bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1009: A novel C-terminal HSP90 inhibitor NCT-58 targets cancer stem-like properties and suppresses migratory ability in triple-negative breast cancer cells
Authors: Park Soeun , Park Jung Min , Park Minsu , Ko Dongmi , Kim Seongjae , Seo Juyeon , Nam Kee Dal , Kim Yoon-Jae , Kim Ji Young , Seo Jae Hong 
Published: June 2022

Abstract
Background: Although several N-terminal HSP90 inhibitors have been investigated in clinical trials, none have yet been approved for clinical use due to issues including induction of the heat shock response (HSR), off-target effects and toxicity. A major issue for N-terminal inhibitors is induction of the heat shock response (HSR) which triggers cell survival. In the present study, we investigated the effects of NCT-58, a rationally-designed novel HSP90 inhibitor that instead targets the C-terminal domain, and evaluated its capacity to induce apoptosis and target cancer stem-like properties in triple-negative breast cancer.
Materials and Methods: The effect of NCT-58 on TNBC cell lines in vitro was evaluated with cell viability, apoptosis, heat shock response and cell migration. Cancer stem-like properties were examined by Aldefluor positivity, CD44+/CD24- stem-like population and mammosphere formation assays.
Results: NCT-58 induces apoptosis in TNBC cells without triggering the heat shock response (HSR) due to its targeting of the C-terminal region. This is accompanied by potent and simultaneous degradation of AKT, MEK and STAT3. Importantly, NCT-58 kills not only the rapidly proliferating tumor cells and but also effectively eradicates the breast cancer stem-like population (BCSCs). The latter phenomena are accompanied by reductions in the activity of stem/progenitor marker ALDH1 and the CD44+/CD24- stem-like population and as well as impairment of mammosphere formation. Furthermore, NCT-58 markedly impairs cell migratory ability, coinciding with collapse of HSP90 client cytoskeletal proteins including vimentin and F-actin in TNBC cells in vitro. It is noteworthy that NCT-58 exhibits more cytotoxic to tumor cells but minimally cytotoxicity to non-malignant cells.
Conclusion: These findings suggest that NCT-58 may represent an effective therapeutic approach for the simultaneous targeting of HSP90 and its client oncoproteins for the treatment of molecularly heterogeneous TNBC.
Citation Format: Soeun Park, Jung Min Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. A novel C-terminal HSP90 inhibitor NCT-58 targets cancer stem-like properties and suppresses migratory ability in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1009.
Abstract 102: IGFBP6 modulates estrogen receptor alpha phosphorylation and transcriptional activity in breast cancer cells
Authors: Lariz Francisco Javier , Houston Kevin D. 
Published: June 2022

Abstract
Insulin-like growth factors (IGFs) are signaling proteins which bind to insulin-like growth factor 1 receptor (IGF-1R) and induce a signaling cascade to promote proliferation and survival in breast cancer cells. Insulin-Like Growth Factor Binding Protein 6 (IGFBP-6) induces apoptosis by inhibiting IGF-1R upon binding to both IGF-1 and IGF-2, however, the role of IGFBP-6 in breast cancer has not been adequately studied. While IGFBP-6 can bind to both IGF-1 and IGF-2, the binding affinity for IGF2 is 20-fold higher compared to IGF1. To determine if IGFBP-6 modulates breast cancer cells, MCF-7 and T-47D cells were stably transfected with an IGFBP-6 expression plasmid. IGFBP6 over-expression resulted in decreased proliferation rates in both cell lines when compared to empty vector controls. To identify a mechanism of decreased proliferation rates, the activation of the IGF-1R-dependent AKT and MAPK mediators was measured. Reduced phosphorylation of MAPK and AKT was observed in both cell lines over-expressing IGFBP-6 compared to empty vector controls. MAPK and AKT phosphorylate ERα at serine 118 and serine 167 respectively, therefore, ERα phosphorylation at these residues was determined in the presence of IGFBP6 expression. Reduction in phosphorylation was greater in MCF-7 cells than T-47D cells when IGFBP6 was constitutively expressed. To determine if reduced ERα phosphorylation altered expression of known targets of ERα-modulated expression, such as IGF-1R and Progesterone Receptor (PR) was measured. Unexpectedly, IGF-1R and PR protein and transcript levels were greater in IGFBP6 over-expressing cells. Studies have shown that differences in ERα phosphorylation change the recruitment of transcriptional modulators associated with ERα-mediated transcription. These results suggest that despite reducing IGF-1R-dependent cell signaling, compensatory mechanisms may be induced to enhance ERα-mediated expression.
Citation Format: Francisco Javier Lariz, Kevin D. Houston. IGFBP6 modulates estrogen receptor alpha phosphorylation and transcriptional activity in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 102.
Abstract 1028: Phosphate dysregulation as a novel therapeutic strategy in ovarian and uterine cancers
Authors: Bondeson Daniel , Paolella Brenton , Asfaw Adhana , Rothberg Michael , Skipper Thomas , Mesa Gabriel , Gonzalez Alfredo , Surface Lauren E. , Ito Kentaro , Kazachkova Mariya , Colgan William N. , Warren Allie , Dempster Joshua , Krill-Burger J Michael , Ericsson Maria , Tang Andrew , Fung Iris , Chambers Emily S. , Abdusamad Mai , Dumont Nancy , Doench John , Piccioni Federica , Root David , Boehm Jesse , Hahn William C. , Mannstadt Michael , McFarland James , Vazquez Francisca , Golub Todd 
Published: June 2022

Abstract
Precision medicine promises to improve the treatment of cancer patients, but a lack of therapeutic targets and associated predictive biomarkers limit this reality. To identify novel strategies, we integrate genome-scale CRISPR viability screens across many cancer models with cellular and molecular features to systematically define The Cancer Dependency Map. Using this data, we have identified that XPR1, an inorganic phosphate exporter protein, is a highly selective dependency gene in ovarian and uterine cancers. These cancers are sensitive to loss of XPR1 due to over-expression of SLC34A2, a phosphate importer protein. These data suggest a synthetic lethal relationship in which intracellular phosphate homeostasis is dysregulated in cancer. As proof-of-concept of pharmacological inhibition of XPR1, we have developed protein ligands based on the receptor binding domain of viruses which use XPR1 for cellular entry. These ligands inhibit XPR1 and kill cancer cells in an on-mechanism manner, but may be limited in their clinical utility. As such, we are deepening our understanding of the mechanisms of XPR1-dependent phosphate efflux, and have identified a novel partner protein that is integral to phosphate efflux, possibly revealing functional domains that small molecule inhibitors might target. Overall, these data highlight a novel mechanism to treat cancers by leveraging cancer-specific phosphate dysregulation and further reinforce the Cancer Dependency Map as a powerful engine to uncover novel therapeutic vulnerabilities.
Citation Format: Daniel Bondeson, Brenton Paolella, Adhana Asfaw, Michael Rothberg, Thomas Skipper, Gabriel Mesa, Alfredo Gonzalez, Lauren E. Surface, Kentaro Ito, Mariya Kazachkova, William N. Colgan, Allie Warren, Joshua Dempster, J Michael Krill-Burger, Maria Ericsson, Andrew Tang, Iris Fung, Emily S. Chambers, Mai Abdusamad, Nancy Dumont, John Doench, Federica Piccioni, David Root, Jesse Boehm, William C. Hahn, Michael Mannstadt, James McFarland, Francisca Vazquez, Todd Golub. Phosphate dysregulation as a novel therapeutic strategy in ovarian and uterine cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1028.
Abstract 1051: Combination of senaparib with temozolomide for the treatment of cancer
Authors: Cai Sui Xiong , Ma Ning , Wang Xiaozhu , Ma Jie , Guo Mingchuan , Zhou Ruiyu , Liu Lan , Hsieh Chih-Yi , Tian Ye Edward 
Published: June 2022

Abstract
Poly (ADP-ribose) polymerase (PARP) is a critical enzyme for DNA repair and PARP inhibitors have been found to be efficacious against cancers with defects in DNA repair pathways such as with BRCA mutations. In addition, in vitro and in vivo studies have found that for PARP inhibitors with good trapping activity, combination with temozolomide (TMZ) produced the best synergetic effects among different types of chemotherapies. Several clinical combination studies of PARP inhibitors with TMZ have been reported, such as the combination of olaparib with TMZ in small cell lung cancer (SCLC). In this presentation, we will report in vitro and in vivo studies of PARP inhibitor senaparib (IMP4297) in combination with TMZ. Synergetic effects were observed when senaparib was combined with TMZ in vitro against human SCLC NCI-H209 cells. In vivo studies of high-dose senaparib in combination with low-dose TMZ once a day continuously in human SCLC NCI-H209 xenograft model was found to be highly synergetic and well tolerated. A clinical study of senaparib in combination with TMZ in patients with advanced solid tumors and SCLC is ongoing (ClinicalTrials.gov Identifier: NCT04434482).
Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Jie Ma, Mingchuan Guo, Ruiyu Zhou, Lan Liu, Chih-Yi Hsieh, Ye Edward Tian. Combination of senaparib with temozolomide for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1051.
Abstract 107: Reciprocal Sox2 regulation by SMAD1 and SMAD3 is critical for anoikis resistance and metastasis in ovarian cancer
Authors: Shonibare Zainab M. , Monavarian Mehri , O'Connell Kathleen , Altamore Diego , Shelton Abigail , Mehta Shubham , Jaskula-Sztul Renata , Phaeton Rebecca , Berchuck Andrew , Nixon Andrew B. , Arend Rebecca , Lee Nam Y. , Miller Ryan , Hempel Nadine , Mythreye Karthikeyan 
Published: June 2022

Abstract
The tumor ascites environment is enriched with cytokines and growth factors especially members of the Transforming Growth Factor-β (TGF-β) family, that play crucial roles in modulating anoikis sensitivity and consequently metastatic progression in ovarian cancer. Here, we demonstrated for the first-time significant broad dichotomy between these TGF-β members: BMPs and TGF-β/activin and their regulated SMADs in this process. We previously reported BMP9/GDF2 to be in low to undetected levels in ovarian cancer patient-derived ascites and promoted anoikis resistance in both breast and ovarian cancer cell lines. We have now identified additional BMPs -BMP2, BMP4 and BMP9 as promoting anoikis sensitivity in a spectrum of ovarian cancer cells. Conversely, we found TGF-βs (1 and 2) to be in much higher expression and demonstrated that TGF-β and activin promoted anoikis resistance in ovarian cancer. Hence, in an attempt to identify genes downstream of BMPs that may provide anoikis resistance, transcriptomics was performed leading to the identification of Sox2, a developmental gene with prior established roles in OVCA, as being significantly downregulated in response to BMP9. We further uncovered Sox2 to be reciprocally regulated by anoikis-promoting BMPs (2, 4 and 9) and anoikis suppressing TGF-β and activin A. Our findings highlight a novel contrasting SMAD dependent regulation of Sox2 as a central node for controlling tumor cell survival in ovarian cancers demonstrating a subset of BMPs as a therapeutic strategy in cancer. The studies presented here begin to elucidate the mechanisms of reciprocal epigenetic regulation of Sox2 by BMP and TGF-β/activin in the context of ovarian cancer, which is the most lethal gynecologic malignancy in women due to peritoneal metastatic spread.
Citation Format: Zainab M. Shonibare, Mehri Monavarian, Kathleen O'Connell, Diego Altamore, Abigail Shelton, Shubham Mehta, Renata Jaskula-Sztul, Rebecca Phaeton, Andrew Berchuck, Andrew B. Nixon, Rebecca Arend, Nam Y. Lee, Ryan Miller, Nadine Hempel, Karthikeyan Mythreye. Reciprocal Sox2 regulation by SMAD1 and SMAD3 is critical for anoikis resistance and metastasis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 107.
Abstract 1081: Design of combinatory RNA molecules to simultaneously activate tumor immunity and target several signaling pathways in solid tumors
Authors: Hillmann Petra , Selvaraj Justin A. , Zimmerli Sina E. , Birrer Pascale G. , Bohnert Claudia C. , Zuideveld Klaas P. , Scherer Stefan J. , Metzger Friedrich 
Published: June 2022

Abstract
Combination therapy is implicated for many oncological indications to circumvent resistance mechanisms that reduce efficacy of targeted drugs. In recent years, mRNA has been successfully utilized preclinically to deliver cytokines to tumors locally at efficacious doses.
Versameb has developed a technology platform which enables combinatorial approaches for intra-tumoral application of nucleotide therapeutics that comprise an mRNA element covalently linked to up to three independent siRNA elements targeting various tumor-relevant genes. Such constructs allow a dose-synchronized treatment of different components in parallel, which opens the opportunity to address up to four cancer targets within a single RNA molecule.
For proof of concept, we designed a combinatory molecule consisting of mRNA coding for human interleukin 2 (IL-2) linked to a small interfering RNA (siRNA) targeting vascular endothelial growth factor A (VEGFA). Transfection of A549 adenocarcinoma cells led to dose-dependent secretion of efficacious concentrations of IL-2 and simultaneous complete VEGFA knockdown. IL-2 protein functionality was tested in SK-OV-3 cell spheroids co-cultured with human primary peripheral blood mononuclear cells (PBMCs). After treatment, secreted IL-2 protein induced immune cell activation and consecutive spheroid killing by PBMCs from three independent donors. VEGFA functionality was tested in an in vitro vascularization assay in HUVEC cells. Cells were treated with supernatants of vehicle or RNA transfected SCC-4 head & neck cancer cells producing high endogenous VEGFA, and vascular sprouting was analyzed quantitatively. While vehicle-treated cell supernatant induced vessel sprouting, supernatant from RNA treated cells showed much reduced sprouting in vitro consistent with the lower VEGFA levels measured, confirming functionality of the siRNA effect on VEGFA protein expression.
We further provide examples of combinatory molecules targeting up to 4 independent key cancer hallmarks and their functional outcomes in various cancer cell types.
In conclusion, mRNA combination constructs can be developed into cancer therapeutics that target several pro-tumorigenic pathways simultaneously with a single molecule overcoming hurdles of delivery, toxicity, and regulatory requirements for combination therapies.
Citation Format: Petra Hillmann, Justin A. Selvaraj, Sina E. Zimmerli, Pascale G. Birrer, Claudia C. Bohnert, Klaas P. Zuideveld, Stefan J. Scherer, Friedrich Metzger. Design of combinatory RNA molecules to simultaneously activate tumor immunity and target several signaling pathways in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1081.
Abstract 1087: Development and characterization of a bispecific antibody (GB265) against PD-L1 and TIGIT
Authors: Huang Su , Yang Riyao , Huang Cai , Putrevu Saroja , Fay Nathan S. , Wright Kimberly , Zaman Mohd Saif , Huang Betty , Wang Bo , Wright Meredith , Wang Yanan , Tian Xuefei , Liu Yue 
Published: June 2022

Abstract
Background: Cancer immunotherapy has transformed cancer therapy. In particular, blockade of the PD-L1/PD-1 axis with PD-1 or PD-L1 antibodies has achieved successful and durable treatment outcomes in some patients across a variety of cancer types. However, primary or acquired resistance to immunotherapy and adverse effects have been observed in cancer patients, due to a hostile TME and the immunosuppressive activity of various inhibitory checkpoint receptors and their ligands on immune cells and cancer cells. It was recently reported that dual blockade of PD-1/PD-L1 and TIGIT/CD155 could improve treatment efficacy in NSCLC patients. We therefore develop bispecific antibody against both PD-L1 and TIGIT with the aim of enhancing the efficacy of therapy and mitigating potential adverse effects.
Methods: We obtained TIGIT binders by VHH library panning, and constructed PD-L1/TIGIT BsAbs of two different structures either by fusing the TIGIT VHH to a PD-L1 IgG or by fusing the TIGIT VHH to a PD-L1 VHH-Fc. TIGIT binding and CD155 blocking was analyzed by fluorescence-activated cell sorting (FACS) using Jurkat cells stably expressing TIGIT. Function assays were conducted with a co-culture system of H1975 stably expressing OKT3 and induced human exhausted T cells or luciferase reporter Jurkat cells with high expression of PD-1 and TIGIT.
Results: Both bispecific antibodies effectively bind TIGIT on T cells and PD-L1 on PD-L1 positive cancer cells. Interaction between BsAb and the two targets bridge the T cell and the cancer cell and result in the clustering of the antibody-antigen complexes at the contact area of the two cells. Functionally, GB265 antibodies effectively blocked CD155 and PD-1 signal pathways in the cell-based reporter system and exhibited ADCC function specifically to target cancer cells.
Conclusion: GB265 antibodies have the potential to outperform PD-L1 and TIGIT monospecific antibodies or their combinations in rejuvenating anti-tumor immunity in cancer patients due to its bridging activity and dual blockade function.
Citation Format: Su Huang, Riyao Yang, Cai Huang, Saroja Putrevu, Nathan S. Fay, Kimberly Wright, Mohd Saif Zaman, Betty Huang, Bo Wang, Meredith Wright, Yanan Wang, Xuefei Tian, Yue Liu. Development and characterization of a bispecific antibody (GB265) against PD-L1 and TIGIT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1087.
Abstract 1094: SMARCA4-mediated chromatin remodeling regulates osimertinib resistance in EGFR-mutant lung adenocarcinoma
Authors: de Miguel Fernando J. , Cai Wesley L. , Melnick Mary Ann , Robles-Oteiza Camila , Wurtz Anna , Toki Maria I. , Rimm David L. , Homer Robert , Nguyen Don X. , Politi Katerina A. 
Published: June 2022

Abstract
Targeted therapies have transformed the clinical management of many types of tumors, including EGFR-mutant lung adenocarcinomas. Although these treatments are highly beneficial for patient survival, acquired resistance almost inevitably occurs limiting cures with these agents. The tyrosine-kinase inhibitor (TKI) osimertinib is approved for the first-line treatment of EGFR-mutant lung tumors and leads to increased progression-free and overall survival compared to earlier generations of TKIs. However, acquired resistance to osimertinib frequently occurs and is mostly due to off-target mechanisms, many of which are not well-understood. Therefore, it is critical to understand the molecular processes behind these mechanisms of resistance.
We generated osimertinib resistant cell lines and patient-derived models to identify and study novel mechanisms of osimertinib resistance. We found that, in some osimertinib resistant tumors, SMARCA4 is stabilized upon osimertinib treatment and knock-down of SMARCA4 re-sensitizes the resistant cells to osimertinib and globally alters their chromatin profile. ATAC-Seq and RNA-Seq studies revealed that SMARCA4 alters chromatin accessibility in resistant tumors to maintain the transcriptional activity of genes involved in cell proliferation. Furthermore, SMARCA4 enables access to NRF2 binding sites enhancing an antioxidant response necessary for cells to tolerate the increase in reactive oxygen species and oxidative stress created by osimertinib. These processes converge and lead to an increase in the amount of DNA damage that is repaired by ATR. Indeed, we found that these osimertinib resistant tumors are vulnerable to ATR inhibition.
In summary, we have identified a new epigenetic mechanism of resistance to osimertinib driven by SMARCA4 that generates a vulnerability to ATR inhibition, offering new approaches to target TKI-resistant tumors.
Citation Format: Fernando J. de Miguel, Wesley L. Cai, Mary Ann Melnick, Camila Robles-Oteiza, Anna Wurtz, Maria I. Toki, David L. Rimm, Robert Homer, Don X. Nguyen, Katerina A. Politi. SMARCA4-mediated chromatin remodeling regulates osimertinib resistance in EGFR-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1094.
Abstract 1123: c-Met downregulation contributes to Metformin-induced inhibition of MDA-MB-468 triple negative breast cancer cells
Authors: Gant Dana M. , Ma Zhikun , Parris Amanda B. , Yang Xiaohe 
Published: June 2022

Abstract
Triple negative breast cancer (TNBC) is the breast cancer subtype that is most refractory to treatment. Thus, identification of novel molecular targets and drug treatments are needed to improve prognosis for patients. The widely used anti-diabetic drug Metformin has been reported to possess anti-cancer properties. Although it is believed that Metformin may exert its anti-cancer effects through indirect reduction of glucose and insulin levels, and directly activating the AMPK kinase and inhibiting downstream cancer-related pathways, the molecular mechanisms underlying its anti-cancer function in TNBC have yet to be fully elucidated. In this study, we investigated the role and mechanism of Metformin-mediated downregulation of oncogenic c-Met in MDA-MB-468 TNBC cells. Our results demonstrated greater sensitivity of MDA-MB-468 cells to Metformin compared to other breast cancer cell lines. Metformin-induced inhibition of MDA-MB-468 cell proliferation was correlated with the downregulation of c-Met at both protein and mRNA levels. Overexpression of c-Met in MDA-MB-468 cells using a lentiviral vector system rendered the cells resistant to Metformin, which was accompanied by the promotion of cancer stem cell stemness. Functionally, we demonstrated that c-Met induced activation of receptor tyrosine kinase (RTK) signaling pathways play a critical role in c-Met-modulated Metformin responsiveness. These novel findings highlight c-Met as a key regulator of Metformin-mediated inhibition of TNBC cell growth, suggesting that c-Met overexpression may be a critical factor contributing to metformin resistance. To this end, combination of Metformin with c-Met inhibitors could be a useful strategy to improve Metformin-mediated anti-cancer efficacies in TNBC.
Citation Format: Dana M. Gant, Zhikun Ma, Amanda B. Parris, Xiaohe Yang. c-Met downregulation contributes to Metformin-induced inhibition of MDA-MB-468 triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1123.