bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A025: Cytostatic effects and expression modulations in cell cycle genes by a 3rd generation alkyl-phospholipid (erufosine) in liver and lung cancer cells
Authors: Pervaiz Asim , Nasim Marriyam , Shafiq Nazakat , Berger Martin R. 
Published: December 2023

Abstract
Introduction: Alkyl-phospholipids (ALPs) are a family of compounds that have affinity to cell membranes and have demonstrated antineoplastic potential. Erufosine is a 3rd generation ALP that can be injected intravenously for its long (22-carbon) chain with a cis-13,14 double bond. Erufosine, like other ALPs, causes changes in the lipid rafts of the cell membrane and exerts its anticancer effects through cytotoxic and cytostatic mechanisms. In this study, intentions were to investigate erufosine mediated cytostatic effects in liver and lung cancer cells at functional and molecular levels.
Materials and Methods: Liver (HepG2) and lung (H1299) cancer cell lines were exposed to various concentrations of erufosine (1.56-50µM) and resulting anti-proliferative effects were monitored via MTT dye reduction assay. Cytostatic effects of erufosine on the two cancer cell lines were investigated via propidium iodide-based DNA staining and FACS analysis. A real time PCR based panel was used to decipher the impact of erufosine exposure on 84 cell cycle related genes in the two cancer cell lines. Fold changes were identified via the Livak method while untreated cells were used as controls.
Results: Erufosine induced the anti-proliferative effects in both cancer cell lines, however, lung cancer cells were more sensitive (IC50: 6.25µM) as compared to liver cancer cells (IC50: 33µM). The compound induced a comparable cell cycle arrest in S phase in the cancer cell lines as reflected by more accumulation of the cells in this particular phase. Exposure with erufosine (IC50/48 hours) de-regulated the cell cycle related genes in both cancer cell lines. Again, the lung cancer cells were more responsive in comparison to liver cancer cells as reflected by a substantial de-regulation (≥2fold) of 35/84 (42%) and 13/84 (15%) genes, respectively.
Conclusion: The findings of this study confirmed erufosine mediated anti-proliferative and cytostatic effects in the liver and lung cancer cells. Furthermore, the compound induced substantial alterations in cell cycle related genes in the two cancer cell lines. Present findings foster further research to investigate the antineoplastic effects induced by erufosine in liver and lung cancer cells to support its clinical utilization.
Citation Format: Asim Pervaiz, Marriyam Nasim, Nazakat Shafiq, Martin R. Berger. Cytostatic effects and expression modulations in cell cycle genes by a 3rd generation alkyl-phospholipid (erufosine) in liver and lung cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A025.
Abstract B085: Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer
Authors: Taya Marwa , Merenbakh-Lamin Keren , Zubkov Asia , Honig Zohar , Mayer Ori , Shomron Noam , Wolf Ido , Rubinek Tami 
Published: December 2023

Abstract
Purpose: All patients with metastatic breast cancer (BC) expressing estrogen receptor α (ESR1) will eventually develop resistance to endocrine therapies. In up to 40% of cases, this resistance is caused by activating mutations in the ligand-binding domain (LBD) of ESR1. Clinical evidence suggests adverse outcomes for these patients. Our hypothesis was that ESR1 mutations may confer resistance to subsequent treatment lines, specifically chemotherapy.
Experimental Design: MCF-7 cells harboring ESR1 mutations (Y537S and D538G) were used to characterize proliferation, apoptosis, and tumor response to chemotherapy in vivo. JNK/c-Jun/MDR1 pathway was studied using qRT-PCR, western-blot, gene-reporter, ChIP assays and pharmacological inhibition.
Results: Our results revealed that the mutated-ER (mut-ER) cells displayed relative chemoresistance, demonstrated by higher viability and reduced apoptosis. In vivo mouse model confirmed these findings. To elucidate the underlying mechanism, we examined MDR1 expression and JNK pathway activity. We observed elevated MDR1 expression in mut-ER cells, which was also reflected in clinical BC samples. Additionally, increased occupancy of the MDR1 promoter by c-Jun was observed in mut-ER cells. Importantly, inhibition of the JNK pathway resulted in decreased MDR1 expression, particularly in D538G cells. Moreover, JNK inhibition increased apoptosis and reduced viability in all cells, with a more pronounced effect in D538G cells.
Conclusions: Taken together, our data indicate that ESR1 mutations confer chemoresistance in BC through the activation of the JNK/MDR1 axis. These findings suggest that targeting this pathway could be a potential strategy for novel treatments aimed at restoring chemotherapy sensitivity and improving outcomes for patients with metastatic BC.
Citation Format: Marwa Taya, Keren Merenbakh-Lamin, Asia Zubkov, Zohar Honig, Ori Mayer, Noam Shomron, Ido Wolf, Tami Rubinek. Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B085.
Abstract B089: MUC1-C is a common driver of acquired osimertinb resistance in NSCLC
Authors: Haratake Naoki , Ozawa Hiroki , Morimoto Yoshihiro , Yamashita Nami , Daimon Tatsuaki , Bhattacharya Atrayee , Wang Keyi , Nakashoji Ayako , Isozaki Hideko , Hata Aaron , Kufe Donald 
Published: December 2023

Abstract
Background: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance.
Methods: H1975/EGFR(L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance (EMT, MET amplified, C797S mutation, or PCBP2-BRAF fusion) were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity and self-renewal capacity.
Results: We demonstrate that MUC1-C is upregulated in H1975 osimertinib drug tolerant persister (DTP) cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are shown to be dependent on MUC1-C for induction of (i) p-EGFR, p-ERK and p-AKT, (ii) EMT, and (iii) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (i) MET amplified MGH170-1D #2 cells, (ii) MGH121 Res#2/EGFR(T790M/C797S) cells, and (iii) MGH845-1R5/EGFR(19del)/PCBP2-BRAF fusion cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. To extend these results, we established MET amplified MGH170-1D #2 tumors in mice and found that treatment with GO-203 inhibitor, which is a cell-penetrating peptide that blocks MUC1-C homodimerization, nuclear localization, and function, results in more pronounced inhibition and that the GO-203+osimertinib combination is more effective than either agent alone. In support of these results, high MUC1 expression is associated with poor prognosis for patients with EGFR mutant NSCLCs and those treated with osimertinib.
Conclusions: Our findings demonstrate that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib resistant NSCLCs.
Citation Format: Naoki Haratake, Hiroki Ozawa, Yoshihiro Morimoto, Nami Yamashita, Tatsuaki Daimon, Atrayee Bhattacharya, Keyi Wang, Ayako Nakashoji, Hideko Isozaki, Aaron Hata, Donald Kufe. MUC1-C is a common driver of acquired osimertinb resistance in NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B089.
Abstract B142: Discovery of novel and potent TEAD inhibitors, orally available small molecules with anti-tumor activity in hippo pathway- dysregulated cancers
Authors: Moon Sungho , Cho Seon Yeon , Kim Minhye , Beak Soojeong , Kim Jinhyuk , Kim Yongchan , Park Sungil , Kim Jung-In , Kim Hanseong , Lee In Sang , No Kyoung Tai 
Published: December 2023

Abstract
Hippo pathway plays a critical role in cell apoptosis, proliferation, tissue homeostasis. Dysregulation of Hippo pathway was reported to related to overall aspects of tumorigenesis. The higher expression a YAP/TAZ and TEADs or mutation of core components of hippo pathway, such as NF2, MST1/2 and LATS1/2 were reported in various cancer subtypes including mesothelioma, meningioma, glioblastoma, non-small cell lung cancer. TEAD auto-palmitoylation is required for protein stability and its transcriptional activity. Inhibiting TEAD activity regulation present attractive strategy for therapeutic intervention in the Hippo pathway. There are increasing proof that the inhibitor to central pocket of TEAD can be promising candidate for cancer treatment. We validated and optimized the hits, derived from our in silico screening system. Our lead compounds inhibiting palmitoylation of TEADs are the potent in vitro activities in TEAD reporter assay and hippo pathway-dysregulated mesotheliomas. In addition, these compounds reduced the expression of TEAD target genes. Furthermore, our compounds strongly inhibited tumor growth in NF2 deficient mouse xenograft model without any adverse events. In these models, our compounds showed excellent PK-PD correlation. Using these compounds, we also tested the possibility as therapy for combination drugs with KRAS inhibitor, EGFR inhibitors. In summary, we have potent TEAD inhibitor series, that showed inhibitory activities of tumor growth in NF2 deficient in vivo models, and may have therapeutic potential in diverse solid tumors.
Citation Format: Sungho Moon, Seon Yeon Cho, Minhye Kim, Soojeong Beak, Jinhyuk Kim, Yongchan Kim, Sungil Park, Jung-In Kim, Hanseong Kim, In Sang Lee, Kyoung Tai No. Discovery of novel and potent TEAD inhibitors, orally available small molecules with anti-tumor activity in hippo pathway- dysregulated cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B142.
Abstract C094: Blocking flotillin-1 palmitoylation abrogates TNBC tumor growth and metastasis
Authors: McClellan Bryan , Graffenried Linda de 
Published: December 2023

Abstract
Flotillin-1 contributes to invasion and metastasis in triple negative breast cancer (TNBC). Palmitoylation, the process of conjugating palmitoyl-CoA to proteins, plays an essential role in protein stability and trafficking. Flotillin-1 is modified through palmitoylation, however, the role of its palmitoylation in the context of metastasis has not been explored. Using palmitoylation defective flotillin-1 constructs and loss of function experiments, we have demonstrated that flotillin-1 palmitoylation contributes to its protein stability and metastatic capabilities in vivo. To assess the ability to target flotillin-1 palmitoylation therapeutically, we designed a competitive peptide, which displayed efficacy in blocking flotillin-1 palmitoylation in vitro without altering palmitoylation of other zDHHC5 substrates, highlighting its specificity. Additionally, multiple TNBC tumor models displayed attenuated lung metastasis when expressing a doxycycline inducible flotillin-1 palmitoylation inhibiting peptide construct. The current study has demonstrated the palmitoylation of flotillin-1, a known metastasis inducing protein, to be essential for its protein stability. The demonstrated methods in blocking its palmitoylation through the delivery of a competitive peptide provide proof-of-concept data for further development as a potential targeted therapeutic in TNBC.
Citation Format: Bryan McClellan, Linda de Graffenried. Blocking flotillin-1 palmitoylation abrogates TNBC tumor growth and metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C094.
Abstract C130: Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor
Authors: Pan Weiling , Wang Hui , Qi Fangfei , Deng Haibing , Yang Fei , Yu Hongping , Xu Yao-Chang , Chen Zhui , Ying Haiyan 
Published: December 2023

Abstract
Introduction: MTAP is homozygous deleted in ~50% in glioblastoma and many other cancers. PRMT5*MTA inhibition has been shown to be synthetic lethal with MTAP deletion. First generation PRMT5 inhibitors could not distinguish between PRMT5*MTA or PRMT5 alone, thus limited by their shallow therapeutic windows in clinical use. Development of selective PRMT5*MTA inhibitors may improve not only safety but also therapeutic efficacy. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a potent and selective MTA-cooperative and brain-penetrable PRMT5 inhibitor ABK-PRMT5-1, which demonstrates strong anti-tumor activity and brain-penetrating activity in various preclinical models.
Method: Isogenic cell line pairs (MTAP-/- and MTAP+/+) were used to determine the effects of ABSK-PRMT5-1 on cell proliferation and PRMT5-dependednt downstream signaling. Cancer cell line panel was also used to confirm its activity and selectivity. Its in vivo efficacy was evaluated in cell line derived xenograft (CDX) mouse models with tumors harboring MTAP gene deletion.
Results: ABSK-PRMT5-1 strongly inhibits cell proliferation in MTAP-deleted cancer cell lines, with minimal effects on MTAP wildtype cell lines. Furthermore, it significantly reduces SDMA in MTAP-deleted cancer cell lines. Oral administration of ABSK-PRMT5-1 strongly inhibits tumor growth in MTAP-deleted xenograft tumor models. In addition, ABSK-PRMT5-1 demonstrates strong brain penetration with excellent Kp values in animals. DMPK and safety profiling shows good overall drug-like properties of ABK-PRMT5-1.
Conclusion: ABK-PRMT5-1, presented here by Abbisko Therapeutics, is a highly selective MTA-cooperative and brain-penetrable PRMT5 inhibitor. Its superior profile supports fast-track preclinical development.
Citation Format: Weiling Pan, Hui Wang, Fangfei Qi, Haibing Deng, Fei Yang, Hongping Yu, Yao-Chang Xu, Zhui Chen, Haiyan Ying. Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C130.
Abstract IA003: Refining our understanding of ADCs: Drug development insights from 40 years of data
Authors: Colombo Raffaele 
Published: December 2023

Abstract
Antibody drug conjugates (ADCs) have emerged as an effective and promising class of cancer therapeutics. Over the past 40 years, over 300 new ADCs have entered the clinic, culminating in 11 FDA approvals to date. Recently, the increased volume of clinical data related to ADCs has substantially advanced our understanding of this therapeutic class. Despite their rising popularity, there are three prevailing ADC dogma that are widely accepted without challenge: - ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug (the therapeutic window dogma). - A highly stable linker is paramount to the clinical success of the ADC (the stability dogma). - ADCs deliver conjugated drugs selectively to cancer cells while sparing normal cells (the magic bullet dogma). Clinical evidence does not consistently support these beliefs. An improved understanding of how ADCs work is critical to the enhanced design and development of this therapeutic class. Consequently, the canonical ADC dogma need to be refined in light of emerging clinical data. Revised therapeutic window dogma: ADCs do not significantly increase the MTD of their conjugated drugs. Instead, when dosed at or near their MTDs, ADCs exhibit higher efficacy compared to corresponding small molecules. Revised stability dogma: antibody-linker instabilities and linker-drug instabilities are common across many ADCs, including all the approved ADCs (i.e., none of the approved ADCs feature a stable linker). Unexpected toxicities have often emerged among ADCs containing overly stabilized linkers. Revised magic bullet dogma: ADCs significantly alter the exposure of the conjugated drug. Targeted drug delivery and non-targeted uptake, in combination with linker instabilities, contribute to the sustained drug concentration at the tumor site.
Citation Format: Raffaele Colombo. Refining our understanding of ADCs: Drug development insights from 40 years of data [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA003.
Abstract IA015: Leveraging mRNA to design a next-generation cell-based therapeutic cancer vaccine
Authors: Breckpot Karine 
Published: December 2023

Abstract
Monocyte-derived dendritic cell (DC)-based cancer vaccines were shown to activate T cell-mediated antitumor immune responses. To ensure high tumor specificity and potency of the DC-vaccine, we leveraged mRNA for the delivery of tumor antigens and proteins that enhance the DCs’ T-cell stimulatory capacity. With regard to tumor antigens, we studied neoantigens. These originate from erroneous DNA in tumor cells, creating a message for novel and unique tumor antigens of which neoepitopes could be presented by the tumor cells to T cells. Identifying neoepitopes has become possible through advances in next-generation sequencing and bioinformatic prediction algorithms. We developed a synthetic DNA template (SDT) to manufacture in vitro transcribed neoepitope mRNA. A benefit of this platform is the high flexibility and speed to create a neoepitope mRNA library. We showed that mRNA produced with the SDT could be used to validate bioinformatically predicted neoepitopes and could potentially be used to produce a DC-vaccine. With regard to potency, we developed a novel mRNA-based adjuvant, building on the knowledge that interleukin-12 produced by DCs correlates with T-cell activation. The novel mRNA mix, referred to as TetraMix, consists of 4 mRNA molecules encoding (1) constitutively active toll-like receptor 4, (2) CD40 ligand, (3) interferon-gamma and (4) a decoy receptor for interleukin-10. DCs electroporated with TetraMix mRNA showed a viral response gene expression profile. The obtained DC-maturation state enabled activation of tumor killing T cells. In summary, we developed a personalized cancer vaccine consisting of mRNA-engineered DCs, which is ready for evaluation in a clinical setting.&lt;/aaff&gt;
Citation Format: Karine Breckpot. Leveraging mRNA to design a next-generation cell-based therapeutic cancer vaccine [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA015.
Abstract LB_A05: Coadministration of AZD 4573 and gilteritinib exhibits a potent activity in FLT3 inhibitor-sensitive and -resistant AML cells
Authors: Rahmani Mohamed , Salah Baraa Khalid , Yener Burcu , Mahboub Bassam , Grant Steven 
Published: December 2023

Abstract
Acute myeloid leukemia (AML) is caused by the sequential acquisition of mutations that regulate multiple cellular pathways, indicating that multiple pathways must be coordinately inhibited for a successful therapy in this disease. Transcriptomics analysis suggest that exposure of AML cells to the selective CDK9 inhibitor AZD4573 led to activation of multiple survival pathways including MAPK, PI3K, and STAT suggesting that disruption of these signaling pathways may potentiate this agent activity. Notably, combined treatment with AZD4573 and the FLT3 inhibitor gilteritinib resulted in a robust suppression of cell growth and a marked induction of apoptosis in various AML cell lines, particularly those with FLT3 mutations. These were associated with a marked induction of apoptosis reflected by increased Annexin V/PI positivity and cleavage in caspase 3 and its substrate PARP. Importantly, combined treatment was also highly effective in FLT3 mutants AML cells that exhibit significant resistance to various FLT3 inhibitors including gilteritinib. Combined treatment led to a profound disruption of critical survival signaling pathways including MEK/ERK, STAT, and PI3K/AKT pathways. Combined treatment also significantly disrupted the balance between the proapoptotic and anti-apoptotic Bcl-2 members as reflected by downregulation of MCL1 and upregulated of Bim protein levels. Importantly, GILT/AZD4573-induced cell death was fully prevented when Bax and Bak were knocked out using CRISPR system, suggesting that the anti-AML activity of this regimen proceeds mainly via the mitochondrial apoptotic pathway. Finally, using a systemic acute myeloid leukemia xenograft model, co-administration of gilteritinib and AZD4573 sharply reduced leukemia growth and markedly prolonged mice survival. Collectively, these findings demonstrate that dual inhibition of CDK9 and FLT3 exhibits a potent anti-leukemic efficacy in vitro and in vivo. These findings also indicate that this strategy warrants further attention in FLT3-dependent acute myeloid leukemias.
Citation Format: Mohamed Rahmani, Baraa Khalid Salah, Burcu Yener, Bassam Mahboub, Steven Grant. Coadministration of AZD 4573 and gilteritinib exhibits a potent activity in FLT3 inhibitor-sensitive and -resistant AML cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A05.