bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1767: A next generation site-specific ADC targeting breast and gastric cancer
Authors: Italia James Sebastian , Biris Nikos , Li Zhi , Hussain Myer , Boyce John , Warner Audrey 
Published: June 2022

Abstract
Antibody drug conjugates are entering a renaissance period as a promising treatment option for a variety of cancers. Despite some success in the past few decades, developing effective ADCs remains a challenge due to extensive inefficiencies of industry standard conjugation technologies. Industry available methods can be limited by lack of site-specificity, inflexibility on the site of conjugation, and poor overall biophysical characteristics which can alter the efficacy, safety, and bioavailability of these therapeutics. BrickBio’s unique bioconjugation methodology enables precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates which overcome these limitations and achieve the full potential of this highly promising class of therapeutics.
In this work, we incorporate an azide-containing UAAs (unnatural amino acid) into full-length antibodies targeting receptors overexpressed in breast and gastric cancer. Specifically, we have engineered variants of IgG1 antibodies to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as auristatins, via click chemistry to generate ADCs with homogeneous DARs and at different conjugation sites. The resulting BrickADCs exhibit high therapeutic efficacy against receptor-positive cell lines, particularly lines expressing low levels of HER2, in vitro as well as in mouse xenograft models. Not only are the BrickADCs 100x more potent in demonstrated cell lines, but current research indicate that they have an improved safety profile over T-DM1. In other efforts, the BrickADC platform is leveraging a proprietary Modular Multisite Platform (MMP) to address the unmet need of eventual ADC resistance by conjugating multiple distinct payloads in a homogenous fashion. Continued preclinical work is underway for these pipeline candidates as well as investigation into other target areas.
Citation Format: James Sebastian Italia, Nikos Biris, Zhi Li, Myer Hussain, John Boyce, Audrey Warner. A next generation site-specific ADC targeting breast and gastric 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 1767.
Abstract 1778: NR2F2 mediates cell growth and endocrine resistance in NF1 loss, ER+ breast cancer
Authors: Cai Yanyan , Zhao Peihua , Wu Fan , Shao Hong , Razavi Pedram , Xu Guotai , Scaltriti Maurizio , Chandarlapaty Sarat 
Published: June 2022

Abstract
Genomic loss of in Neurofibromin 1 (NF1) is a recurrent mechanism driving metastatic progression and resistance to endocrine therapy in ER-positive breast cancer, via activation of the MAPK pathway, induction of cyclin D1 expression and modulation of estrogen receptor signaling. To identify specific mediators of tumor growth in NF1 mutant cancers, we performed a genetic knockout (KO) screen in isogenic WT and NF1 KO breast cancer cells. After employing stringent cutoff criteria, we found 28 genes that are specifically essential for NF1 KO cells but not WT cells. Among these genes, NR2F2, encoding an orphan nuclear receptor, was one of the top candidates. We validated that its loss significantly impaired the growth of multiple models of NF1 null, ER+ breast cancer.
Loss of NF1 leads to the hyperactivation of Ras which sequentially activates multiple effector pathways, including the MAPK pathway and the PI3K-AKT pathway. We found that MAPK activation upon NF1 loss led to elevated NR2F2 expression levels. A negative correlation between NF1 and NR2F2 expression was further confirmed in public gene expression databases. These data suggested that induction of NR2F2 expression might be one mechanism that mediates endocrine resistance caused by NF1 loss. Consistently, we found that exogenous expression of NR2F2 could confer endocrine resistance while its knockout hypersensitized ER+ breast cancer cells to endocrine therapies and significantly attenuated NF1 loss induced resistance.
RNA-seq analysis revealed that estrogen response gene sets were among the most enriched signatures upon NF1 KO, NR2F2 over-expression (OE) or NR2F2 KO. NF1 KO or NR2F2 OE decreased the expression of early estrogen response genes and impaired their E2-induced expression, most of which could be rescued by NR2F2 KO, suggesting a regulatory effect of NR2F2 on ER transcriptional activity. To further define these mechanisms, ongoing integrative analyses of NR2F2 qPlex-RIME, ER and NR2F2 ChIP-Sequencing and ATAC-Sequencing will be presented.
Taken together, our studies identify NR2F2 as a MAPK driven transcript whose induction mediates endocrine resistance, and may serve as a novel therapeutic target to overcome anti-estrogen resistant breast cancer growth.
Citation Format: Yanyan Cai, Peihua Zhao, Fan Wu, Hong Shao, Pedram Razavi, Guotai Xu, Maurizio Scaltriti, Sarat Chandarlapaty. NR2F2 mediates cell growth and endocrine resistance in NF1 loss, ER+ 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 1778.
Abstract 1783: JNK/MDR1 confers chemo-resistance in breast cancer cells carrying estrogen receptor activating mutations
Authors: Taya Marwa , Merenbakh-Lamin Keren , Rubinek Tami , Wolf Ido 
Published: June 2022

Abstract
Background: Endocrine therapy is the mainstay treatment for estrogen receptor-α (ER) positive breast cancer (BC) patients. However, all metastatic BC patients develop resistance, which in nearly 40% of patients is due to activating mutations, mostly Y537S and D538G, in the ligand-binding domain (LBD). Tumors harboring these mutations are more aggressive and the patients' prognosis is worse. We hypothesized that refractory response to further treatment lines, i.e, chemotherapy, partially accounts for the worse prognosis. Hence, our goal was to study whether LBD-ER BC cells are resistant to chemotherapy and reveal the mechanism of action.
Methods: We used MCF-7 cells stably expressing WT-ER, Y537S or D538G-ER mutations. Cell proliferation and viability were determined using MTT, methylene blue and colony assays. We evaluated apoptosis by monitoring cleaved-PARP and flow cytometry using Annexin/7AAD staining. MDR1 expression was studied using qRT-PCR and western-blot. JNK/c-Jun pathway was studied by pJNK and cJun expressions, cJun transcriptional activity, ChIP assay and pharmacological inhibition.
Results: LBD-ER cells exhibited higher proliferation and viability and exerted less apoptosis compared to WT-ER cells following treatment with paclitaxel, doxorubicin, and 5-FU. MDR1 expression and JNK pathway activity was higher in D538G cells compared to both WT-ER and Y537S cells. Importantly, inhibition of the JNK pathway, using SP600125 and BI-78D3, lead to decreased MDR1 expression, increased cleaved PARP, and decreased viability in the D538G cells. In addition, our results revealed that JNK increased c-Jun binding activity of the MDR1 gene in the D538G mutated cells.
Conclusions: These results indicate that LBD-ER cells confer resistance to chemotherapy. The mechanisms leading to it are diverse, and we found that in D538G increased JNK pathway activation resulted in elevated MDR1 expression and chemo-resistance. This paves the way to therapies aiming at inhibition the JNK pathway in order to restore chemo-resistance. This study also highlights the marked differences between these seemingly similar mutations, strengthening the necessity to adopt a personalized treatment approach for BC patients who developed endocrine resistance.
Citation Format: Marwa Taya, Keren Merenbakh-Lamin, Tami Rubinek, Ido Wolf. JNK/MDR1 confers chemo-resistance in breast cancer cells carrying estrogen receptor activating mutations [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 1783.
Abstract 1795: Molecular vulnerabilities of the polyaneuploid cancer cell state
Authors: Loftus Luke 
Published: June 2022

Abstract
Once cancer has metastasized it remains incurable owing to resistance to nearly all systemic therapies. Classical views of therapeutic resistance include tumor heterogeneity and genetic instability, but our group and others have identified an unappreciated cancer cell phenotype, the polyaneuploid cancer cell (PACC) state, that provides an alternative model. The PACC state is induced upon exposure to a variety of applied stressors, including multiple different classes of chemotherapy, and is characterized by an enlarged cell size, polyploidy of the typically aneuploid cancer genome, and the ability to repopulate tissue through depolyploidization. We have demonstrated that PACCs are present in a variety of cell lines, arise in response to a multitude of stressors in vitro, and are resistant to cisplatin, docetaxel and Ipatasertib treatment. Thus, we hypothesize that the PACC state is driving cancer’s therapeutic resistance to nearly all available treatment regimens and enabling cancer relapse. Elimination of the PACC state is essential to prevent cancer recurrence, and ultimately enable a cure for cancer.To identify candidate drug targets specific to the PACC state, we performed RNA sequencing, NanoString mRNA panels, bulk proteomics and cell surface proteomics of PACCs versus their parental cell line. PACCs were induced from prostate cancer lines PC3 and LNCaP, and breast cancer line MDAMB231 with both cisplatin and docetaxel treatment. Initial datasets with PC3 cells found that 1013 genes are enriched (greater than 1.5 Log2 Fold Change) in cisplatin induced PACCs while 88 genes are enriched in docetaxel induced PACCs. 22 genes were enriched with both chemotherapy treatments implying that there are genes common to the PACC state. NanoString mRNA and proteomic analysis further validated a subset of the overlapping genes, including ATF3, BIRC3, IL6, and NOX5.Our existing data reveals that there are molecular vulnerabilities of the PACC state that can be manipulated for therapeutic elimination. We will further validate candidate genes across numerous stressors and cell lines and then assess the PACC state’s dependence on these pathways through inhibition and engineered cell lines. Information from these studies will directly lead to development of a therapeutic strategy specifically targeting the PACC state, with the intention of eliminating cancer resistance.
Citation Format: Luke Loftus. Molecular vulnerabilities of the polyaneuploid cancer cell state [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 1795.
Abstract 1799: Inhibition of triple negative breast cancer metastasis via Enolase-1 modulation
Authors: Tailor Dhanir , Dheeraj Arpit , Garcia-Marques Fernando Jose , Pandrala Mallesh , Bermudez Abel , Pitteri Sharon , Malhotra Sanjay V. 
Published: June 2022

Abstract
Triple-negative breast cancer (TNBC) is one of the aggressive forms of breast cancer and frequently relapses and metastases. 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 the majority of tissues and many cancer cells have its higher expression. Apart from the glycolytic role in the cytosol, ENO1 also plays different roles in cancer cells including function as a surface receptor. We have developed a chemical small molecule (CET12) that strongly binds to ENO1 and restrain its activity and subcellular localization. CET12 treatment arrests the TNBC cells in the mitotic phase and leads the apoptotic cell death via AMPK activation. Global proteome profiling suggested that CET12 pushes the cells toward oxidative phosphorylation. It also inhibits cell migration and invasion in vitro. In vivo studies using 4T1 and EMT6 syngeneic mouse models are also in-line with in vitro results and revealed that SU0212 treatment inhibits tumor progression and metastasis. These results were further supported by tail vain lung metastasis assay and intracardiac injection mouse model. This study provides compelling preclinical data for further development of CET12 for the treatment of TNBC.
Citation Format: Dhanir Tailor, Arpit Dheeraj, Fernando Jose Garcia-Marques, Mallesh Pandrala, Abel Bermudez, Sharon Pitteri, Sanjay V. Malhotra. Inhibition of triple negative breast cancer metastasis via Enolase-1 modulation [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 1799.
Abstract 1812: Therapeutic targeting and development of IDH inhibitors for the treatment of chondrosarcoma
Authors: Sheikh Tahir N. , Lu Chao , Schwartz Gary K. 
Published: June 2022

Abstract
Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Recurrent somatic mutations in the isocitrate dehydrogenase I (IDH1) genes have been identified in a spectrum of human malignancies, including chondrosarcoma. Mutations in these genes lead to impaired ability of IDH1 to catalyze the conversion of isocitrate to alpha ketoglutarate and to gain of a neomorphic enzymatic activity which results in production of oncometabolite 2-hydroxyglutarate (2HG). Our preliminary data indicated that compared to samples that were wild type, IDH1 mutant samples showed a significant increase in intra-tumoral 2HG levels. In the present study, we hypothesized that 2-HG accumulation induces DNA and histone hypermethylation and altered gene expression, ultimately resulting in a block in cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Therefore, we proposed that inhibition of IDH should mediate its antitumor effects through the induction of differentiation. To test this hypothesis, we utilized human chondrosarcoma cell lines including IDH wild type (CH2879) and IDH1 mutant (JJ012) and the IDH1 inhibitor FT6535. Results from our in vitro cell viability assay and histone methylation showed that selective inhibition of IDH1 resulted in modest inhibition of cell proliferation and suppression of histone methylation in IDH1 mutant chondrosarcoma cells. Next we elected to test the IDH inhibitor in combination with differentiating agents including retinoic acid. Cell viability assays showed that when compared to either agent alone, the combination of retinoic acid and FT6535 resulted in a significant decrease in cellular proliferation. Western blot analysis showed induction of COL1A2 and SOX9 (differentiation markers) with suppression of histone methylation H3K27me3 or H3K9me3, Taken together, our data strongly suggests that combination treatment with the IDH1 inhibitor FT6535 and retinoic acid represents a novel approach to suppress cell growth by epigenetic modulation to induce differentiation and merits further evaluation as a potential treatment modality in chondrosarcoma.
Citation Format: Tahir N. Sheikh, Chao Lu, Gary K. Schwartz. Therapeutic targeting and development of IDH inhibitors for the treatment of 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 1812.
Abstract 1829: Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma
Authors: Tsai Tsung-Lin (Gavin) 
Published: June 2022

Abstract
BACKGROUND: Glioblastoma (GBM) is a highly infiltrative and aggressive malignancy with few treatment options; all patients develop recurrence after initial therapy. Due to the dismal outcome of these patients, identification of GBM-specific targets for therapeutic development is urgently needed. PRMT5 is a protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine residues within histones marks, resulting in chromatin restructuring, which in turn promotes oncogenic processes. PRMT5 inhibition has shown efficacy against multiple malignancies; MTAP loss has been associated with increased sensitivity to PRMT5 inhibitors. Here, we examined the effects of pharmacological abrogation of PRMT5 function using highly specific, brain penetrant, orally bioavailable inhibitors and assessed the role of MTAP and p53 expression on sensitivity to these agents. MATERIALS AND
METHODS: Using pharmacological inhibition of PRMT5 using with the highly specific inhibitors PRT808 and PRT811, we examined their effects on apoptosis, cell proliferation, cell cycle distribution, and methylation markers in patient-derived glioma stem-like cells (GSC) with epigenetic and genetic signaling. Additional studies to identify transcriptomic (RNA-seq), and proteomic (RPPA) landscape related to PRMT5 in gliomas are ongoing.
RESULTS: PRT808 and PRT811 induced potent reduction of symmetrical dimethylation (SDMA) protein marks in all GSC tested. However, treatment of GSC214 (mutant p53), GSC262 (mutant p53), GSC811 (truncated p53), and GSC11 (wild type p53) showed that wild type and truncated p53-expressing lines (GSC811 and GSC11) were more sensitive than GSC cell lines expressing mutant p53 (GSC214 and GSC262). There was no correlation between MTAP status and sensitivity to PRMT5 inhibition. In addition, PRMT5 inhibition resulted in reduced proliferation and alteration of several cell survival pathways; induction of apoptosis in GSC cell lines at late time points around 8-9 days after single dose treatment even though SDMA reduction occurred as early as 3 days.
CONCLUSIONS: Our results demonstrate pharmacological PRMT5 inhibition induced SDMA reduction and late apoptosis in genetically and epigenetically heterogeneous patient-derived GSC lines and that mutant p53 lines are less sensitive to PRMT5 inhibition. Additional studies related to splicing defects upon PRMT5 inhibition are ongoing and will be presented at the meeting.
Citation Format: Tsung-Lin (Gavin) Tsai. Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma [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 1829.
Abstract 1850: Characterizing senescence response to PARP inhibition may provide opportunities for enhanced efficacy through combinations with senolytic agents
Authors: Lombard Alan P. , Lou Wei , Evans Christopher P. , Gao Allen C. 
Published: June 2022

Abstract
Background: Inhibition of poly (ADP-ribose) polymerase (PARP) is an exciting treatment strategy recently approved for prostate cancer patients with homologous recombination repair defects. Despite this advance in the field, it remains unclear how PARP inhibitor (PARPi) sensitive cells respond to treatment. We previously demonstrated that treatment with the PARPi olaparib induces not only cell death, but also G2/M arrested senescence characterized by activation of the p53 signaling pathway. We hypothesize that targeting PARPi induced senescence may provide a means to enhance the efficacy of PARPi treatment. In our current work, we sought to 1) understand whether senescence induction is a generalized response to all PARPi’s and 2) characterize senescence induction to guide the development of novel treatment strategies combining a PARPi with a senolytic drug.
Methods: PARPi sensitive LNCaP and C4-2B prostate tumor cells were treated with olaparib, rucaparib, niraparib, or talazoparib for 5 days to induce senescence. Both vehicle treated and quiescent cells (LNCaP and C4-2B cultured in FBS-low (0.2%) conditions) were used as controls. Cell viability, flow cytometry, and beta-galactosidase activity assays tested response to PARPi’s. Western blot was used to detect PARP activity, apoptosis, and DNA damage response. RNA-sequencing was performed to characterize senescence induced signaling alterations.
Results: We found that exposure to rucaparib, niraparib, and talazoparib all induce a robust G2/M arrested senescence response in LNCaP and C4-2B cells, suggesting that senescence induction is a class effect of PARPi’s. PARPi induced senescence is characterized by activation of the p53 signaling pathway and significantly increased expression of the cyclin-dependent kinase inhibitor p21. Furthermore, PARPi induced senescence is distinct from quiescence, suggesting that response to PARP inhibition is phenotypically different from a more general growth arrest. RNA-sequencing revealed several signaling changes associated with senescence which may provide novel treatment opportunities.
Conclusions: Senolytics are a class of drugs thought to specifically target senescent cells. Our results demonstrate that PARPi’s induce senescence. Future work will be directed at further characterizing PARPi induced senescence, leading to rationally selected senolytic drug combinations which may enhance the efficacy of PARPi therapy.
Citation Format: Alan P. Lombard, Wei Lou, Christopher P. Evans, Allen C. Gao. Characterizing senescence response to PARP inhibition may provide opportunities for enhanced efficacy through combinations with senolytic agents [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 1850.