bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB004: Upregulation of STAT3 signaling in tumor cells fosters a TME-dependent secondary resistance of BRCA1-deficient HGSOC to PARP inhibition
Authors: Ding Liya , Wang Qiwei , Kearns Michael , Jiang Tao , Cheng Xin , Qian Changli , Zhao Jean 
Published: June 2022

Abstract
PARP inhibitors (PARPi) have demonstrated potent therapeutic efficacy in patients with ovarian cancer. However, acquired resistance to PARPi is a major challenge in the clinic. Therefore, understanding the resistance mechanism and developing new treatment approaches are important to overcome therapeutic resistance to PARP inhibition. By using our GEM of Brca1-deficient ovarian tumor model, we uncovered a new mechanism underlying a secondary resistance to PARP inhibition mediated by tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Mechanistically, PARP inhibition induced the STAT3 signaling pathway in tumor cells, which in turn promoted pro-tumor polarization of TAMs in the TME of ovarian cancer. Ablation of STAT3 in tumor cells mitigated polarization of M2-like pro-tumor macrophages in the TME and increased tumor infiltration T cells in response to PARP inhibition. Furthermore, we demonstrated that STING agonists reprogramed myeloid cells in the TME of ovarian tumor into antitumor M1-like macrophages and activated dendritic cells (DCs) in a myeloid cell STING-dependent manner. These findings were recapitulated in patient-derived PARPi-resistant ovarian tumor models. Finally, we show that STING agonism was able to overcome the secondary resistance to PARPi in ovarian cancer rendered by immunosuppressive TME. Our study elucidates a new mechanism of PARPi resistance and provides a new treatment strategy to overcome the TME-induced therapeutic resistance to PARP inhibition in ovarian cancers.
Citation Format: Liya Ding, Qiwei Wang, Michael Kearns, Tao Jiang, Xin Cheng, Changli Qian, Jean Zhao. Upregulation of STAT3 signaling in tumor cells fosters a TME-dependent secondary resistance of BRCA1-deficient HGSOC to PARP inhibition [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 LB004.
Abstract LB021: Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression
Authors: Northey Jason J. , Yui Yoshihiro , Hayward Mary-Kate , Stashko Connor , Kai FuiBoon , Mouw Janna , Thakar Dhruv , Lakins Jonathon , Ironside Alastair , Samson Susan , Mukhtar Rita , Hwang E. Shelley , Weaver Valerie 
Published: June 2022

Abstract
Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression. Tissue-specific factors linking stem-progenitor cell frequency to cancer risk and progression remain ill defined. Using a genetically engineered mouse model that promotes integrin mechanosignaling with syngeneic manipulations, spheroid models, and patient-derived xenografts we determined that a stiff extracellular matrix and high integrin mechanosignaling increase stem-progenitor cell frequency to enhance breast tumor risk and progression. Studies revealed that high integrin-mechanosignaling expands breast epithelial stem-progenitor cell number by potentiating progesterone receptor-dependent RANK signaling. Consistently, we observed that the stiff breast tissue from women with high mammographic density, who exhibit an increased lifetime risk for breast cancer, also have elevated RANK signaling and a high frequency of stem-progenitor epithelial cells. The findings link tissue fibrosis and integrin mechanosignaling to stem-progenitor cell frequency and causally implicate hormone signaling in this phenotype. Accordingly, inhibiting RANK signaling could temper the tumor promoting impact of fibrosis on breast cancer and reduce the elevated breast cancer risk exhibited by women with high mammographic density.
Citation Format: Jason J. Northey, Yoshihiro Yui, Mary-Kate Hayward, Connor Stashko, FuiBoon Kai, Janna Mouw, Dhruv Thakar, Jonathon Lakins, Alastair Ironside, Susan Samson, Rita Mukhtar, E. Shelley Hwang, Valerie Weaver. Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression [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 LB021.
Abstract LB036: Molecular insight into ERG transcriptional activity to unravel novel therapeutic options for ERG-positive castration resistant prostate cancer
Authors: Lorenzin Francesca , Fracassi Giulia , Ciani Yari , Gasperini Paola , Rickman David , Demichelis Francesca 
Published: June 2022

Abstract
Gene fusions of the AR-regulated gene TMPRSS2 with the ETS family transcription factor ERG characterize about 40% of castration resistant prostate cancer (CRPC) - an advanced and lethal stage of prostate cancer. AR-mediated overexpression of ERG hijacks AR inhibiting lineage-specific differentiation and increases cell invasion and migration. In vivo work revealed a causal role of ERG in initiating prostate cancer. Notably, in vitro and in vivo models of CRPC endogenously bearing T2ERG depend on ERG activity for proliferation and survival. Thus, pursuing the development of ERG-based therapeutic strategies represents a promising route for CRPC treatment, although major challenges in targeting transcription factors such as ERG have been reported. Yet, synthetic lethality approaches including genome-wide loss-of-function screens can be employed to avoid direct ERG targeting. Here, we used metastatic PCa cell lines (LNCaP, 22Rv1 and DU145) engineered with inducible systems to overexpress ERG to show that high levels of ERG expression lead to an apparent reduction in the fitness of AR-positive and negative cells. Prolonged overexpression of a mutant form of ERG, which is not able to bind DNA, does not affect cell viability indicating that ERG DNA binding and transcriptional activity are necessary for the induction of this phenotype. The ERG-mediated reduction in cellular fitness is influenced by cell adhesion and is characterized by cell cycle arrest mediated by several cell cycle inhibitors induced by ERG. As revealed by gene expression analyses and functional assays, ERG induces a less proliferative, more dedifferentiated and invasive phenotype, which lead to an apparent reduction of cellular fitness in vitro, but is characteristic of more aggressive tumor cells in vivo. Altogether, these results underscore the reliability of the developed in vitro models for ERG activity, which will be used for screening to identify therapeutic vulnerabilities unlocked by ERG in CRPC. Importantly, we also uncovered confounding factors (i.e. loss of ERG-positive cells not due to screen selection) that could impinge on the results arising from in vitro screens.
Citation Format: Francesca Lorenzin, Giulia Fracassi, Yari Ciani, Paola Gasperini, David Rickman, Francesca Demichelis. Molecular insight into ERG transcriptional activity to unravel novel therapeutic options for ERG-positive castration resistant prostate 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 LB036.
Abstract LB045: β-catenin antagonist peptide, ST316, attenuates Wnt-dependent oncogenic activity
Authors: Ghamsari Lila , Gallagher Erin , Darvishi Emad , Leong Siok , Koester Mark , Ramirez Rick , Gonzales Jerel , Merutka Gene , Kappel Barry , Rotolo Jim A. 
Published: June 2022

Abstract
Constitutive activation of the Wnt/β-catenin signaling pathway underlines many breast and colorectal cancers, promoting cancer cell survival, proliferation and migration. B-cell CLL/lymphoma 9 protein (BCL9), a co-activator of β-catenin transcriptional activity, is overexpressed in many tumors and facilitates β-catenin nuclear localization. Disruption of the β-catenin and BCL9 interaction has been shown genetically to suppress oncogenic Wnt/β-catenin transcription, without impacting β-catenin homeostatic functions, and represents a powerful approach to inhibit this previously ‘undruggable’ target. Here, we investigate the impact of ST316, a peptide antagonist of β-catenin that inhibits its interaction with BCL9, on cells displaying hyperactivation of the Wnt/β-catenin pathway. Administration of ST316 to HCT116 human colorectal carcinoma cells, which carry a degradation-escape, gain-of-function mutation in β-catenin, dramatically reduced nuclear β-catenin localization. Furthermore, ST316-mediated loss of nuclear β-catenin was associated with a significant decrease in the expression of Wnt/β-catenin target genes in HCT116 cells stimulated with Wnt3a, including Axin2, hTCF7, Fox01 and CDK4. ST316 reduced β-catenin target gene expression by up to ∼70%, whereas no impact was observed following administration of a negative control peptide. A significant anti-proliferative and dose-dependent cytotoxic effect was observed on HCT116 cells 48 hours post ST316 exposure, with an EC50 of 4.4 µM, and on patient-derived, APC-mutant colorectal adenocarcinoma and breast carcinoma cells 72 hours post ST316 exposure, with EC50 values ranging from 1.5 to 2.6 µM. To extend these findings, we investigated the impact of ST316 on HCT116 tumors in vivo. ST316 (5 mg/kg) administered three times weekly by subcutaneous injection resulted in 99.6% tumor growth inhibition vs. vehicle controls (p&lt;0.05), while a negative control peptide had no significant impact on tumor growth. These data demonstrate the potential of ST316 as a potent therapeutic candidate for Wnt/β-catenin-dependent cancers.
Citation Format: Lila Ghamsari, Erin Gallagher, Emad Darvishi, Siok Leong, Mark Koester, Rick Ramirez, Jerel Gonzales, Gene Merutka, Barry Kappel, Jim A. Rotolo. β-catenin antagonist peptide, ST316, attenuates Wnt-dependent oncogenic activity [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 LB045.
Abstract LB077: Reengineering ponatinib to minimize cardiovascular toxicity
Authors: Hnatiuk Anna Pavlovna , Bruyneel Arne A. , Taylor Dhanir , Pandrala Mallesh , Dheeraj Arpit , Li Wendy , Fernandez Ricardo Serrano , Feyen Dries A. , Wu Michelle M. , Amatya Prashila , Morgado Isabel , Wiebking Volker , Porteus Matthew H. , Malhotra Sanjay , Mercola Mark 
Published: June 2022

Abstract
Introduction and Purpose of the Study: The advent of small molecule Tyrosine Kinase Inhibitors (TKIs) has revolutionized cancer treatment and greatly improved patient survival. However, the life-threatening cardiovascular toxicity of many TKIs present major concerns. Ponatinib is the most effective treatment for patients harboring the common T315I mutation of BCR-ABL that drives Chronic Myeloid Leukemia (CML) yet is one of the most cardiotoxic of TKIs. Ponatinib-induced events include myocardial infarction, heart failure, stroke, peripheral vascular disease and venous thrombosis. The aim of this study is to reengineer the chemical structure of ponatinib to minimize its adverse cardiovascular effects by using in vitro and in vivo models of cardiovascular toxicity.
Experimental Procedures: We developed in vitro cardiovascular toxicity assays using human iPSC-cardiomyocytes (hiPSC-CMs) and human microvascular endothelial cells (HMVECs), and assessed anti-tumor efficacy in T315I mutated K562 CML cells. The cardiotoxicity was determined by impairment of cardiomyocyte contractility function, the vascular toxicity was defined by inability to form capillary-like networks in vasculogenesis assays. In vitro screening of ponatinib analogues probed chemical moieties responsible for its cardiovascular toxicity that were confirmed using mice xenograft mice models with human T315I mutant K562 cells.
Summary of Unpublished Data: Compared to ponatinib, refined analogues showed markedly decreased adverse effects on HMVECs vasculogenesis and hiPSC-CMs contractility in vitro. The therapeutic window was increased in vivo, leading to regression of human T315I mutant CML xenografts comparable to ponatinib but without increasing serum levels of cardiac troponin. The kinase inhibition profiles of the “safe” analogues compared to ponatinib identified candidate mediators of ponatinib-induced toxicity. Validation by selective knockdown revealed likely mediators of cardiotoxicity, including FGFR.
Conclusions: We succeeded in engineering a cardiovascular safe TKI that retained effective therapeutic properties against BCR-ABL T351 mutated form of CML, but with substantially decreased cardiovascular toxicity.
Citation Format: Anna Pavlovna Hnatiuk, Arne A. Bruyneel, Dhanir Taylor, Mallesh Pandrala, Arpit Dheeraj, Wendy Li, Ricardo Serrano Fernandez, Dries A. Feyen, Michelle M. Wu, Prashila Amatya, Isabel Morgado, Volker Wiebking, Matthew H. Porteus, Sanjay Malhotra, Mark Mercola. Reengineering ponatinib to minimize cardiovascular toxicity [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 LB077.
Abstract LB084: AXL as a therapeutic target in adenoid cystic carcinoma: preclinical evaluation of AXL targeting antibody-drug conjugate (ADCT-601)
Authors: Humtsoe Joseph O. , Jones Leilani , Naara Shorook , Zammarchi Francesca , Burr Nicole Spardy , van Berkel Patrick H. , Ha Patrick K. , Kang Hyunseok 
Published: June 2022

Abstract
Background: Adenoid cystic carcinoma (ACC) is a rare cancer of salivary gland cancer with a significant unmet clinical need. Conventional systemic therapy has limited efficacy and there are currently no FDA approved drugs for these patients with metastatic disease. Advances in molecular profiling led identification of potential therapeutic targets, and previous studies with proteomic analysis identified AXL as a potential therapeutic target in ACC. AXL, a member of the TAM tyrosine kinase receptor family has been generally associated with poor prognosis, and its overexpression and activation is implicated in conferring resistance to conventional systemic therapies in solid tumors. ADCT-601 is an antibody drug conjugate targeting human AXL carrying novel pyrrolobenzodiazepine dimer cytotoxin as the payload.
Methods: The goal of this study is to determine the in vitro and in vivo anti-tumor activity of ADCT-601 in ACC cell lines and patient-derived xenograft (ACCX) models with varying AXL expression determined by Western blot. ADCT-601 treated cell lines in vitro were analyzed by MTT-based cytotoxic assay and immunoblotting, and anti-tumorigenicity was assessed in two ACCX models.
Results: ADCT-601 induced a potent dose-dependent cytotoxic effect in ACC cell lines, but its cytotoxic activity was attenuated after AXL knockdown. Biochemical data indicated that ADCT-601 treatment led to DNA damage and induction of apoptotic factors accompanied by phosphorylation of gamma-H2AX. In high AXL expressing ACCX6 model, a single dose of either 0.5 or 1.0 mg/kg ADCT-601 significantly suppressed tumor growth resulting 3/5 partial responders (PRs) at 1mg/kg and 2/5 PRs at 0.5 mg/kg, compared to the vehicle or isotype-ADC control treated mice (0/5 PR and 1/5 PR, respectively). ADCT-601 appears to eliminate tumor, as no evidence of recovery in tumor growth was observed during a 60-day period. In low AXL expressing ACCX9 model, ADCT-601 treatment (at either the 0.5 or 1.0 mg/kg dose) delayed tumor growth compared to isotype-ADC control, but did not lead to durable partial responses.
Conclusion: This study demonstrated that ADCT-601 induced a potent and specific in vitro and in-vivo anti-tumor activities in AXL expressing ACC models and suggests further development of ADCT-601 in biomarker driven clinical trials.
Citation Format: Joseph O. Humtsoe, Leilani Jones, Shorook Naara, Francesca Zammarchi, Nicole Spardy Burr, Patrick H. van Berkel, Patrick K. Ha, Hyunseok Kang. AXL as a therapeutic target in adenoid cystic carcinoma: preclinical evaluation of AXL targeting antibody-drug conjugate (ADCT-601) [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 LB084.
Abstract LB127: Reduced expression of annexin-a6 induces metabolic reprogramming that favors rapid fatty acid oxidation in triple-negative breast cancer cells
Authors: Williams Stephen D. , Widatalla Sarrah E. , Sakwe Amos M. 
Published: June 2022

Abstract
The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin A6 (AnxA6) in the metabolic adaptation of rapidly growing versus invasive TNBC cells as well as in Lapatinib resistant (Lap-R) TNBC cells. AnxA6 expression in cultured TNBC cell lines, Lap-R cells and in crude isolates of mitochondria was determined by Western blotting and/or immunofluorescence assays. The oxygen consumption rates (OCR), extracellular acidification rates (ECAR) and mitochondria activity were assessed using the Seahorse XF Analyzer. Intracellular metabolites were detected by 1H-NMR analysis. Using model proliferative basal-like and invasive mesenchymal-like TNBC cell lines, we show that TNBC cells also exhibit metabolic heterogeneity. Down regulation of AnxA6 in TNBC cells attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity, resulting in a quiescent cellular energy phenotype. We further show that AnxA6-depletion was associated with decreased lipid droplet accumulation and the lipolytic phenotype by enhancing the uptake and mitochondrial fatty acid oxidation for ATP production. Chronic Lapatinib-induced up regulation of AnxA6 in AnxA6-low TNBC cells reversed their lipolytic to a more lipogenic/glycolytic metabolic phenotype with gluconeogenic precursors as additional metabolites. Collectively, these data suggest that the expression status of AnxA6 in TNBC cells underlies significant metabolic adaptation during stress and/or chronic Lapatinib treatment and provide additional insights into the potential of AnxA6 as a biomarker for not only therapeutic intervention but also the metabolic subtyping of TNBC subsets.
Citation Format: Stephen D. Williams, Sarrah E. Widatalla, Amos M. Sakwe. Reduced expression of annexin-a6 induces metabolic reprogramming that favors rapid fatty acid oxidation 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 LB127.
Abstract LB138: DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast cancer
Authors: Mahmud Iqbal , Tian Guimei , Hutchison Tarun , Kim Brandon , Liao Daiqing 
Published: June 2022

Abstract
Elevated lipid metabolism including lipogenesis is a major metabolic feature in cancer cells. In breast and other cancer types, genes involved in lipogenesis are highly upregulated, but the mechanisms that control their expression remain poorly understood. DAXX modulates gene expression through binding to numerous transcription factors although the functional impact of these diverse interactions remains to be defined. Our recent analysis indicates that DAXX is overexpressed in diverse cancer types and metastases. However, mechanisms underlying DAXX’s oncogenic function remains elusive. Using global integrated transcriptomic and lipidomic analyses, we show that DAXX plays a key role in lipid metabolism in triple-negative breast cancer (TNBC) cells. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipid synthesis and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and a DAXX mutant unable to bind SREBPs are incapable of promoting lipogenesis and tumor growth. In TNBC patients, DAXX expression levels are increased in breast cancer brain metastasis and correlate with poor patient survival. Our results identify the DAXX-SREBP axis as an important pathway for tumorigenesis in TNBC. (This work is supported by Florida Department of Health Grants.)
Citation Format: Iqbal Mahmud, Guimei Tian, Tarun Hutchison, Brandon Kim, Daiqing Liao. DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast 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 LB138.
Abstract LB200: Pdgf/Pi3k/akt axis activation by hey1-ncoa2 fusion and potential target in the treatment of mesenchymal chondrosarcoma
Authors: Qi Wenqing , Wang Lu 
Published: June 2022

Abstract
Mesenchymal chondrosarcoma is a rare and often aggressive cancer mostly affecting children and young adults. Genetically, this tumor is mainly characterized by the recurrent HEY1-NCOA2 fusion. Localized tumor is managed surgically; traditional chemotherapy and radiation therapy, however, did not appear to substantially improve the event-free survival rate of mesenchymal chondrosarcoma patients. It is clear that better therapeutic options are needed for the treatment of this tumor. In our previous study, an in vitro model for studying mesenchymal chondrosarcoma tumorigenesis was developed using stably transduced iPSC-derived mesenchymal stem cells (iPSC-MSCs) with inducible-expression of HEY1-NCOA2. With the in vitro model, we performed genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq to identify HEY1-NCOA2-dependent transcriptional regulation and demonstrated the dramatic activation of PDGF-PDGFR and PI3K-AKT signaling pathways (manuscript in review). Our data also suggested that PDGFB is one of the direct targets of HEY1-NCOA2 fusion protein. In the present study, with the in vitro iPSC-MSC model, we verified that HEY1-NCOA2 fusion protein, but not wild-type HEY1 or NCOA2, dramatically increased phospho-AKT (Ser473, a readout of PI3K) expression by western blotting. Further on, we tested the effect of two kinase inhibitors CP-673451 and PF-04691502, a potent and selective PDGFR inhibitor and the mTOR/PI3K inhibitor, respectively. Stably transfused iPSC-MSC were treated with the kinase inhibitors, respectively, at different dosages (0.1 µM, 0.5 µM and 1.0 µM) for one week. At the concentration of 1.0 µM, CP-673451 efficiently suppressed AKT phosphorylation by ~23% as well as suppressed cell growth by ~67% which is significantly higher than that observed in the controls (e.g. ~20% suppression in HEY1- and NCOA2- expression iPSC-MSCs). Similarly, at the concentration of 0.5 µM, PF-04691502 suppressed the HEY1-NCOA2-expression iPSC-MSCs growth by ~24% more than that in the control (p=0.02). In summary, both CP-673451 and PF-04691502 were active against the in vitro mesenchymal chondrosarcoma model tested. Based on these data, the potential benefit of targeting PDGF/PI3K/AKT signaling pathways in the treatment of mesenchymal chondrosarcoma was suggested.
Citation Format: Wenqing Qi, Lu Wang. Pdgf/Pi3k/akt axis activation by hey1-ncoa2 fusion and potential target in the treatment of mesenchymal chondrosarcoma [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 LB200.