bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4809: A novel microfluidic platform for PDAC organoid culture and drug screening
Authors: Geyer Marlene , Schreyer Daniel , Gaul Lisa-Marie , Goubert Désiréé , Pfeffer Susanne , Pilarsky Christian , Queiroz Karla S. 
Published: April 2023

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type, will become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. Current standard-of-care for patients with PDAC includes chemotherapeutic regimens and pancreatic cancer surgery. However, only 20% of the patients are eligible for surgery due to late diagnosis. Although chemotherapeutic regimens are the leading treatment to PDAC patients, these are still very limited and the development of resistance to treatment is often observed. PDAC tumors are characterized by high-density stroma and hypovascularization, therefore these present high interstitial pressure and hypoxia. These features potentially interfere with the efficiency of chemotherapeutic drugs and highlight the urgent need for novel PDAC screening platforms. Here, we describe the establishment of PDAC organoid cultures in the MIMETAS OrganoPlate®. The aim of this project was to determine the treatment response of PDAC organoids in mono-, and co-culture with pancreatic stellate cells (PSCs) under hypoxic and normoxic conditions. To recapitulate in-vivo like conditions, the 2-lane OrganoPlate® from MIMETAS was used to study organoid growth and sensitivity to treatment. Several standard of care (chemo-)therapeutics were tested on PDAC organoids embedded within an extracellular matrix in the Organoplate® 2-lane. These were exposed to chemotherapeutic treatments for 72h. PDAC organoids showed an overall better survival when grown in co-culture with PSCs. Interestingly, organoids grown in co-culture showed a higher survival rate under hypoxic conditions. In contrast, when grown in monoculture cell viability was higher or similar under normoxic conditions than in hypoxia for the different chemotherapeutics. The OrganoPlate® 2-lane provides an excellent platform for (co-) cultivation and high-throughput phenotypic drug screening of PDAC organoids, thereby potentially enabling the development of novel in-vivo like model systems for efficient patient stratification and drug discovery.
Citation Format: Marlene Geyer, Daniel Schreyer, Lisa-Marie Gaul, Désiréé Goubert, Susanne Pfeffer, Christian Pilarsky, Karla S. Queiroz. A novel microfluidic platform for PDAC organoid culture and drug screening. [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 4809.
Abstract 4849: PPARγ and FoxO1 expression and activity in aqueous cinnamon extract treated cells
Authors: Mild Sean , Swartz Cole , Aulthouse Amy , Stockert Amy 
Published: April 2023

Abstract
Peroxisome-proliferator activated receptor (PPARγ) has been proven to have inhibitory effects on tumor angiogenesis. Research has demonstrated that natural PPARγ ligands are anti-tumorigenic due to growth inhibition and anti-proliferative effects. Cinnamon is one potential PPARγ ligand tested to explore its effects on PPARγ and FoxO1 expression and activity. Literature also suggests that breast cancer proliferation is increased with obesity and co-cultures of adipocytes with MCF-7 cells have suggested an increase in lipase activity. We therefore sought to explore the effects of cinnamon on these transcription factors and lipase activity in 3T3-L1 cells to determine if cinnamon is a plausible co-therapeutic for breast cancer patients. 3T3-L1 cells were cinnamon treated for 48-96 hours post differentiation. Nuclear protein was extracted for ELISA quantification of PPARγ and FoxO1 binding potential. Cytosolic and nuclear protein extracts were analyzed via Western blot of FoxO1 and PPARγ. Copy DNA was produced from the total RNA and expression levels of PPARγ and FoxO1 were examined by TaqMan real-time PCR assays. A lipase activity assay was performed on freshly extracted protein from cultured cells. Western blot data demonstrates an increase in FoxO1 protein with cinnamon treatment at 96 hours post differentiation. PPARγ data shows no significant changes in protein quantity, however ELISA data suggests increases in binding potential PPARγ as well as FoxO1 transcription factors with cinnamon treatment. Preliminary expression analysis suggests changes in both PPARγ and FoxO1. Lipase activity data suggests a significant increase in cinnamon treated adipocytes. Data from the study suggests that cinnamon activates PPARγ and that it may play a role in decreasing tumorigenic activity. However, with particular concern in breast cancer cells, the activation of PPARγ in adipocytes appears to increase the lipase activity, thus producing more free fatty acids and potentially enhancing energy dependent proliferation.
Citation Format: Sean Mild, Cole Swartz, Amy Aulthouse, Amy Stockert. PPARγ and FoxO1 expression and activity in aqueous cinnamon extract treated 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 4849.
Abstract 4860: PI3K inhibition sensitize cancer cells to tumor treating fields (TTFields)
Authors: Klein-Goldberg Anat , Voloshin Tali , Zemer-Tov Efrat , Paz Rom , Koren Lilach , Wainer-Katsir Kerem , Volodin Alexandra , Koltun Bella , Brant Boris , Barsheshet Yiftah , Kan Tal , David Cfir , Khalil Tharwat Haj , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: April 2023

Abstract
Introduction: Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is approved for treatment of adult patients with glioblastoma (GBM) or unresectable pleural mesothelioma. Clinical trials are underway in other solid tumors, including ovarian cancer and non-small cell lung carcinoma (NSCLC). The objective of this study is to identify possible mechanisms involved in reduced sensitivity of cancer cell to TTFields, and explore strategies to circumvent them.
Methods: Ovarian cancer A2780, GBM U-87 MG, and NSCLC H1299 cells with reduced sensitivity to TTFields were generated by continuous long-term application of TTFields. Luminex multiplex assay was employed to examine changes in signaling pathways in these cells, and specific pathway markers were validated by Western blot. In vivo validation was performed by immunohistochemistry of ovarian cancer, hepatocellular carcinoma, and NSCLC tumor sections from animals treated with TTFields. Next, TTFields concomitant with alpelisib, an isoform specific PI3K inhibitor, was evaluated both in vitro and in an in-vivo model of ovarian cancer.
Results: TTFields inflicted a continuous cytotoxic effect on the different cancer cells albeit sensitivity to treatment was reduced following prolonged duration of application. Luminex analysis revealed activation of the PI3K/AKT signaling pathway in treated cells, and kinetics experiments showed that amplitude of AKT signaling increased over time, with significant increases in phosphorylation levels of AKT and focal adhesion kinase (FAK). AKT phosphorylation was also demonstrated in tumor sections of animals treated with TTFields. Experiments performed with concomitant alpelisib sensitized the cells to TTFields and enhanced cytotoxicity in vitro and treatment efficacy in vivo.
Conclusions: The current study demonstrates that the PI3K/AKT signaling pathway is involved in reduced cancer cell sensitivity to TTFields, and that PI3K inhibition can further sensitize cancer cells to TTFields.
Citation Format: Anat Klein-Goldberg, Tali Voloshin, Efrat Zemer-Tov, Rom Paz, Lilach Koren, Kerem Wainer-Katsir, Alexandra Volodin, Bella Koltun, Boris Brant, Yiftah Barsheshet, Tal Kan, Cfir David, Tharwat Haj Khalil, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. PI3K inhibition sensitize cancer cells to tumor treating fields (TTFields). [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 4860.
Abstract 4873: Pimavanserin suppresses glioblastoma progression by modulating the Akt/FOXO/Bim signaling axis
Authors: Agrawal Manas Yogendra , Ramachandran Sharavan , Zabel Carson , Srivastava Sanjay K. 
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) is a highly aggressive grade IV malignant brain tumor with an average survival time of around 15 months; and a 5-year survival rate of 5%. Drug resistance, blood brain barrier (BBB) impermeability, and drug toxicity are some caveats in treating this malignancy. Current chemotherapeutic agents fail to address these challenges. In this study, we aim to repurpose an FDA-approved anti-psychotic agent Pimavanserin Tartrate (PVT), for the treatment of GBM and further delineate its mechanism. To unravel the oncolytic effects of PVT, cytotoxicity assay on several human (SF268, SF188, SF295, U251) and murine (CT2A-Luc) GBM cell lines was performed. Our results demonstrate that PVT inhibited the growth of various GBM cells with IC50 ranging 5 to 8 µM, contrary to Temozolomide (TMZ), a standard care therapy which has an IC50 ranging 600 to 1,300 µM after 48- and 72-hours of treatment. Moreover, PVT treatment enhanced the activity of TMZ when given in combination. Pro-apoptotic proteins such as cleaved caspase-3 and Bax were upregulated by PVT treatment as evaluated confirming apoptosis to be the mode of cell death. The apoptotic cell population increased in a dose-dependent fashion, for example, 10µM PVT exhibited 70% increase in apoptosis as observed in the annexin assay. PVT treatment suppressed the phosphorylation of PI3K and Akt, and increased the expression of FOXO proteins, which are the negative downstream regulators of Akt. FOXO proteins translocate to the nucleus leading to the enhanced transcription of Bim, a pro-apoptotic protein resulting in apoptosis. Oral administration of 10mg/kg PVT significantly suppressed the growth of intracranially implanted GBM tumors without any other organ toxicity. Our observations provide a robust foundation for PVT’s anti-cancer efficacy against GBM by modulating Akt/FOXO/Bim pathway.
Citation Format: Manas Yogendra Agrawal, Sharavan Ramachandran, Carson Zabel, Sanjay K. Srivastava. Pimavanserin suppresses glioblastoma progression by modulating the Akt/FOXO/Bim signaling axis. [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 4873.
Abstract 490: Discovery of novel, potent and orally available MAT2A inhibitors
Authors: Chen Xuxing , Li Jing , Chen Yanhong 
Published: April 2023

Abstract
The methylthioadenosine phosphorylase (MTAP) gene is co-deleted with CDKN2A in approximately 15% of all cancers, but targeting a loss of function mutant is not trivial due to the lack of a target protein. The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We describe here potent and orally bioavailable MAT2A inhibitors (“Euregen MAT2Ais”) with superior potency and selectivity compared to AG-270. Euregen MAT2Ais bind at the interface of two MAT2A subunits and exhibit low nanomolar IC50s in biochemical assay. These compounds demonstrated more than 20-fold selective for MTAP−/− cell lines over isogenic MTAP WT. Oral administration of Euregen MAT2Ais drived dose-dependent antitumor activity without meaningful body weight loss in HCT116 MTAP−/− xenograft model. Furthermore, Euregen MAT2Ais revealed excellent oral bioavailability and PK properties in pre-clinical species. We are optimizing multiple MAT2A inhibitors that exhibit activity across a wide range of cancers with MTAP-deletion.
Citation Format: Xuxing Chen, Jing Li, Yanhong Chen. Discovery of novel, potent and orally available MAT2A inhibitors [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 490.
Abstract 4904: Glutamine antagonist DRP-104 enhances anti-tumor responses in KEAP1 mutant lung cancer
Authors: Pillai Ray , LeBoeuf Sarah , Rashidfarrokhi Ali , Huang Shih Ming , Karakousi Triantafyllia , Zavitsanou Anastasia-Maria , Wu Warren , Sayin Volkan , Wild Robert , Koralov Sergei , Papagiannakopoulos Thales 
Published: April 2023

Abstract
KEAP1 is mutated in approximately 20% of non-small cell lung cancer (NSCLC) and is associated with poor response rates to checkpoint blockade. Given the therapeutic challenge presented by KEAP1 mutant tumors and the great potential held by immunotherapeutic approaches, there is an urgent need to identify the mechanisms that mediate immune evasion in patients with KEAP1 mutant lung adenocarcinoma.
We previously demonstrated that metabolic rewiring in KEAP1 mutant tumors leads to increased dependency on glutamine as a substrate for multiple anabolic pathways. DRP-104 (Sirpiglenastat) is a novel glutamine antagonist which inhibits all glutamine consuming reactions. Using pre-clinical mouse models and patient derived xenograft models we demonstrate that DRP-104 robustly impairs the growth of KEAP1 mutant tumors. Furthermore, using an immunocompetent orthotopic lung adenocarcinoma mouse model we find that treatment with DRP-104 increases survival of Keap1 mutant tumor bearing mice treated with anti-PD1 therapy.
We have dissected the mechanism by which DRP-104 impacts KEAP1 mutant tumors and the surrounding immune microenvironment. Notably, DRP-104 impairs nucleotide synthesis in KEAP1 mutant tumors and thereby inhibits cancer cell growth. In addition, DRP-104 reduces exhausted T cell and T regulatory populations within the tumor microenvironment as well as increases effector T cell function. Overall, we find that DRP-104 impairs the growth of KEAP1 mutant tumors through both targeting of tumor intrinsic metabolic vulnerabilities and through tumor extrinsic immunostimulatory mechanisms such as promoting the expansion of functional anti-tumor T cell populations. This data provides additional rationale for the ongoing phase I/II clinical trial (NCT04471415) using DRP-104 in NSCLC with mutations in KEAP1 as well as for combining DRP-104 with checkpoint blockade.
Citation Format: Ray Pillai, Sarah LeBoeuf, Ali Rashidfarrokhi, Shih Ming Huang, Triantafyllia Karakousi, Anastasia-Maria Zavitsanou, Warren Wu, Volkan Sayin, Robert Wild, Sergei Koralov, Thales Papagiannakopoulos. Glutamine antagonist DRP-104 enhances anti-tumor responses in KEAP1 mutant lung 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 4904.
Abstract 491: Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations
Authors: Kwon Young-Ju , Kim Dong Young , Kim Uk-Il , Meng Xue , Lee Ho Kyun , Bang Hyung Tae , Kim Jae-Sung , Kim Kyungjin 
Published: April 2023

Abstract
Mitogen-activated protein kinase (MEK) inhibitors have shown promising results in KRAS-mutated cancers with constitutive activation of the RAS/RAF/MEK pathway. However, the intrinsic and acquired resistance to MEK inhibitors is frequently observed in clinical trials. Wnt/β-catenin signaling hyper-activation is reported to be responsible for such resistance in colorectal cancer (CRC). Herein, we introduce a novel tankyrase inhibitor STP1002 to revert the intrinsic and acquired resistance to MEK inhibitors in KRAS-mutated CRC. Dual combination of STP1002 and MEK inhibitor synergistically reduced the oncogenic activity of KRAS (G12V or G12D)-mutated CRC cell lines. Data also showed that concomitant treatment with STP1002 and MEK inhibitor dramatically inhibited tumor growth of KRAS (G12V)-mutated CRC xenograft animal models. Moreover, the combination treatment sensitized the acquired MEK inhibitor-resistant CRC cells and suppressed the Wnt/YAP pathway which is the bypass mechanism of MEK inhibitor resistance. Dual combination of STP1002 and MEK inhibitor is a promising candidate to overcome resistance to MEK inhibitors in colorectal cancer with KRAS-G12V/G12D mutations. The phase 1 clinical trial study is ongoing in order to show safety margin.
Citation Format: Young-Ju Kwon, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim, Kyungjin Kim. Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations [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 491.
Abstract 4915: Sensitivity to NAMPT inhibition: In vitro and in vivo characterization in ovarian cancer
Authors: Hong Jenny J. , McDermott Martina S. , O'Brien Neil A. , Guandique Enrique , Luo Tong , Slamon Dennis J. 
Published: April 2023

Abstract
Previous in vitro work on determining the unique sensitivities of various cancers to nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) has demonstrated promising effects of treating cancer cells with NAMPTis such as FK866 and KPT9274. These inhibitors act by disrupting cellular energy metabolism and reducing intracellular NAD+ levels. NAMPT inhibition thereby suppresses the proliferation of cancer cells which depend more heavily on the NAMPT enzyme to produce NAD+ than noncancerous cells. Using pan-cancer in vitro screens in a large panel of molecularly characterized cell lines (n = 496) we identified a subset of ovarian cancer, a cancer with a high unmet need due to lack of diverse targeted therapies, as being extremely sensitive to NAMPT inhibition. Subsequent in vivo work using CD-1 nude mice demonstrate that NAMPT inhibitors can successfully reduce the ovarian tumor burden and may be an effective treatment option of some ovarian cancers.
Moreover, NAD+’s function as a substrate to the poly ADP-ribose polymerase (PARP) enzyme makes NAMPTis rational candidates for including in combination therapies with PARP inhibitors, several of which are approved for maintenance therapy for ovarian cancer. By using NAMPTis to disrupt the cellular metabolic process while simultaneously inhibiting PARP activity, an essential DNA damage repair enzyme, it is possible to exploit the dependence of ovarian cancer cells on functional PARP activity. This is particularly important in homologous recombination deficient subtypes. In addition to a synergistic growth inhibitory response in ovarian cancer cells, preclinical combination studies of NAMPTis with olaparib, an approved PARP inhibitor, exhibited higher levels of DNA damage accumulation than with single drug treatments. Our in vitro and in vivo characterizations of NAMPT inhibition suggest that NAMPTis as either single agents or in combination treatments with PARP inhibitors should be investigated further as potential treatment options for ovarian cancer patient populations.
Citation Format: Jenny J. Hong, Martina S. McDermott, Neil A. O'Brien, Enrique Guandique, Tong Luo, Dennis J. Slamon. Sensitivity to NAMPT inhibition: In vitro and in vivo characterization in ovarian 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 4915.
Abstract 4925: Cannabidiol and Cannabis Sativa as a potential treatment in vitro prostate cancer cells silenced with RBBp6 and PC3 xenograft
Authors: Motadi Lesetja Raymond , Jantjies Zodwa E. 
Published: April 2023

Abstract
Background: Prostate cancer is the second most frequently occurring carcinoma in males worldwide and one of the leading causes of death in men around the world. Recent studies estimate that over 1.4 million males are diagnosed with prostate cancer on an annual basis, with approximately 375 000 succumbing to the disease annually. With current treatments continuing to show severe side effects, there is a need for new treatments. In this study we looked at the effect of cannabis sativa extract, cannabidiol and cisplatin on prostate cancer cells, PC3.
Methods: In addressing the above questions, we employed the MTT assay to measure the antiproliferative effect on PC3 cells following treatment with varying concentrations of Cannabis sativa extract, cisplatin and cannabidiol. xCELLigence was also used to confirm the IC50 activity in which cells were grown in a 16 well plate coated with gold and monitor cell attachment. Caspase 3/7 activity was also measured using 96 well-plate following treatment. Western-blot and qRT-PCR was also used to measure the gene expression of tumor suppressor genes, p53, Bax and Bcl2. Animal studies were employed to measure the growth of PC3-mouse derived cancer to evaluate the effect of compounds in vivo.
Results: From the treatment with varying concentrations of Cannabis sativa extract, cannabidiol and cisplatin, we have observed that the three compounds induced antiproliferation of PC3 cancer cell lines through the activation of caspase 3/7 activity. We also observed induction of apoptosis in these cells following silencing of retinoblastoma binding protein 6 (RBBP6), with upregulation of p53 and bax mRNA expression, and a reduction in Bcl2 gene expression. The growth of tumors in the mouse models were reduced following treatment with cisplatin and cannabidiol.
Conclusion: We demonstrated that cannabidiol is a viable therapy to treat prostate cancer cells, in combination with silencing of RBBP6. This suggests that cannabidiol rather Cannabis sativa extract may play an important role in reducing cancer progression.
Citation Format: Lesetja Raymond Motadi, Zodwa E. Jantjies. Cannabidiol and Cannabis Sativa as a potential treatment in vitro prostate cancer cells silenced with RBBp6 and PC3 xenograft. [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 4925.