bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3011: Cancer of Unknown Primary: novel therapeutic opportunities from patient-derived cell cultures and in vivo models
Authors: Laprovitera Noemi , Fumarola Claudia , Porcellini Elisa , Cairo Stefano , Gallerani Giulia , Gelsomino Francesco , Salamon Irene , Naddeo Maria , Ardizzoni Andrea , Cavazzoni Andrea , Ferracin Manuela 
Published: July 2021

Abstract
Patients with occult primary cancer or cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies, which are typically tumor-type oriented. Moreover, experimental in-vitro and in-vivo models summing up CUP features and heterogeneity are currently unavailable.
We derived and expanded two CUP cell lines, and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines, one spontaneously growing as organoid, and PDXs were subjected to histological, immune-phenotypical, molecular and genomic (CNV and target sequencing) characterization to show their ability to recapitulate the original tumor. MicroRNA profile and genomic information were used to identify a possible primary site and patient-specific therapeutic approaches. Data on CUP most frequently altered genes were used to design a custom CUP-specific, 92-gene panel for target NGS analysis with Sure Select XS technology (Agilent Technology).
Drug-screening assays were performed in vitro and in vivo on two models targeting the most promising actionable pathways. We obtained unexpected and promising results on drug combinations efficacy. This study brings personalized therapy closer to CUP patients and paves the way to future applications of personalized medicine for metastatic patients with adverse prognosis.
This work was supported by grants from the Italian Association for Cancer Research (AIRC) to MF (IG 18464).
Citation Format: Noemi Laprovitera, Claudia Fumarola, Elisa Porcellini, Stefano Cairo, Giulia Gallerani, Francesco Gelsomino, Irene Salamon, Maria Naddeo, Andrea Ardizzoni, Andrea Cavazzoni, Manuela Ferracin. Cancer of Unknown Primary: novel therapeutic opportunities from patient-derived cell cultures and in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3011.
Abstract 3027: Role of BCOR in retinoblastoma
Authors: Zhang Michelle Garying , Owens Dawn , Kurtenbach Stefan , Kuznetsov Jeffim , Fields Matthew , Pelaez Daniel , Harbour James W. 
Published: July 2021

Abstract
Retinoblastoma, which is usually initiated by the biallelic mutational inactivation of RB1, is the most common primary eye cancer in children and is fatal if left untreated. While retinoblastoma is initially sensitive to chemotherapy, it demonstrates a strong propensity for therapeutic escape, which is a leading cause of ocular morbidity, eye loss, and reduced survival. This problem is exacerbated by a poor understanding of how retinoblastoma progresses after the initial loss of RB1. Genomic analysis of primary retinoblastoma tumors has revealed the corepressor BCOR as the second most common target of mutations in retinoblastoma. Here, we explored the role of BCOR in normal retinal development to provide insights into its role in retinoblastoma. Mass spectrometry following immunoprecipitation of wildtype BCOR in primary retinoblastoma cells revealed novel BCOR interacting proteins in the Polycomb and MiDAC epigenetic complexes. Subsequent studies revealed potential functional consequences of BCOR mutation that may promote retinoblastoma progression. This work reveals new insights the role of epigenetic deregulation in retinoblastoma progression, and they nominate new candidates for therapeutic intervention.
Citation Format: Michelle Garying Zhang, Dawn Owens, Stefan Kurtenbach, Jeffim Kuznetsov, Matthew Fields, Daniel Pelaez, James W. Harbour. Role of BCOR in retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3027.
Abstract 303: Surface modification of paclitaxel-loaded nanoparticles based on polydopamine with pH sensitive property for targeted therapy in hepatocellular carcinoma
Authors: Wu Mingfang , Xia Xinming , Sun Danna , Zhong Chen 
Published: July 2021

Abstract
Drug-loaded nanocarrier is a promising treatment for targeted therapy in hepatocellular carcinoma (HCC) due to their sustained release and outstanding tumor-targeting properties. Nevertheless, a limitation of current nanocarriers is the contradiction between multiple functions and favorable biocompatibility, owing to most of functional substances are non-biological. In this study, we introduced a targeting arginine-glycine-aspartic acid (RGD)-peptide on the surface of polydopamine (PDA)-ploy (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) to develop a novel nanoparticle, which were employed as a drug delivery system loaded with paclitaxel (PTX) for HCC therapy. Paclitaxel-loaded PHBV nanoparticles (PHBV-PTX-NPs) were prepared by emulsion solvent evaporation. As a gatekeeper, the pH-sensitive coating was formed by self-polymerization of dopamine. The RGD and PDA coated nanoparticles were combined through the Michael addition. The chemical structures and properties of these nanoparticles were characterized by dynamic light scattering-autosizer, transmission electron microscope, fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetry and X-ray photoelectron spectroscopy. As expected, these RGD-PDA-PHBV-PTX-NPs achieved excellent targeting efficiency, which was revealed by the cellular uptake and cytotoxicity assay in HCC cells. Compared with that of free PTX, the RGD-PDA-PHBV-PTX-NPs showed more superior antitumor efficacy in the xenograft mouse model. Notably, in addition to efficient anticancer activities, RGD-PDA-PHBV-PTX-NPs exhibited lower toxicity than PTX to normal hepatocytes and mouse in vitro and in vivo, respectively. These studies suggest the potential beneficial use of RGD-PDA-PHBV-PTX-NPs in future HCC-targeted therapy with drug-loaded nanocarriers.
Citation Format: Mingfang Wu, Xinming Xia, Danna Sun, Chen Zhong. Surface modification of paclitaxel-loaded nanoparticles based on polydopamine with pH sensitive property for targeted therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 303.
Abstract 3042: Generation, characterization and functional validation of novel preclinical models for human pediatric glioma
Authors: Zohar Or , Moshe Itai , Britta Ismer , Jones David T. , Friedmann-Morvinski Dinorah 
Published: July 2021

Abstract
Tumors of the central nervous system are the most common form of childhood malignancy, and remain the leading cause of cancer-related morbidity and mortality in children. Despite extensive efforts, the efficacy of the traditional treatments is limited and the overall prognosis is poor. In recent years it has become apparent that pediatric gliomas differ from their adult counterparts, explaining in part why the therapies extrapolated from adult gliomas have failed, and further supporting the need to understand the biology of the childhood disease. Deep sequencing studies on brain tumor specimens within various cancer genome consortia (e.g. ICGC PedBrain, TCGA) has yielded a wealth of information about molecular aberrations that had accumulated in tumors. This has unravelled a considerable degree of heterogeneity and thus resulted in the delineation of different molecular subgroups. Furthermore, it has provided comprehensive insights into tumor genomes deduction. Nevertheless, validation of oncogenically relevant genes and therapeutically actionable targets in an in vivo context still remains a major challenge in the process of developing novel treatment approaches. We have generated state-of-the-art in vivo methodologies based on somatic gene transfer for generating animal models faithfully recapitulating the molecular and clinical characteristics of the respective human counterpart. In this study, we focused on NTRK2 fusions and FGFR1 mutations and characterized the tumors obtained by either in utero electroporation or lentiviral injection into postnatal (P0-P1) mice. Tumor derived cell lines grown in stem cell media were tested for conventional therapies (e.g. TMZ) and screening of available small inhibitor compounds. In addition, we have characterized the tumor microenvironment of these lesions, mainly the infiltrating immune cell populations. This study thus represents an important contribution to the understanding of pediatric glioma biology as well as to translational efforts in developing new treatment approaches for these malignant tumors.
Citation Format: Or Zohar, Itai Moshe, Ismer Britta, David T. Jones, Dinorah Friedmann-Morvinski. Generation, characterization and functional validation of novel preclinical models for human pediatric glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3042.
Abstract 3046: In situ analysis of microenvironmental glycogen in Ewing's sarcoma patient samples by mass spectrometry imaging
Authors: Young Lyndsay E. , Conroy Lindsey R. , Clarke Harrison A. , Allison Derek B. , Drake Richard R. , Gentry Matthew S. , Sun Ramon C. 
Published: July 2021

Abstract
Ewing's sarcoma (ES) is a rare pediatric cancer of the bone and soft tissues affecting adolescents and young adults, with peak incidence from ages 10 to 15 years. A clinical feature of ES is the accumulation of Periodic acid-Schiff positive (PAS+) aggregates. PAS+ staining in ES histopathology analysis has been speculated to be glycogen accumulation, however, this has not been confirmed. To interrogate these aggregates, we developed a novel workflow for the high-sensitive detection of in situ glycogen via enzymatic release of glycogen substrates coupled to matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) from formalin-fixed patient tissues. We utilized this method to study the nature of PAS+ staining in a cohort of ES patient samples surgically removed from tibia, rib, chest, shoulder, abdomen and testicle tissues. Using this innovative technique, we discovered profound intra-tumoral glycogen accumulation compared to adjacent stroma, normal, muscle and/or necrotic tissue. Further, intra-tumoral glycogen also has an increased phosphate content and distinct chain length profile compared to normal glycogen found in adjacent and patient-matched tissue. Notably, genetic manipulation and pharmacological inhibition of glycogen synthesis, or removal of glycogen phosphates, blunted ES tumor growth in xenografted mouse models. These findings suggest an important role of ES glycogen aggregates in tumor growth. Together, application of this novel MALDI-IMS technique, and the insights provided by formalin-fixed ES patient samples, reveals a distinct role of ES glycogen aggregates and uncovers a new therapeutic opportunity for this rare pediatric cancer.
Citation Format: Lyndsay E. Young, Lindsey R. Conroy, Harrison A. Clarke, Derek B. Allison, Richard R. Drake, Matthew S. Gentry, Ramon C. Sun. In situ analysis of microenvironmental glycogen in Ewing's sarcoma patient samples by mass spectrometry imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3046.
Abstract 3049: Tumor treating fields induce DNA damage and apoptosis in medulloblastoma
Authors: Nitta Ryan T. , Li Gordon 
Published: July 2021

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for approximately 20% of all pediatric central nervous system tumors. Current multimodal treatment has led to a 70-90% five-year overall survival rate, however, the prognosis for patients with tumor dissemination and recurrent MB remains poor. Additionally, the majority of survivors exhibit long-term neurocognitive and neuroendocrine complications because of the cytotoxic drugs and high dose radiation. Consequently, more effective and less toxic treatments are necessary in order to raise the quality of life for these young patients. Tumor Treating Fields (TTFields) are an exciting new therapeutic opportunity for MB. TTFields are low intensity, alternating electric fields that disrupt cell division through physical interactions with key molecules during mitosis. The side effects from TTFields treatments are incredibly low, making it an ideal candidate for MB therapy. Currently TTFields were found to increase the survival of adult brain tumor patients by dysregulating the cytoskeletal network leading to mitotic arrest and as well as other varied multi-modal mechanisms of action. To determine if TTFields can be an effective treatment for MB, we conducted an in vitro study treating multiple MB cell lines with TTFields. We discovered that TTFields treatment reduced MB cell growth (Daoy, Med1-MB, D425, and D283) with an optimal frequency of 200-250 kHz. We also observed that TTFields treatment dysregulated actin polymerization that corresponded with a reduction in cell motility and invasion. TTFields treatment also caused DNA damage (γH2AX, 53BP1) that correlated with an increase in apoptotic cells. To expand on these initial findings, we conducted a combinatorial study with the small molecule inhibitor, CX-4945. CX-4945 is an inhibitor to casein kinase 2 and is currently being used in a phase I clinical trial to treat recurrent MB (NCT03904862). We discovered that CX-4945 enhanced the growth reduction of TTFields treatment. In addition, combining CX-4945 and TTFields increased the number of cells with dysregulated actin which correlated with a decrease in MB migration and invasion. Our findings demonstrate that TTFields may be a novel and less toxic method to treat MB patients.
Citation Format: Ryan T. Nitta, Gordon Li. Tumor treating fields induce DNA damage and apoptosis in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3049.
Abstract 308: Therapeutic implications of silver nanoparticles in the management of skin cancer
Authors: Dasari Shaloam R. , Tchounwou Paul B. , Yedjou Clement G. , Brodell Robert T. , Cruse Allison 
Published: July 2021

Abstract
Skin cancer (SC) is the most common carcinoma affecting 3 million people annually in the United Sates and millions of people worldwide. It is classified as melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC). NMSC represents approximately 80% of NMSC and includes squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). MSC, however, has a higher mortality rate than SC because of its ability to metastasize. SC is a major health problem in the United States with significant morbidity and mortality in the Caucasian population. Treatment options for SC include cryotherapy, excisional surgery, Mohs surgery, curettage and electrodessication, radiation therapy, photodynamic therapy, immunotherapy, and chemotherapy. Treatments are chosen based on the type of skin cancer and the potential for side effects. Novel targeted therapies are being used with increased frequency for large tumors and for metastatic disease. The objective of this review is to highlight new chemotherapeutic agents that utilize silver nanoparticles in the management of SC. A scoping literature search on PubMed, Google Scholar, and Cancer Registry websites revealed that traditional chemotherapeutic drugs have little effect against SC after the cancer has metastasized. Following a discussion of SC biology, epidemiology, and treatment options, this review focuses on the mechanisms of advanced technologies that use silver nanoparticles in SC treatment regimens.
Citation Format: Shaloam R. Dasari, Paul B. Tchounwou, Clement G. Yedjou, Robert T. Brodell, Allison Cruse. Therapeutic implications of silver nanoparticles in the management of skin cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 308.
Abstract 3082: Synergistic inhibition of TNBC cell growth by novel doxorubicin/salinomycin-encapsulated dual drug-nanoparticles
Authors: Mohammad Anees , Tiwari Sachchidanand , Mehrotra Neha , Korczak Bozena , Appajosyula Sireesh , Laumas Steve , Kharbanda Surender M. , Singh Harpal 
Published: July 2021

Abstract
Triple negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a worse clinical outcome as compared with other breast cancer subtypes. Doxorubicin (DOX) is considered to be one of the most effective agents in the treatment. Unfortunately, resistance to DOX is very common due to drug efflux mediated by overexpression of ABC transporter. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. In the present study, SAL and DOX were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) (novel Quatramer Technology) to efficiently co-deliver these agents to treat TNBC cells. Generated SAL-DOX co-encapsulated dual drug NPs showed an average diameter of 91 ± 2 nm, zeta potential of -9.4 ± 1.1mV and PDI of less than 0.1. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (DOX:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug NPs. The results demonstrate that, in contrast to 1:1 and 1:3, treatment of TNBC cells with 3:1 ratio of DOX:SAL dual drug NPs, was associated with significant inhibition of growth in vitro and more interestingly, was synergistic as compared to either agent alone. The IC50 of DOX and SAL in single drug-encapsulated NPs is 0.56 uM and 3.56 uM respectively. Importantly, the IC50 of DOX and SAL in dual drug-encapsulated NPs is 0.13 uM and 0.034 uM respectively. Furthermore, bi-weekly treatment of BALB/c wild-type mice harboring EAT cells (as syngeneic mouse model) with DOX-SAL (3:1) dual drug NPs at a dose of 3 mg/kg i.v. resulted in significant tumor growth inhibition (TGI). The TGI effect was synergistic with dual-NPs as compared to either agent alone. The TGI by dual drug NPs was without any significant effect on the body weights of the mice. These results demonstrate that a novel dual drug NP formulation of DOX and SAL in a unique ratio (3:1) represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.
Citation Format: Anees Mohammad, Sachchidanand Tiwari, Neha Mehrotra, Bozena Korczak, Sireesh Appajosyula, Steve Laumas, Surender M. Kharbanda, Harpal Singh. Synergistic inhibition of TNBC cell growth by novel doxorubicin/salinomycin-encapsulated dual drug-nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3082.
Abstract 3084: KLF8 is a required downstream effector of OGT/O-GlcNAcylation in regulating breast cancer stem-like cells
Authors: Minh Giang Le , Akella Neha M. , Dhameliya Tejsi , Reginato Mauricio J. 
Published: July 2021

Abstract
One of the main challenges in treating breast cancer is the intra-tumor heterogeneity, which, partly, is maintained and promoted by a sub-population of breast cancer cells called breast cancer stem-like cells (BCSCs). BCSCs shares traits of mammary stem cells, capable of self-renewing and differentiating, while promotes invasion, metastasis, drug resistance and relapse. BCSCs are highly adaptive, capable of reprogramming metabolism and signaling activity in response to tumor microenvironment. One key component of cell nutrient sensing mechanism, linking alteration in metabolism to cell signaling, is O-GlcNAc transferase (OGT). OGT is responsible to adding O-GlcNAc moieties to target nuclear, cytoplasmic and mitochondrial proteins from UDP-GlcNAc - final product of the hexosamine biosynthetic pathway. This modification is termed O-GlcNAcylation and both OGT and O-GlcNAcylation are upregulated in many cancers. Recently, we showed that OGT/O-GlcNAcylation is enriched in BCSCs, promoting the stemness and tumorigenesis of breast cancer cells in vitro and in vivo. RNA-seq analysis of BCSC-enriched mammospheres with OGT overexpression revealed Kruppel-like-factor 8 (KLF8) as a downstream target of OGT in promoting BCSCs. Here, we showed that KLF8 expression in breast cancer cells is regulated by OGT at protein and mRNA level. Knockdown of KLF8 reduced mammosphere forming efficiency (MFE) and NANOG expression in breast cancer cells, while overexpressing KLF8 increased MFE, NANOG+ and CD44H/CD24L BCSC population. Importantly, KLF8 knockdown abolished the effect of elevated OGT and O-GlcNAcylation in breast cancer cell MFE and BCSC population, while KLF8 overexpression rescued OGT inhibition in MFE and BCSC population. suggesting that KLF8 is required in promoting BCSCs. Interestingly, KLF8 knockdown in breast cancer cell reduced OGT expression, while KLF8 overexpression increased OGT and O-GlcNAcylation, suggesting a possible feed-forward loop between OGT and KLF8 in promoting BCSCs. Supporting the idea that KLF8 and OGT are critical for breast cancer progression, breast cancer patient survival was lower with high KLF8 or OGT levels. Furthermore, overexpression of KLF8 showed increase in resistance to paclitaxel in triple-negative breast cancer cells in vitro, suggesting a possible role of KLF8 in promoting chemotherapy resistance in breast cancer[LM1] . Together, our results suggested that KLF8 is a downstream target of OGT/O-GlcNAcylation in promoting breast cancer stem-like cells population.
Citation Format: Giang Le Minh, Neha M. Akella, Tejsi Dhameliya, Mauricio J. Reginato. KLF8 is a required downstream effector of OGT/O-GlcNAcylation in regulating breast cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3084.