bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5738: Repurposing disulfiram for cancer: A drug delivery and population-based approach
Authors: Heroux Devon , Leung Ada W. , Gilabert-Oriol Roger , Bally Marcel B. 
Published: March 2024

Abstract
Purpose: Disulfiram was approved by the FDA for treatment of alcohol abuse in 1951, although for over 40 years there has been evidence supporting disulfiram’s use as an anti-cancer drug. Upon administration, disulfiram is hydrolyzed to form two molecules of DDC, which upon binding Cu forms Cu(DDC)2, the proposed active form against cancer. It was our goal to formulate the water-insoluble Cu(DDC)2 in liposomes to facilitate its repurposing for breast and colon cancers. In addition, we also initiated an ongoing population-based study assessing the protective and treatment effects of disulfiram with cancer.
Methods: Cu(DDC)2 liposomes were generated by the thin-film hydration method followed by extrusion, using DSPC and cholesterol (55:45 molar ratio). DDC and CuSO4 were added to the liposomes forming Cu(DDC)2, which was transported inside the liposomes. Anti-tumor activity was evaluated in tumor-bearing mice with or without competent immune systems, and immune system activation was assessed via a cancer vaccination model and the expression of markers of immunogenic cell death (ICD). A study was also initiated for cancer cases and controls in British Columbia (BC Cancer) with at least one prescription of disulfiram from 1996-2022 (PharmaNET), patients treated with immune-modulating therapies (BC Cancer), and outcome of death (Vital Statistics).
Results: Liposomes encapsulating Cu(DDC)2 had a size of 100 nm and polydispersity of 0.1, and caused a 40% reduction in tumor burden in a MDA-MB-231 xenograft model. In a syngeneic tumor model of breast cancer the response with immune-competent mice was greater than mice lacking immune function, and a cancer vaccination model and the presence of ATP, HMBG1 and surface-exposed calreticulin indicated the presence of ICD.
Conclusions: Cu(DDC)2 was formulated in liposomes facilitating its parenteral administration, and its anti-cancer activity was found to be due in part to activation of the adaptive immune system through ICD. A case-control study is currently being employed to examine the clinical potential of disulfiram, as a protectant and as an adjuvant with immune-activating therapies such as checkpoint inhibitors and anthracyclines to potentially improve efficacy through induction of ICD.
Citation Format: Devon Heroux, Ada W. Leung, Roger Gilabert-Oriol, Marcel B. Bally. Repurposing disulfiram for cancer: A drug delivery and population-based approach [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 5738.
Abstract 5758: Gold nanoparticles with graphene quantum dots as drug delivery platforms for anticancer applications
Authors: Suárez Fabiola M. Rosa , Morell Gerardo , Weiner Brad , Medina Nataniel , Pantoja Wenndy 
Published: March 2024

Abstract
Cancer is a global health challenge that has a profound impact on the lives of people worldwide, either directly affecting individuals or their loved ones. Among the various types of cancer, prostate cancer stands out as one of the most prevalent in men. Prostate cancer is primarily identified by symptoms related to urinary health. Conventional medical approaches often rely on drug-based treatments to address this form of cancer. However, like many treatments, drug therapy comes with its own set of challenges. In our research project, we propose an alternative approach for managing prostate cancer. Our innovative idea centers around utilizing nanoparticles as a means of drug delivery. Specifically, we are investigating the use of Taxol, also known as Paclitaxel, as the drug of interest. Taxol possesses a significant challenge due to its hydrophobic nature, which hinders its circulation within the bloodstream. Its solubility is extremely low, at 0.00025 mg per milliliter. To overcome this limitation, we have undertaken the synthesis and integration of AuNPs (gold nanoparticles) with GQDs (graphene quantum dots). This combination enhances the drug's hydrophilic properties, making it more effective in transportation. Our research has led us to conduct experiments on prostate cancer cells (specifically the PC3 cell line). We aim to compare the IC50 value, which represents the drug concentration required to kill 50% of the cancer cells, when using the drug alone versus when using the drug in conjunction with the nanoparticles. Taxol's IC50 value is determined to be 5.73nM. In addition to assessing the impact on cancer cells, we have also examined how the nanoparticles interact with blood, and how this interaction influences the morphology of red blood cells. Furthermore, we have characterized the system using various analytical techniques, including FTIR, NMR, Fluorescence, and UV-Vis spectroscopy. To pinpoint the accumulation sites of the drug and delivery agents, we have employed confocal microscopy on the cancer cells. Our ultimate objective is to equip the drug with the necessary components to facilitate its entry into prostate cancer cells effectively.
Citation Format: Fabiola M. Rosa Suárez, Gerardo Morell, Brad Weiner, Nataniel Medina, Wenndy Pantoja. Gold nanoparticles with graphene quantum dots as drug delivery platforms for anticancer applications [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 5758.
Abstract 58: Immunocytokines with specificity for invariant region of CAR molecules enhance effector function of multiple CAR T cell therapies
Authors: Keane J T. , Dagher Oula K. , Liu Fang , Posey Avery D. 
Published: March 2024

Abstract
The effector functions of CAR T cells can be enhanced through delivery of immunostimulatory cytokines, such as IL-12, IL-18, or IL-23. However, systemic delivery of recombinant cytokines or paracrine secretion by CAR T cells can elicit toxicities due to non-specific targeting of the cytokines. Here, we designed immunocytokines with antibodies specific for the invariant linker peptides that join variable domains in the CAR scFv and immunostimulatory cytokines. The immunocytokines were capable of targeting CAR molecules agnostic of target antigen, demonstrating broad applicability without the need for further genetic engineering of CAR therapies, such as co-expression of a surrogate molecule (tEGFR, etc.). The addition of immunocytokines enhanced CAR T cell cytolytic activity and secretion of type I cytokines, even at low concentrations of immunocytokine. In a stringent Nalm6 xenograft model, the addition of immunocytokines delivering IL-12 enhanced the anti-tumor activity of anti-CD19 CAR T cells and overall survival compared to controls of antibody alone or PBS. This technological development presents the opportunity to specifically enhance the activity of multiple CAR T cell therapies in the absence of non-specific toxicities.
Citation Format: J T. Keane, Oula K. Dagher, Fang Liu, Avery D. Posey. Immunocytokines with specificity for invariant region of CAR molecules enhance effector function of multiple CAR T cell therapies [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 58.
Abstract 5800: Ultrasound-mediated nano-drug delivery system to enhance cancer treatment efficacy: An in vitro study
Authors: Kashkooli Farshad Moradi , Jakhmola Anshuman , Hornsby Tyler K. , Ferrier Graham A. , Tavakkoli Jahangir (Jahan) , Kolios Michael C. 
Published: March 2024

Abstract
Conventional non-targeted nano-sized drug delivery systems face limitations such as restricted drug penetration depth and treatment efficacy in solid tumors. External stimulus such as ultrasound waves can trigger targeted, on-demand drug release from the nanocarriers. We demonstrate a first-of-its-kind use of low-intensity pulsed ultrasound (LIPUS) to induce Doxorubicin release from the surface of gold nanoparticle drug carriers. Our 1-MHz LIPUS beam is capable of penetrating tissue to sufficient depths with the required power/intensity for drug release applications with a nominal intensity of around 3 W/cm2 in the region of interest (ROI). This level of intensity is necessary to elevate the tissue temperature to the mild hyperthermia range of 41 to 45 °C. Our in vitro experiments demonstrate a remarkable 22% enhancement in drug release with the addition of LIPUS. Measurements of drug release kinetics, with and without LIPUS, suggest that LIPUS shifts the drug release mechanisms from static (Fickian) to dynamic (non-Fickian) release in vitro. Thus, revealing the intricate interactions between ultrasound and drug release from gold nanoparticle drug carriers. To assess the efficacy of the delivery system, we developed an in vitro cell culture model with a customized ultrasound exposure setup. The LIPUS device was situated at the bottom base of a water tank, directing ultrasound beam upward toward a region of interest where the MDA-MB-231 breast cancer cells were located 35 mm away from the LIPUS element. We found that the LIPUS device operating at an acoustic power of around 4 W increased cell killing efficacy by approximately 15% ± 2% when compared to conventional nano-drug delivery, highlighting a significant improvement attributed to ultrasound-induced mechanical effects. At the cellular level, these results underscore the potential advantages of ultrasound-mediated nano-drug delivery over conventional chemotherapy and non-targeted nano-drug delivery.
Citation Format: Farshad Moradi Kashkooli, Anshuman Jakhmola, Tyler K. Hornsby, Graham A. Ferrier, Jahangir (Jahan) Tavakkoli, Michael C. Kolios. Ultrasound-mediated nano-drug delivery system to enhance cancer treatment efficacy: An in vitro study [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 5800.
Abstract 5819: An anti-TROP2-CPT113 ADC, exhibits potent targeted antitumor activity and favorable pharmacokinetic properties
Authors: Guo Huihui , Kong Xiangfei , Du Yong , Ye Zhicang , Chen Yongxiang , Guo Zhixiang , Zhang Lingli , Bai Lu , Jia Junxiang , Zheng Yunxia , Zheng Wei , Zheng Jun , Li Wenjun , Huang Yuanyuan , Fan Zhongliang , Liu Mengmeng , Chen Binbin , Dai Meng , Wang Juan , Chen Miaomiao , Yang Qingliang , Zhao Robert Y. 
Published: March 2024

Abstract
Trophoblast cell surface antigen 2 (TROP2) is highly expressed in a number of epithelial cancer types and is considered to be a poor prognostic marker. We have developed an anti-TROP2 antibody-drug conjugate, DXC1002, that contains a potent inhibitor of DNA topoisomerase I payload (CPT113) attached to the antibody mainly in the Fab region via a unique hydrophilic CrossConju™ linker. The anti-tumor activities of DXC1002 were studied in various human cancer cell lines and xenograft mouse models and pharmacokinetic profile of DXC1002 were evaluated in cynomolgus monkeys and rats. DXC1002 demonstrated potent anti-tumor activity in TROP2 tumor cells of various expression levels in vitro, and at low dose of 1 mg/kg for one injection, in both high and moderate Trop2 expression xenograft models. In plasma stability studies, wherein DXC1002 was incubated in the plasma of five different species for 168 hours (7 days) at 37 oC, over 90% ADC was intact, exhibiting good stability of the CrossConju™ linker. Pharmacokinetic studies of DXC1002 in monkeys (TROP2 cross-species) and rats (non-TROP2 cross-species) showed half-lives of about 61.27 and 236.77 hours, respectively. Systemic clearance in monkey and rat was 0.41-0.67 and 0.279-0.309 mL/h/kg, respectively. The longer half-lives and slower clearance observed in rats the results offered a more direct assessment of the linker stability as target-mediated clearance played no role in rats. In summary, with the conjugation of a DNA topoisomerase I inhibitor payload to Trop2 antibody via the CrossConju™ linker, DXC1002 demonstrates remarkable anti-tumor properties and pharmacokinetic profile, with a potential to be further validated in clinical applications.
Citation Format: Huihui Guo, Xiangfei Kong, Yong Du, Zhicang Ye, Yongxiang Chen, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Juan Wang, Miaomiao Chen, Qingliang Yang, Robert Y. Zhao. An anti-TROP2-CPT113 ADC, exhibits potent targeted antitumor activity and favorable pharmacokinetic properties [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 5819.
Abstract 5843: Exploring the implications of LPAR-1 expression in TKI-resistant NSCLC
Authors: Srinivasan Varsha , Li Zhaohui , Kannan Raghuraman , Upendran Anandhi 
Published: March 2024

Abstract
Introduction: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer in the United States with a 5-year survival rate hovering between 20-30%. Mutations in EGFR can initially cause the tumors to respond to tyrosine kinase inhibitors (TKI). Osimertinib, a third generation TKI, is the preferred first or second line of treatment and despite being effective, recent reports indicate that patients develop resistance within 10-18 months of treatment. TKI resistance limits therapeutic options for patients and therefore, alternative strategies are being explored. In this context, Lysophosphatidic acid receptors (LPARs), a family of G-protein coupled receptors consisting of LPARs 1-6 expressed differentially in prostate, breast, ovarian, pancreatic, and brain cancers are being explored as potential targets for drug resistant cancers. Specifically, LPAR-1 has been shown to play a role in tumor cell clonogenicity, migration, and response to therapy in EGFR mutant NSCLC cells. Pharmacological inhibition or CRIPSR based deletion of LPAR-1 in EGFR mutant NSCLC cell lines HCC827 and NCI-H3255, increased TKI sensitivity by reducing clonogenic potential. Further, detailed pathway analysis in TKI sensitive and resistant EGFR mutant cell lines suggests that LPAR-1 expression influences drug sensitivity. Surprisingly, the role of LPAR-1 in TKI sensitivity is not well understood. In the present study, we have performed detailed investigation on the implications of LPAR-1 expression in the development of Osimertinib resistance.
Methods: Osimertinib resistant EGFR mutant cell lines (OR) were generated using dose-escalation method and drug-tolerant persisters (DTPs) were generated using a short-term high exposure method. Gene and protein expressions were examined using qPCR and western blotting. Subcutaneous tumor cell derived xenografts were generated for in vivo studies.
Results: LPAR-1 is downregulated in Osimertinib resistant NSCLC cells. Further, we also observe that LPAR-1 levels are lower in DTP cells, confirming a progressive loss of LPAR-1 with Osimertinib treatment. In vivo studies in cell derived xenografts correlated with the in vitro studies.
Conclusion: Our studies indicate LPAR-1 downregulation correlates to Osimertinib resistance in EGFR mutant NSCLC cell lines. LPAR-1 downregulation has a key role in development of Osimertinib resistance. Future studies will focus on delineating LPAR-1 signaling pathways related to TKI resistance and investigating the effect of LPAR-1 overexpression using CRISPR technology.
Citation Format: Varsha Srinivasan, Zhaohui Li, Raghuraman Kannan, Anandhi Upendran. Exploring the implications of LPAR-1 expression in TKI-resistant NSCLC [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 5843.
Abstract 5860: Understanding the biological role of MMP16 in cisplatin resistance in ovarian cancer
Authors: Bonilla-Liriano Jesennia , Rivera-Serrano Mariela , Reyes-Burgos Victor , Rolon-Perez Jose , Valiyeva Fatima , Vivas-Mejia Pablo 
Published: March 2024

Abstract
High-Grade Serous Ovarian Cancer (HGSOC) is the most common and lethal of Ovarian Cancer (OC) types, which accounts for eighty percent of deaths. Treatment for OC includes surgery and platinum-based therapy. However, around 70% of women with HGSOC become resistant to chemotherapy. Therefore, new therapeutic agents with higher specificity and efficacy are needed for women with advanced and drug-resistant OC. Matrix metalloproteases (MMPs) are a group of enzymes involved in the degradation of the extracellular matrix (ECM). Deregulation of MMPs contributes to tumor growth and metastasis in several cancer types. Preliminary studies of our research team found that MMP16 is higher in cisplatin-resistant as compared with cisplatin-sensitive OC cells. The aim of this project is to understand the role of MMP16 in the cisplatin resistance of OC cells. We hypothesize that MMP16 increased expression may contribute to cancer progression and drug-resistance. We performed experiments in A2780/A2780CP20 and OVCAR3/OVCAR3CIS human OC cells. To assess the MMP16 protein levels we used western blot analysis. To measure the mRNA levels, we used qRT-PCR. Kaplan-Meier survival curves were generated by interrogation of the KM Plotter patient database. The MMP16 protein and qRT-PCR experiments confirmed that protein and mRNA levels are more abundant in cisplatin-resistant as compared with cisplatin-sensitive cells. Interrogation of the KM plotter database showed that OC patients with higher MMP16 mRNA levels live less as compared with OC patients with lower MMP16 levels. Ongoing experiments are testing the biological effect of small interference RNA (siRNA) targeting MMP16 in cisplatin-resistant OC cells.
Citation Format: Jesennia Bonilla-Liriano, Mariela Rivera-Serrano, Victor Reyes-Burgos, Jose Rolon-Perez, Fatima Valiyeva, Pablo Vivas-Mejia. Understanding the biological role of MMP16 in cisplatin resistance in ovarian 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 5860.
Abstract 5888: Novel immune-therapeutic target for lung cancer uncovered by SpliceIO™, an innovative platform that identifies disease-specific alternative splicing
Authors: Manzanares Miguel A. , Anderson Kendall , Zumrut Hasan , Gera Sakshi , Habib Nayab , Williams Nicole , Stanton Shaleigh , Floyd Taylor , Shah Sanjana , Trahan Devon , Akerman Martin , Arun Gayatri 
Published: March 2024

Abstract
Alternative splicing (AS) plays a critical role in generating tumor-specific neoantigens targetable through an arsenal of immunotherapeutic modalities. Previous studies have demonstrated tumor-promoting activity of deregulated AS isoforms and mutated splicing factors, both of which increase the yield of neoantigen-encoding AS isoforms. Therefore, the identification of AS isoforms has the potential to produce novel therapeutic targets, especially in lung tumors where splicing deregulation is frequent. Envisagenics has developed SpliceIO, a proprietary software platform for AS-derived neoantigen discovery. SpliceIO uses RNA-seq data to uncover extracellular neoantigens encoded by transmembrane proteins. This predictive ensemble maximizes the value of RNA-seq data to predict fundamental aspects of neoantigen activity, such as protein localization, epitope accessibility, and cancer pathway relevance. Here, we summarize the discovery and validation of novel AS-derived neoantigens identified using SpliceIO in non-small cell lung cancer (NSCLC). Our novel SpliceIO-identified neoantigens in NSCLC were validated following our well-established experimental pipeline. We have confirmed RNA expression of the neoantigen-expressing transcripts in lung cancer cell lines and patient samples using a combination of RT-PCR as well as RNA-ISH. Further, we have validated the membrane-bound extracellular localization of neoantigen-containing isoforms at the protein level using Western blotting, GFP and c-Myc tagged isoform generation, eukaryotic cells transfection, and microscopy. Our top target showed high tumor specificity, heterogeneous distribution in tumor samples, high prevalence, confirmed novel extracellular N-terminal domain, and strong biological relevance in lung cancer. This demonstrates the potential of utilizing RNA splicing for identifying many more membrane associated proteins for tumor specific immunotherapeutic targeting. The combination of computational and experimental approaches to neoantigen identification using SpliceIO allows for novel target discovery amenable for targeted immunotherapeutic development for lung cancer treatment and other indications driven by deregulated AS.
Citation Format: Miguel A. Manzanares, Kendall Anderson, Hasan Zumrut, Sakshi Gera, Nayab Habib, Nicole Williams, Shaleigh Stanton, Taylor Floyd, Sanjana Shah, Devon Trahan, Martin Akerman, Gayatri Arun. Novel immune-therapeutic target for lung cancer uncovered by SpliceIO™, an innovative platform that identifies disease-specific alternative splicing [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 5888.
Abstract 5890: ZNF451 and doxorubicin resistance
Authors: Rees Amy , Blackman Alexandra , Evans Della , Delaney Joe 
Published: March 2024

Abstract
Precision medicine most often utilizes mutations in patient selection, however targetable mutations are exceedingly rare in high-grade serous ovarian cancer (OV). Aneuploidy and chromosome instability are major contributors to such genomic changes in OV. Genes are pervasively disrupted by copy-number alterations: 39% of all genes in the median solid tumor of all cancer types, and 67% in OV. A common second-line OV chemotherapeutic is peggylated-liposomal doxorubicin, a topoisomerase-II poison. To address which genes in OV contribute to doxorubicin sensitivity and resistance, we performed a CRISPR-Cas9 screen on 19,114 human genes in the presence or absence of doxorubicin. Positive control genes involved in drug-efflux and DNA repair were significant hits. The gene with both the highest significance and greatest magnitude of doxorubicin sensitization upon knockout was the E3 SUMO2/3 ligase ZNF451. ZNF451 exhibits a copy-number loss in 14% of patients and corresponds to ZNF451 protein reduction. ZNF451 is an attractive target for future combination therapies with doxorubicin to induce conditional lethality. ZNF451 may be valuable to study as a prognostic biomarker for topoisomerase-II inhibitor chemotherapy.
Citation Format: Amy Rees, Alexandra Blackman, Della Evans, Joe Delaney. ZNF451 and doxorubicin resistance [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 5890.