bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 324: Nickel exposure alters extracellular vesicles biogenesis to carry NUPR1 and mediate cancer progression
Authors: Liu Shan , Ortiz Angelica , Iovanna Juan , Costa Max 
Published: April 2023

Abstract
Nickel (Ni), a group I human carcinogen by the International Agency for Research on Cancer (IARC) alters expression of various oncogenic molecules in cells resulting in adoption of cancer cell phenotypes, such as anchorage-independent growth, migration, and invasion. Cancer cell phenotypes are altered by internal genetic or epigenetic changes or in response to external signals mediated by soluble proteins or extracellular vesicles. However, few studies have linked extracellular vesicles (EVs) in response to environmental pollutants, such as Ni. Nuclear Protein 1 (NUPR1) is a stress response protein that is upregulated in cancer cells and it is also upregulated in cells following chronic Ni exposure. However, the role of NUPR1 in EV biogenesis or EV-mediated cancer progression is unknown. To explore the potential role of EVs in Ni-induced cancer progression, this study examined the effect of Ni-exposure on EV signature. Sizes and concentration of EVs from BEAS-2B cells, 6 weeks-Ni-treated BEAS-2B cells (Ni-6W) and Ni-transformed BEAS-2B cells (Ni-3) were identified by nanoparticle-tracking analysis (NTA) and transmission electron microscopy (TEM). In the results, showed that Ni-6W and Ni-3 released more EVs compared to the control. The transcription expression levels of EVs biogenesis markers, CD63, CD82 and Flotillin-1 (FLOT) were coincidentally increased in Ni-6W and Ni-3 compared to the BEAS-2B. We further identified that inhibition of NUPR1 by using the shRNA or NUPR1 inhibitor ZZW-130 can rescue the increased releasing of EVs induced by Ni exposure. Here we demonstrated that Ni exposure elevated EV release and that these Ni-altered EVs contributed to a pro-inflammatory environment associated with tumorigenesis and cancer progression. Moreover, we provided a new method of regulating EVs biogenesis by targeting NUPR1, this would be crucial for EV-based cancer therapy.
Citation Format: Shan Liu, Angelica Ortiz, Juan Iovanna, Max Costa. Nickel exposure alters extracellular vesicles biogenesis to carry NUPR1 and mediate cancer progression [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 324.
Abstract 3251: The immunostimulatory effect of 9-ING-41, a small molecule GSK-3 inhibitor, in sarcomas
Authors: MacDonald William J. , Lew Samuel , Huntington Kelsey E. , Lulla Rishi R. , DeNardo Bradley D. , El-Deiry Wafik S. 
Published: April 2023

Abstract
Due to the rarity and genomic disparity of soft tissue and bone sarcomas, actionable therapeutic targets have been elusive. However, inhibition of GSK-3β has emerged as a potentially promising therapy that could be of great benefit to pediatric and adult sarcoma patients. Saos-2 osteosarcoma and 93T449 liposarcoma cell lines were pretreated at IC5072 with small molecule GSK-3β inhibitor 9-ING-41 (elraglusib). The cells were harvested for western blot analysis after 48 hours of treatment. Additionally, both cancer cell lines as well as TALL-104 T-cells and NK-92 NK cells were treated with 0.5 μM 9-ING-41 for 24 hours and harvested for Luminex cytokine profiling. The western blots demonstrated an increase in cPARP, an apoptotic marker, in both cancer cell lines after 9-ING-41 treatment. Additionally, an increase in PD-L1 expression was observed. The cytokine analysis revealed stimulation of immune cell activity in response to 9-ING-41. Treated T-cells had an increase in CXCL11, which is associated with T-cell recruitment, as well as an increased level of IL-18, which is shown to induce increased IFN-γ in Th1 cells. Additionally, NK-92 cells demonstrated an increase in IL-8 chemokine and an increase in soluble TRAIL (TRAIL/TNFSF10). The cancer cell lines showed a homogenous increase in growth factor TGF-ɑ, however, only the Saos-2 osteosarcoma cell line demonstrated an increase of IL-6. We are further validating the data with follow-up cytokine profiling. The increase in immunostimulatory cytokines as well as the increased expression of PD-L1 suggest a rationale for combining 9-ING-41 with immune checkpoint blockade therapy. The potential synergistic effect of these two therapies is currently under investigation with co-culture experiments of sarcoma and immune cells. The treatment cohorts for these experiments include 9-ING-41 combined with either anti-PD-L1, anti-PD-1, or anti-CTLA-4 immune checkpoint inhibitors. Our results suggest a promising combination therapeutic strategy for patients with soft tissue and bone sarcomas and future work will strive to better elucidate the mechanisms of efficacy.
Citation Format: William J. MacDonald, Samuel Lew, Kelsey E. Huntington, Rishi R. Lulla, Bradley D. DeNardo, Wafik S. El-Deiry. The immunostimulatory effect of 9-ING-41, a small molecule GSK-3 inhibitor, in sarcomas [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 3251.
Abstract 3309: Genomic features, evolutionary patterns, and minimal residual disease at surgical margins as novel prognostic/predictive biomarkers in locally advanced rectal cancer
Authors: Li Li , He Kewen , Li Aijie , Xu Yang , Pang Jiaohui , Mu Dianbin , Ma Jie , Ge Hong , Maleki Aurian , Qin Xueting , Zhang Xian , Ou Qiuxiang , Tang HaiMeng , Shao Yang , Yu Jinming , Yuan Shuanghu 
Published: April 2023

Abstract
Background: Locally advanced rectal cancers (LARC) are treated with neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision (TME), and adjuvant chemotherapy, and identifying reliable prognostic/predictive biomarkers is currently warranted for LARC.
Methods: Comprehensive genomic profiling was performed in 76 LARC patients who received nCRT plus TME. All 76 patients had baseline tissue biopsies, 72 had paired baseline tissue biopsies and surgical tumor samples, and 55 had paired surgical tumor and margin samples. Post-nCRT tumor regression grade (TRG) and post-surgical disease-free survival (DFS) were used to assess treatment outcomes.
Results: Baseline KRAS mutation (P=0.022) and MYC amplification (P=0.047) appeared to be independent prognostic factors for nCRT, with KRAS/MYC-mutated patients having higher tumor regression grade (TRG) and lower immune infiltration. Intriguingly, high radiation doses during nCRT were correlated with improved nCRT response in KRAS/MYC-positive patients. Additionally, aberrations in multiple signaling pathways, especially JAK-STAT (P=0.022), were enriched in TRG3 patients after nCRT, implying that they might be resistance mechanisms that impair nCRT efficacy. The post-surgical FBXW7 mutation was significantly associated with shorter disease-free survival (P=0.01), while treatment-induced branched tumor evolutionary pattern and the molecular level of residual tumor at the surgical margin were significantly correlated with both poorer nCRT response and higher post-surgical recurrence risk.
Conclusions: Comprehensive genomic profiling helps identify multiple molecular prognostic and/or predictive biomarkers that could predict patients’ clinical outcomes to nCRT and TME and direct nCRT treatment regimen, thus facilitating more accurate prognostic estimation, a better balance between treatment efficacy and quality of life, and timely adjusted treatment decisions.
Citation Format: Li Li, Kewen He, Aijie Li, Yang Xu, Jiaohui Pang, Dianbin Mu, Jie Ma, Hong Ge, Aurian Maleki, Xueting Qin, Xian Zhang, Qiuxiang Ou, HaiMeng Tang, Yang Shao, Jinming Yu, Shuanghu Yuan. Genomic features, evolutionary patterns, and minimal residual disease at surgical margins as novel prognostic/predictive biomarkers in locally advanced rectal 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 3309.
Abstract 3315: Evaluating biomarker potential of germline genomic factors for predicting clinical outcomes in prostate cancer
Authors: Zeltser Nicole , Houlahan Kathleen E. , Al-Hiyari Sarah M. , Eng Stefan E. , Patel Yash , Yamaguchi Takafumi N. , Tao Shu , Huang Rong Rong , Reiter Robert E. , Ye Huihui , Kinnaird Adam S. , Boutros Paul C. 
Published: April 2023

Abstract
Prostate cancer is the second-most diagnosed cancer and the second leading cause of cancer death in American men. Early detection is common, but is followed by the more challenging task of prognosing a highly variable clinical course. Current clinical risk-assessment strategies such as serum abundance of prostate specific antigen (PSA), tumor size & extent, and tumor grade based on biopsy are highly imprecise: over a third of patients are over-treated. An improved method of risk stratification may lie in hereditary factors. Prostate cancer is one of the most strongly inherited (h2 = 57%), with accumulating evidence associating rare variants, common variants, and genetic ancestry to clinical outcomes. We have performed germline sequencing on blood from thousands of patients diagnosed with localized prostate cancer and with extensive follow-up data. We quantify the interactions of rare and common variants, and demonstrate that germline features provide insights into patient outcomes and optimal management strategies.
Citation Format: Nicole Zeltser, Kathleen E. Houlahan, Sarah M. Al-Hiyari, Stefan E. Eng, Yash Patel, Takafumi N. Yamaguchi, Shu Tao, Rong Rong Huang, Robert E. Reiter, Huihui Ye, Adam S. Kinnaird, Paul C. Boutros. Evaluating biomarker potential of germline genomic factors for predicting clinical outcomes in prostate 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 3315.
Abstract 337: Antitumor effect of oncomagnetic therapy in glioblastoma
Authors: Pandey Arvind , Hambarde Shashank , Baskin David S. , Helekar Santosh A. 
Published: April 2023

Abstract
Background: Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15-20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as standalone therapy. We have reported recently that brief 2 - 6 h of daily brain stimulation with a new noninvasive, non-contact, magnetic stimulation device causes &gt;30% reduction of contrast-enhanced tumor (CET) volume in an end-stage recurrent GBM patient after a ~30-day treatment.
Purpose: The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) and other cancer cells while sparing normal developing neurons and astrocytes in vitro. The spinning oscillating magnetic field (sOMF) generated by this device disrupts electron transport in the mitochondrial respiratory chain leading to a marked increase in reactive oxygen species (ROS) and consequent cancer cell death. However, the downstream molecular mechanism of sOMF action is under investigation. We studied the cellular and molecular effects of sOMF treatment on GBM cell lines and investigated the response to Oncomagnetic monotherapy (OMT) in a syngeneic mouse model. We treated LN229 and U87 GBM cells with sOMF with and without a sub-therapeutic dose of TMZ in vitro. To study the anticancer effect of sOMF in vivo, we developed syngeneic GBM tumors in BALB/c mice by stereotactic intracranial injection of GL261WT cells. Tumor growth was monitored periodically by MRI scans.
Results: Our results showed that sOMF significantly reduce cell proliferation and cell survival in vitro. We observed that sOMF induces DNA damage and arrests cells in G1 phase of cell cycle. OMT of tumor-bearing mice using a whole-body sOMF stimulation method caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4 T MRI scans. OMT also showed significant increase in overall survival in these mice.
Conclusion: These experiments contribute to unraveling the mechanism of action underlying the response to OMT in GBM and provide a strong rationale for a standalone Oncomagnetic therapy for GBM.
Citation Format: Arvind Pandey, Shashank Hambarde, David S. Baskin, Santosh A. Helekar. Antitumor effect of oncomagnetic therapy in glioblastoma [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 337.
Abstract 3413: RTK/SHP2 dependency and feedback adaptation to MEK inhibition defines sensitivity of RAS-mutant proteins to SHP2 inhibitor-based therapies
Authors: Baars Beau , Adamopoulos Christos , Orive-Ramos Ana , Aaronson Stuart A. , Poulikakos Poulikos I. 
Published: April 2023

Abstract
Activating RAS mutations constitute the majority of recurrent mutations found in MAPK-driven human tumors. However, RAS mutants have long been considered undruggable, and therefore efforts have been predominantly focused on targeting downstream MAPK signaling. We and others have shown that, MAPK inhibition using MEK inhibitors (MEKi) have limited effectiveness in such tumors due to adaptive resistance. A major mechanism of adaptive resistance involves relief of negative feedback that promotes reactivation of RTK signaling, which in turn activates RAS and results in MAPK rebound. The recent development of direct (i.e. RAS(G12C)) and indirect (i.e. SHP2i, SOSi) inhibitors of RAS have uncovered the dependence of activity of RAS(G12C) and of other RAS mutants on upstream signaling.
We and others have previously characterized sensitivity of various RAS mutants in cancer to either SHP2 inhibition (SHP2i), or to combination of SHP2i with MEKi, but a systematic characterization of most RAS mutants commonly expressed in cancer has been lacking. In this study, by combining biochemical and chemical genetic approaches we identified two classes of RAS-mutants, based on their degree of dependency on RTK/SHP2 signaling and adaptation to MEK inhibition. One class of RAS mutants, including most RASQ61X, show complete independence from RTK/SHP2 signaling and are fully resistant to either SHP2i alone or in combination with MEKi. The other class includes the majority of RAS mutants and is characterized by relative resistance to SHP2i, or the combination of SHP2i plus MEKi, compared to cells expressing wild-type RAS, including normal cells. Early clinical data using single agent SHP2i or combinations of SHP2i with MEKi for the treatment of patients with RAS-mutant tumors suggested modest activity as well as dose-limiting on-target (i.e. MAPK pathway related) toxicities. Our findings predict that achieving an acceptable therapeutic index by either approach for treatment of RAS-mutant tumors will be challenging, and they support instead SHP2i-based therapeutic efforts in patients with MAPK-driven tumors expressing wild-type RAS, or in combination with RAS-mutant selective inhibitors.
Collectively this work provides a framework for the design of SHP2i-based treatments for patients with MAPK-driven tumors, the majority of which currently have no effective targeted therapeutic options.
Citation Format: Beau Baars, Christos Adamopoulos, Ana Orive-Ramos, Stuart A. Aaronson, Poulikos I. Poulikakos. RTK/SHP2 dependency and feedback adaptation to MEK inhibition defines sensitivity of RAS-mutant proteins to SHP2 inhibitor-based therapies [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 3413.
Abstract 3415: Preclinical characterization of a brain penetrant RAF inhibitor, BDTX-4933, targeting oncogenic BRAF Class I/II/III and RAS mutations
Authors: Han Yoon-Chi , Ng Pui-Yee , Ogawa Luisa Shin , Yang Shao Ning , Chen Miao , Ishiyama Noboru , Lin Tai-An , Buck Elizabeth 
Published: April 2023

Abstract
Mutations in BRAF and RAS are often oncogenic and lead to a constitutively active MAPK pathway that promotes aberrant cell proliferation and tumor growth. Currently approved BRAF inhibitors are selective against monomeric BRAF V600 mutants. These drugs are largely inactive against non-V600 dimeric BRAF mutants and have poor brain penetration. Although there is an FDA-approved KRAS G12C mutant-selective inhibitor, there are no approved inhibitors for cancer patients who harbor other (non-G12C) KRAS and NRAS mutations which promote tumor growth likely through constitutively active RAF dimers. There remains a high unmet clinical need for a highly CNS penetrant oral RAF inhibitor that targets a broad spectrum of BRAF mutations and constitutively active RAF dimers without paradoxical activation of the MAPK signaling pathway. BDTX-4933 is a potent, reversible, CNS penetrant RAF MasterKey inhibitor designed to target a large family of oncogenic BRAF mutations including BRAF monomers and RAF dimers. The compound inhibits not only all classes (I, II, and III) of BRAF mutations but also targets constitutively active RAF dimers promoted by upstream oncogenic MAPK pathway alterations, such as RAS mutations. In a panel of cancer cell lines that endogenously express BRAF or RAS mutations, BDTX-4933 demonstrates inhibition of the MAPK pathway signaling without paradoxical activation, resulting in potent inhibition of cellular proliferation. BDTX-4933 shows target engagement, inhibiting ERK phosphorylation, in tumor models in vivo, achieving strong anti-tumor efficacy and tumor regression across tumor models driven by either BRAF or RAS mutations. Furthermore, BDTX-4933 exhibits high CNS exposure leading to dose-dependent tumor growth inhibition, and survival benefit in mice implanted intracranially with xenograft BRAF mutant tumors. BDTX-4933 has a best-in-class profile to treat cancer patients harboring BRAF mutations or RAF dimer-promoting upstream genetic alterations. IND-enabling studies for BDTX-4933 are on-going.
Citation Format: Yoon-Chi Han, Pui-Yee Ng, Luisa Shin Ogawa, Shao Ning Yang, Miao Chen, Noboru Ishiyama, Tai-An Lin, Elizabeth Buck. Preclinical characterization of a brain penetrant RAF inhibitor, BDTX-4933, targeting oncogenic BRAF Class I/II/III and RAS 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 3415.
Abstract 3522: DICER1 Platform domain missense variants led to tumor susceptibility via failure of precursor miRNA binding
Authors: Pelletier Dylan , Chong Anne-Laure , Albert Sophie , Fabian Marc , Foulkes William 
Published: April 2023

Abstract
DICER1 is a key protein in the micro(mi)RNA biogenesis pathway responsible for cleaving precursor (pre)-miRNA stemloops with its RNase IIIa and IIIb domains into mature single stranded miRNAs. DICER1 syndrome is a pleiotropic tumor predisposition syndrome in which clinical manifestations are normally first seen during childhood. This genetic disorder is defined by the presence of inherited or de novo germline pathogenic variants (GPVs) in the DICER1 gene. While many germline loss of function variants fail to generate DICER1 protein, a subset of patients has germline missense variants that are predicted to produce full-length DICER1 protein that cluster in the DICER1 Platform domain, a region that plays a role in binding to the 5’ phosphate of pre-miRNA stemloops. Due to the uncertainty surrounding the pathogenicity of missense variants in DICER1 syndrome, clinical actionability can be limited. To determine how Platform mutations predispose to DICER1 syndrome we characterized a number of these variants using in vitro pre-miRNA binding and cleavage assays. Interestingly, four of these variants displayed impaired pre-miRNA binding and processing, with three of them localizing to a hydrophobic pocket in the Platform domain. In keeping with in vitro results, DICER1 mutants displayed impaired miRNA processing when introduced into mesenchymal stem cells. Furthermore, we identified a second somatic hit in the RNase IIIb domain of DICER1 in thyroid nodular hyperplasia DNA from a patient affected by one of these variants. Taken together, these results identify a key region in the DICER1 protein that is essential for pre-miRNA processing and help the classification of these germline variants as pathogenic to ensure proper clinical management of affected patients. Additionally, these results provide insight on the molecular basis involved in DICER1 syndrome predisposition.
Citation Format: Dylan Pelletier, Anne-Laure Chong, Sophie Albert, Marc Fabian, William Foulkes. DICER1 Platform domain missense variants led to tumor susceptibility via failure of precursor miRNA binding. [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 3522.