla Mahmoud, Jianyu Chen, Jianfeng Cai, Hao Xie. Discovery of helical sulfonyl-γ-AApeptides targeting LC3 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3101.
Abstract 312: The ATR inhibitor ART0380 shows preclinical efficacy in monotherapy or in combination with gemcitabine, aPD1, PARP inhibitors and topoisomerase 1 poisons
Authors: Majithiya Jayesh Bhanabhai , Luzarraga Marina Roy , Newman Richard , Costales Paula , Jones Philip , Francesco Maria Emilia Di , Giuliani Virginia , Caroll Chris , Do Mary Geck , Heffernan Tim , Feng Ningpeng , Ma XiaoYan , lively Sarah , Johnson Michael G. , Geo Lerin , Piscitello Desiree , Rajendra Eeson , Grinkevich Vera , Ranzani Marco , Stockley Martin , Langford Gillian , Heald Robert , Robinson Helen M. , Smith Graeme C. 
Published: June 2023

Abstract
ART0380 is a potent, selective and orally active inhibitor of ataxia telangiectasia and Rad3-related (ATR) that has been developed for treatment for cancer patients with DNA repair defects. Here we show preclinical data of ART0380 in a range of tumour xenograft models, both as monotherapy and in combination with other DNA-damaging agents. As monotherapy, ART0380 exhibits tumour PD (γH2AX) effects and efficacy comparable to the ATR inhibitor BAY-1895344 but causing less toxicity to the gut. As ATM has been highlighted as synthetic lethal with ATR, ART0380 monotherapy was also evaluated in ATM-deficient models showing strong tumour growth inhibition using both continuous and intermittent scheduling. ART0380 was also shown to have enhanced efficacy when dosed in combination with other anti-cancer agents. Here we show strong synergy when combining ART0380 with gemcitabine, the PARP inhibitor olaparib, the topoisomerase 1 poison irinotecan as well as the immuno-oncology therapeutic aPD1. Overall, these data demonstrate the high potential of ART0380 as an anti-cancer agent given as monotherapy or in combination
Citation Format: Jayesh Bhanabhai Majithiya, Marina Roy Luzarraga, Richard Newman, Paula Costales, Philip Jones, Maria Emilia Di Francesco, Virginia Giuliani, Chris Caroll, Mary Geck Do, Tim Heffernan, Ningpeng Feng, XiaoYan Ma, Sarah lively, Michael G. Johnson, Lerin Geo, Desiree Piscitello, Eeson Rajendra, Vera Grinkevich, Marco Ranzani, Martin Stockley, Gillian Langford, Robert Heald, Helen M. Robinson, Graeme C. Smith. The ATR inhibitor ART0380 shows preclinical efficacy in monotherapy or in combination with gemcitabine, aPD1, PARP inhibitors and topoisomerase 1 poisons [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 312.
Abstract 316: Engineering large chromosomal deletions to advance precision oncology for prostate cancer
Authors: Wu Jinjin , Wu Chen , Lawitts Joel A. , Bock Cheryl B. , Huang Jiaoti , Chen Ming 
Published: June 2023

Abstract
Human prostate cancer is notable for its high number of somatic copy number alterations (CNAs), which include both focal and broad arm-level amplifications and deletions. Up to 90% of prostate tumors harbor aberrant CNAs, and genomic deletions affect about 40% of these tumors. Many chromosomal deletions are highly recurrent and occur in more than 10% of prostate tumors, including 8p (40~50%), 6q14-16, 10q23, 13q14, and 16q22-24 (20~30% each). Most of these deletions are large, often including hundreds of genes. Notably, several large deletions, including 6q14-16 and 16q22-24, are significantly associated with poor patient outcomes, suggesting that these large chromosomal deletions play a functional role in prostate tumorigenesis, and highlighting the critical need for elucidation of the mechanisms underlying large-deletion driven tumorigenesis. However, due to the limited cloning capacity of targeting vectors and the rarity of on-target homologous recombination events in traditional gene-targeting technology, modelling large chromosomal deletions has proven highly challenging, and the role of such lesions in tumorigenesis has therefore been significantly understudied. Here, we developed an innovative approach to engineering the chromosome over large genetic distances through CRISPR/Cas9 technology in both mouse embryonic stem (ES) cells and human prostate cancer cells. Upon completion of the desired genome edits, the resulting mouse ES clones make possible the creation of conditional knockout mice that accurately mimic prostate cancer-associated large deletions, while the engineered human cancer cell clones serve as an indispensable in vitro model to validate the biological relevance of large chromosomal deletions in prostate tumorigenesis. Further characterization of the human prostate cell line bearing 10q23 deletion revealed that 10q23 loss conferred RWPE1 cells growth advantage. The development and characterization of these in vivo and in vitro models will contribute greatly to the implementation of precision oncology research, open new opportunities for modelling human diseases associated with large chromosomal deletions, and lead to novel insights into the biology of prostate cancer-associated large deletions, which will facilitate the identification of deletion-specific vulnerabilities that can be exploited for prostate cancer treatment.
Citation Format: Jinjin Wu, Chen Wu, Joel A. Lawitts, Cheryl B. Bock, Jiaoti Huang, Ming Chen. Engineering large chromosomal deletions to advance precision oncology for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 316.