bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5841: A genome wide CRISPR-Cas9 screen identifies mediators of resistance to dual PI3K/mTOR inhibition in glioblastoma multiforme
Authors: Ferrotta Annalisa V. , Izawa-Ishiguro Arianna , Grogan Meaghan , Mellinghoff Ingo K. 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a devastating 5-year survival rate of 6.8%. The current standard of care, consisting of surgery, radiation, and temozolomide (TMZ), has remained unchanged for over the past 15 years despite its limited efficacy and the serious therapy-related adverse events associated to this regimen. Although some frequent genetic alterations have been identified in GBM, no targeted therapies have shown efficacy in these patients to date. Among these, the phosphoinositide 3-kinase (PI3K) pathway is a signaling network that regulates cell growth, proliferation, migration, and invasion. Extensive molecular characterization of GBM has identified alterations in the components of the PI3K pathway in 80% of primary GBMs, including amplification of receptor tyrosine kinases (RTKs), activating mutations in the PI3K catalytic subunit (PIK3CA), loss-of-function mutations in the PI3K regulatory subunit (PIK3R1), and loss of the major tumor suppressor of the pathway, phosphatase and tensin homologue (PTEN). Despite the universal upregulation of PI3K pathway signaling associated with these genetic alterations, clinical trials investigating PI3K inhibitors in GBM have failed due to insufficient antitumor activity and dose-limiting toxicities. To elucidate mechanisms of resistance to PI3K inhibition in GBM, we used a genome-wide functional CRISPR-Cas9 knockout screen to identify genes that mediate resistance to the dual PI3K/mTOR inhibitor XL765 in PTEN-null SF295 GBM cells. We identified reactivation of the PI3K pathway and inhibition of autophagy as potential resistance mechanisms to dual PI3K/mTOR inhibition. Using orthogonal approaches, we will functionally validate our candidate hits through mechanistic studies, with patient-derived models, and with in vivo orthotopic xenografts. Our findings will elucidate novel mechanisms of resistance to PI3K/mTOR inhibition in GBM and will streamline rational drug combinations aimed to overcome resistance, thus eventually maximizing therapeutic responses to PI3K inhibitors in GBM.
Citation Format: Annalisa V. Ferrotta, Arianna Izawa-Ishiguro, Meaghan Grogan, Ingo K. Mellinghoff. A genome wide CRISPR-Cas9 screen identifies mediators of resistance to dual PI3K/mTOR inhibition in glioblastoma multiforme [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 5841.
Abstract 5879: Role of the inner mitochondrial membrane protein (Mic60) in MAPKi-resistant melanoma
Authors: Ghosh Jagadish C. , Aguila Segundo Del , Li Haiyin , Villanueva Jessie , Altieri Dario C. 
Published: March 2024

Abstract
Introduction: Metastatic melanoma is one of the most aggressive cancers, despite recent improvements in therapy. The rising melanoma incidence and mortality, along with its high propensity for metastasis highlights the urgency to find more effective therapeutic targets. The efficacy of targeted MAPK signaling pathway inhibitors (MAPKi) in metastatic melanoma therapy is limited by the development of resistance mechanisms that result in disease relapse. This situation necessitates alternative treatments for melanoma patients who develop resistance to targeted therapy. We have recently found out that there exists a group of human tumors that express lower levels of Mic60, a mitochondrial structural protein also known as mitofilin or inner membrane mitochondrial protein (IMMT). In a model of prostate cancer, we showed that Mic60-low tumors have lower mitochondrial fitness, but increased cell motility, invasion, and propensity to metastasize. However, a potential differential expression of Mic60 in melanoma has not been investigated and whether reduced mitochondrial fitness in Mic60-low tumors can expose new therapeutic vulnerabilities in combination with targeted therapies has not been determined.
Experimental Procedures: We analyzed melanoma-specific TMA for differential expression of Mic60 in tumor vs. adjacent normal tissue by IHC. Differential mRNA expression levels were examined by single-cell RNA-Seq and quantified by bioinformatics analysis. Differential therapeutic vulnerabilities of Mic60-low melanoma cell lines to mitochondrial-targeted small molecule Hsp90 inhibitor, Gamitrinib, were assessed for cell death induction and mitochondrial dysfunction.
Results: We identified subsets of melanoma patients with constitutively reduced or outright undetectable expression of Mic60, in vivo. By single-cell RNA-Seq, Mic60-low melanomas were characterized by reduced oxidative phosphorylation and decreased ATP production, slower cell cycle progression but paradoxically increased cell motility and invasion. Loss of Mic60 exposed new, actionable therapeutic vulnerabilities, and the combination of Gamitrinib plus MAPKi potently induced mitochondrial cell death in MAPKi-resistant melanoma cell lines.
Conclusion: Mic60 is heterogeneously expressed and often reduced in melanoma. Although this is associated with increased cell invasion and metastatic propensity, the combination of Gamitrinib plus MAPKi restored mitochondrial cell death in therapy-resistant, Mic60-low melanoma cells.
Citation Format: Jagadish C. Ghosh, Segundo Del Aguila, Haiyin Li, Jessie Villanueva, Dario C. Altieri. Role of the inner mitochondrial membrane protein (Mic60) in MAPKi-resistant melanoma [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 5879.
Abstract 592: A novel pMEK inhibitor ABM-4095 for the treatment of pancreatic cancer
Authors: Xu Min , Hu Yong , Zhao Lanjiao , Chen Xiuquan , Chen Youqin , Yang Chen , Li Jizhi , Chen Chen , Lv Xiaobing 
Published: March 2024

Abstract
The MEK-ERK pathway is often activated in tumors by mutations of upstream BRAF- or RAS-proteins. The RAS is frequently mutated in several cancers, especially in pancreatic cancer with an about 95% rate. Pancreatic cancer has the highest mortality rate with a 5-year survival rate of 8% and a median survival of 6 months. Targeted therapies have been extensively evaluated in pancreatic cancer, however, survival improvement of this aggressive disease using a targeted strategy has been minimal. The only currently approved targeted therapy is erlotinib in combination with the chemotherapy drug gemcitabine. To date, four MEK inhibitors that block RAF-activation have been approved by the FDA, but their ability to inhibit ERK signal activated by RAS-mutations is limited due to the induction of MEK phosphorylation by relief of ERK-dependent feedback inhibition of RAF. Here, we report a novel small molecule, ATP-uncompetitive, pMEK inhibitor ABM-4095 that potently prevents phosphorylation of MEK by RAF with moderate inhibition of MEK kinase activity. Most of MEK inhibitors approved by FDA or in clinical trials increase pMEK levels instead. ABM-4095 has a good cell permeability. Its anti-cancer efficacy has been demonstrated both in the in vitro cancer cell line proliferation assay and in vivo xenograft models. ABM-4095 showed a synergy effect with erlotinib in pancreatic cancer cells. In a Miapaca-2 xenograft model, ABM-4095 showed good dose-dependent tumor inhibition as a single agent or combining with the KRAS G12C inhibitor AMG-510, and tumor regressions were observed. In summary, ABM-4095 is a potent pMEK inhibitor with a high activity against the RAS-mutant pancreatic cancer in vitro and in vivo. Detailed preclinical results will be presented.
Citation Format: Min Xu, Yong Hu, Lanjiao Zhao, Xiuquan Chen, Youqin Chen, Chen Yang, Jizhi Li, Chen Chen, Xiaobing Lv. A novel pMEK inhibitor ABM-4095 for the treatment of pancreatic 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 592.
Abstract 5923: Innovative cyclic peptide disrupts IL-17RB/MLK4 Interaction for targeted pancreatic cancer therapy
Authors: Lo Yung-Chen , Ko YL , Huang CH , Lee JH , Wu DN , Wu YT , Yu HM , hu Cn-Mei 
Published: March 2024

Abstract
Interleukin-17B (IL-17B) and its receptor IL-17RB drive oncogenic signaling in pancreatic cancer by interacting with mixed-lineage kinase 4 (MLK4) and phosphorylating IL-17RB's tyrosine-447 site. Our study highlights a therapeutic peptide (amino acids 403-416 of IL-17RB) that disrupts MLK4 binding. Improving its efficacy, we transformed the linear peptide into a disulfide-bonded cyclic form, exhibiting enhanced uptake and stability. The modified cyclic peptide outperformed the linear counterpart, effectively inhibiting the growth and metastasis of PDAC tumor cells in vitro and in a mouse model. Molecularly, we identified the critical role of cysteine (C) residue C408 in IL-17RB, mediating interaction with arginine (R)216 in MLK4's kinase domain. This interaction is pivotal for the cyclic peptide's efficacy. Additionally, lysine (K) residue K410 in IL-17RB maintains the cyclic peptide's structural integrity. These findings provide a comprehensive molecular understanding of IL-17RB and MLK4 interaction, offering innovative strategies for designing therapeutic molecules against pancreatic cancer.
Citation Format: Yung-Chen Lo, YL Ko, CH Huang, JH Lee, DN Wu, YT Wu, HM Yu, Cn-Mei hu. Innovative cyclic peptide disrupts IL-17RB/MLK4 Interaction for targeted pancreatic cancer therapy [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 5923.
Abstract 5926: YB-1 inhibition as an effective approach for the treatment of osteosarcoma
Authors: Stefan Kirsten , Dheeraj Arpit , Tailor Dhanir , Davis Lara E. , Malhotra Sanjay V. 
Published: March 2024

Abstract
Background: Osteosarcoma (OS) is a bone cancer primarily affecting adolescents and young adults, with about 20% of patients having detectable metastatic disease at the time of diagnosis. Despite a large number of clinical trial efforts, metastatic sarcoma remains a lethal disease, and there have been no meaningful advances in therapy or improvements in patient outcomes for decades. Y-box binding protein 1 (YB-1) is a multifunctional cold-shock protein that translationally activates diverse stress response factors with pro-metastatic activities in many cancer types. Importantly, YB-1 is strongly associated with poor outcomes in sarcoma patients and is a major metastatic driver in high-risk sarcomas.
Methods: We recently described a novel compound, CET056, that inhibits cancer progression via YB-1 inhibition. We hypothesized that CET056 had the potential to suppress the progression of OS and could provide a new treatment for this disease. We screened osteosarcoma human and mouse cell lines for YB-1 protein expression. OS cells were functionally characterized for responses to CET056 in vitro and in vivo.
Results: YB-1 expression was seen in nearly all cell lines tested. CET056 treatment of OS cells resulted in reduced cell viability and YB-1 protein expression in a dose- and time- dependent manner, as well as reduced formation of colonies and spheroids. In vivo efficacy studies, which employed a syngeneic subcutaneous tumor model, revealed that CET056 effectively inhibited tumor progression and enhanced overall survival in contrast to vehicle treated control mice.
Conclusion: These results support our hypothesis and illustrate that YB-1 inhibition by CET056 is a promising candidate for further development as a therapy for OS.
Citation Format: Kirsten Stefan, Arpit Dheeraj, Dhanir Tailor, Lara E. Davis, Sanjay V. Malhotra. YB-1 inhibition as an effective approach for the treatment of osteosarcoma [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 5926.
Abstract 5935: Non-allosteric inhibition of enolase 1 sensitizes triple-negative breast cancer for checkpoint inhibitors
Authors: Tailor Dhanir , Garcia-Marques Fernando Jose , Bermudez Abel , Li Wenqi , Dheeraj Arpit , Pitteri Sharon J. , Malhotra Sanjay V. 
Published: March 2024

Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that commonly returns and spreads. Currently, very few options are available for TNBC treatment. Cancer cells exploit glycolytic machinery for the Warburg effect and aerobic glycolysis. Enolase 1 (ENO1) is the glycolytic enzyme expressed in most tissues, and many cancer cells have higher expression. Apart from the glycolytic role in the cytosol, ENO1 also plays different roles in cancer cells, including as a surface receptor.
Method: non-allosteric chemical inhibition was developed and tested in vitro for its efficacy and target validation. Subsequently, in vivo examinations were conducted on emerging small molecules in syngeneic and patient-derived murine models of breast cancer to unveil their anti-tumor efficacy.
Results: Our non-allosteric small molecule inhibitor, SU212, binds to ENO1 and restricts its movement within cells. SU212 treatment leads to the accumulation of ENO1 in the nucleus where it restrains the activity of c-Myc. The treatment causes the production of truncated ENO1 called myc promoter-binding protein 1 (MBP-1), which limits the activity of c-Myc. Stand-alone treatment of SU212 restrains the tumor progression and metastasis in orthotopic syngeneic and PDX mouse models. Combining SU212 and Anti-PD1 significantly inhibits tumor growth and metastasis in mouse models. C-Myc is linked to protein transcription that aids immune resistance and tumor evasion of immune surveillance. Suppression of c-Myc activity via SU212 treatment sensitizes the TNBC tumors for anti-PD1 therapy.
Conclusions: This study provides compelling preclinical data for further development of SU0212 as an immune therapy sensitizer for the treatment of TNBC.
Citation Format: Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Wenqi Li, Arpit Dheeraj, Sharon J. Pitteri, Sanjay V. Malhotra. Non-allosteric inhibition of enolase 1 sensitizes triple-negative breast cancer for checkpoint inhibitors [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 5935.
Abstract 5946: ZM-412, a potent and selective KIF18A inhibitor with robust efficacy as monotherapy in CIN-positive tumors and in combination with MMAE-conjugated ADC in CIN-negative tumors
Authors: Zhou Feng , Zhou Lei , Wang Ruina , Xue Liting , Qin Xiaokang , Li Zhengtao , Yu Jian , Tang Renhong 
Published: March 2024

Abstract
Chromosomal instability (CIN), a hallmark of human cancer, is defined as the perpetual missegregation of whole chromosomes during mitosis. KIF18A has emerged as a potential therapeutic target of synthetic lethality to induce CIN tumor cell death because it is more required for the proliferation of CIN tumor cells than normal diploidy cells. Here, we identified a potent and selective KIF18A inhibitor ZM-412. In vitro, ZM-412 inhibited the kinesin motor enzymatic activity with an IC50 less than 30 nM, and arrested OVCAR3 cells in the G2/M phase with an EC50 around 2.0 nM. ZM-412 also selectively inhibited the proliferation of a panel of CIN-positive tumor cell lines with IC50 values less than 50 nM, whereas it didn’t affect the proliferation of CIN-negative cells such as PBMC and near-diploidy HCT116 as indicated by IC50 values over than 5 μM. A CIN-positive HCT116CIN model was established by cytochalasin D induction. Compared to parent HCT116 cells, it was sensitive to ZM-412 treatment, suggesting the high selectivity of ZM-412 to CIN tumors as monotherapy. Both KIF18A inhibitors and monomethyl auristatin E (MMAE) regulate microtubule dynamics, which provides a potential combination strategy. ZM-412 showed a significantly synergic effect with free MMAE or MMAE-conjugated ADC on the inhibition of proliferation in multiple kinds of cancer cell lines, including CIN-positive/negative tumor cell lines. In vivo, ZM-412 potently inhibited tumor growth in a dose-dependent manner in OVCAR3 and HT29 xenograft models. Moreover, ZM-412 showed a remarkable synergic effect on tumor growth inhibition with MMAE-conjugated LIV-1 ADC in OVCAR3 xenograft model. In conclusion, we discovered ZM-412 as a novel potent and selective KIF18A inhibitor, which has potential for the treatment of CIN cancers as monotherapy and for combination therapies for extended cancer types with MMAE-ADC.
Citation Format: Feng Zhou, Lei Zhou, Ruina Wang, Liting Xue, Xiaokang Qin, Zhengtao Li, Jian Yu, Renhong Tang. ZM-412, a potent and selective KIF18A inhibitor with robust efficacy as monotherapy in CIN-positive tumors and in combination with MMAE-conjugated ADC in CIN-negative tumors [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 5946.
Abstract 5969: VRK1 can be a therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix
Authors: Kobayashi Mariya , Nakagawa Satoshi , Kanda Mizuki , Kamei Yuji , Tatsuo Masuda , Kakuda Mamoru , Hiramatsu Kosuke , Kimura Toshihiro , Ueda Yutaka , Enomoto Takayuki , Inoue Masahiro , Kimura Tadashi 
Published: March 2024

Abstract
Objective: Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is extremely rare but highly aggressive and its prognosis is usually poor. Vaccinia-related kinase (VRK)1 is a serine/threonine protein kinase that is involved in cell proliferation by regulating cell-cycle progression and inducing cell-cycle arrest in response to stress signals. VRK2 belongs to the same family as VRK1, and they are paralogs. VRK1 has been reported as a potential therapeutic target in nervous system tumors with low VRK2 expression. Previously, we identified high expression of VRK1 in SCNEC through proteomic analysis of isolated organoids. The objective of the present study is to investigate the effect of VRK1 on the proliferation of SCNEC and its potential as a therapeutic target.
Methods: The mRNA and protein expression of VRK1 and VRK2 in ten organoids and two cell lines derived from SCNEC were examined and compared with cervical cancer of other histological subtypes by RNA microarray and western blot analysis. The effect of VRK1 on tumor growth in vitro and in vivo (xenograft model) were evaluated by shRNA-mediated knockdown of VRK1 (shVRK1). RNA-seq was performed from the xenograft tumors. The effects of shVRK1 on cell proliferation were evaluated under various levels of oxidative stress induced by H2O2.
Results: VRK1 expression was higher in organoids and cell lines derived from SCNEC than those derived from squamous cell carcinoma and adenocarcinoma, while VRK2 expression was lower in SCNEC. Tumor growth was suppressed significantly by shVRK1 in vivo (mean weight: cell line 1: 0.62 vs 0.06g, p&lt;0.05, 2: 1.79 vs 0.58g, p&lt;0.01). Gene ontology analysis of RNA-seq data suggested that VRK1 is related to cellular responses to stress. Proliferation was slightly suppressed by shVRK1 under normal conditions; however, it was significantly enhanced under oxidative stress (Cell line 1: in shVRK1, -14.0% without oxidative stress vs -54.9% under H2O2 750μM, p&lt;0.01, Cell line 2: similar to Cell line 1).
Conclusion: SCNEC exhibited high VRK1 and low VRK2 expression, and the tumor suppressive effect of shVRK1 was more significant in vivo than in vitro. VRK1 may play a role in the tumor microenvironment, including oxidative stress, and is a potential therapeutic target for SCNEC.
Citation Format: Mariya Kobayashi, Satoshi Nakagawa, Mizuki Kanda, Yuji Kamei, Masuda Tatsuo, Mamoru Kakuda, Kosuke Hiramatsu, Toshihiro Kimura, Yutaka Ueda, Takayuki Enomoto, Masahiro Inoue, Tadashi Kimura. VRK1 can be a therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix [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 5969.
Abstract 5976: R9: A novel NuRD complex inhibitor for targeted therapy in triple negative breast cancer (TNBC)
Authors: Zhang Kun , Jacob Sheeba , Dozmorov Mikhail , Babic Ivan , Nurmemmedov Elmar , Faber Anthony C. 
Published: March 2024

Abstract
Triple Negative Breast Cancer (TNBC) is a highly aggressive breast cancer subtype, disproportionately affecting young and African American populations. TNBC constitutes up to 15% of breast cancers that lack effective targeted therapy. The Nucleosome Remodeling and Deacetylase (NuRD) complex, a pivotal chromatin remodeling entity, plays a crucial role in cancer development and progression. Specifically, the NuRD complex associates with SALL4 in cancer cells, contributing to the silencing of tumor-suppressor genes like PTEN. In this study, we discover R9, a novel small-molecule nucleotide analog, a first-in-class NuRD inhibitor. Utilizing computational and cellular methods, R9 demonstrated selective engagement with RBBP4, a key NuRD complex subunit. Cellular target engagement technology has been utilized to verify direct interaction of R9 with NuRD complex as well as to guide medicinal chemistry efforts. Mass spectrometry thermal proteome profiling (TPP) affirmed RBBP4 as the primary target of R9 with minimal off-target effects. In vitro studies reveal R9 displaying robust toxicity in TNBC cells, while sparing normal tissue derived cells. Encouragingly, R9 effectively impeded TNBC tumors growth in mice without inducing toxicity. Mechanistically, we demonstrate R9 induces DNA damage in sensitive TNBC cells, and the sensitivity correlates to DNA damage-vulnerable cancer cells, indicating DNA damage is a major effector of NuRD complex inhibition in TNBCs. We further demonstrate that R9 induces DNA damage through a c-MYC dependent manner. Ongoing studies aim to elucidate key transcription factors involved in NuRD complex inhibition and the role of MYC and DNA damage in response to NuRD complex inhibition. This research positions R9 as a promising candidate for targeted therapy in TNBC, offering potential insights into the intricate molecular pathways involved in TNBC tumor progression.
Citation Format: Kun Zhang, Sheeba Jacob, Mikhail Dozmorov, Ivan Babic, Elmar Nurmemmedov, Anthony C. Faber. R9: A novel NuRD complex inhibitor for targeted therapy in triple negative breast cancer (TNBC) [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 5976.