bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 326: Engineered toxin bodies (ETBs) targeting Trop2
Authors: Cornelison Garrett L. , Bartos Adam , Brieschke Brigitte , Momb Jessica , Pedraza Ileana , Kapeel Elizabeth M. , Martin Rebecca , Pletka Channing , Gonzalez Adrian , Dekker Joseph D. , Zhao Jay , Majercak John , Robinson Garrett L. 
Published: June 2022

Abstract
Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forced internalization, undergoing retrograde translocation to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes resulting in the inhibition of protein synthesis and induction of apoptosis through ribotoxic stress mechanisms.
Additionally, Molecular Templates has developed the Antigen Seeding Technology (AST) platform to generate ETBs with the unique ability to deliver foreign protein antigen to targeted populations of tumor cells. This MOA allows for the intracellular processing of antigen and subsequent surface MHC-I presentation required for activation of a re-directed T lymphocyte response and the capacity to restore a functional immune clearance program against the tumor.
Three ETBs are in clinical development (MT-5111 targeting HER2, MT-0169 targeting CD38, and AST enabled MT-6402 targeting PD-L1). The novel mechanisms of action have potential benefit in different indications including in the relapsed setting, when disease has progressed after chemotherapies and other targeted therapies, and additionally may be able to combine with standard of care.
ETBs are being developed that target other cell surface receptors expressed on solid tumors including tumor-associated calcium signal transducer 2 (Trop2). Trop2 is a clinically validated target of antibody drug conjugate (ADC) therapy in metastatic triple-negative breast cancer (mTNBC) and other cancers such as metastatic urothelial carcinoma (mUC).
In vitro, tumor cells expressing Trop2 are effectively, specifically, and directly killed with picomolar activity by targeted ETBs. AST enabled Trop2 targeted ETBs are capable of delivering viral antigens for multiple HLA types and inducing cytokine secretion and T-cell mediated killing in a co-culture assay of Trop2 target cells with antigen matched HLA type and antigen specific T-cells. These pre-clinical in vitro data suggest AST enabled Trop2 targeted ETBs have the potential to deplete Trop2 positive malignancies through multiple unique mechanisms of action.
Citation Format: Garrett L. Cornelison, Adam Bartos, Brigitte Brieschke, Jessica Momb, Ileana Pedraza, Elizabeth M. Kapeel, Rebecca Martin, Channing Pletka, Adrian Gonzalez, Joseph D. Dekker, Jay Zhao, John Majercak, Garrett L. Robinson. Engineered toxin bodies (ETBs) targeting Trop2 [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 326.
Abstract 3269: Dual targeting of FLT3 and LSD1 disrupts the MYC super-enhancer complex in acute myeloid leukemia
Authors: Yashar William M. , Smith Brittany M. , VanCampen Jake , Kong Garth L. , Macaraeg Jommel , Coleman Daniel J. , Druker Brian J. , Maxson Julia E. , Braun Theodore P. 
Published: June 2022

Abstract
Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by development of resistance. A major contributor of resistance is epigenetic adaptation to kinase inhibitor therapy. We present evidence that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) augments the response to inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-mutant AML. We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cell lines and primary patient samples. High-resolution epigenetic sequencing revealed that the combination therapy synergistically suppresses pro-proliferative MYC-bound promoters and activates pro-differentiative PU.1-bound enhancers. Regulon enrichment analysis in primary AML samples nominated STAT5 (a downstream target of activated FLT3 signaling) as a putative regulator of MYC gene expression. STAT5 is highly bound to the MYC blood super-enhancer and FLT3 inhibition results in a loss of both STAT5 binding and MYC blood super-enhancer chromatin accessibility. In contrast, LSD1 inhibition suppresses MYC target genes by accumulation of repressive H3K9me1 marks. We validated these findings in 72 primary AML samples, including 19 FLT3-ITD positive AML samples. The combination improved responses in the vast majority of patient samples, and high MYC regulon activity was a predictor of response. Gene expression profiling in treated primary AML samples confirmed that dual FLT3 and LSD1 inhibition activates PU.1 target genes and suppresses MYC target genes. Finally, single cell ATAC-seq on primary AML blasts treated ex vivo with combined FLT3 and LSD1 shifted cells from a MYC super-enhancer high to MYC super-enhancer low state. Collectively, these data provide preclinical rationale for the investigation of dual FLT3 and LSD1 inhibition in clinical trial.
Citation Format: William M. Yashar, Brittany M. Smith, Jake VanCampen, Garth L. Kong, Jommel Macaraeg, Daniel J. Coleman, Brian J. Druker, Julia E. Maxson, Theodore P. Braun. Dual targeting of FLT3 and LSD1 disrupts the MYC super-enhancer complex in acute myeloid leukemia [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 3269.
Abstract 3274: Targeting NSD family histone methyltransferase activity with irreversible inhibitors
Authors: Howard Christina , Zari Sergei , Li Shuangjiang , Huang Huang , Kim EunGi , Park Se Ra , Purohit Trupta , Miao Hongzhi , Zhang Xiaotian , Nikolaidis Caroline , Li Hao , Ndoj Juliano , Cho HyoJe , Grembecka Jolanta , Cierpicki Tomasz 
Published: June 2022

Abstract
Nuclear SET domain containing (NSD) family member proteins are histone methyltransferases that mono- and di-methylate histone 3 at lysine 36 (H3K36) to alter gene expression in a context-dependent manner. NSD1 and NSD3 are two members of this family which share greater than 80 percent sequence similarity in the catalytic SET domain. NSD1 is found as a fusion with NUP98 in aggressive cases of pediatric leukemia, and the lysine methyltransferase (KMTase) activity of NUP98-NSD1 drives bone marrow progenitor proliferation. Similarly, high levels of enzymatically active NSD3 mRNA are correlated with reduced disease-free survival in breast cancer and catalytic NSD3 expression is sufficient to rescue tumor growth in a xenograft model of triple negative breast cancer. Selective and potent inhibitors of NSD1 and NSD3 KMTase activity are needed to further investigate the therapeutic potential of targeting this function in leukemia and/or solid cancers. Here, we report the development of irreversible small molecule inhibitors of the NSD1 and NSD3 SET domains. We utilized a NMR-based fragment screen of the NSD1 SET domain to identify the hit BT1, which binds reversibly to the SET domain of NSD1. BT1 was extensively optimized into a series of potent irreversible ligands. Mass spectrometry and structural studies revealed that these compounds react with a cysteine near the autoinhibitory loop, providing a rational for the strong inhibition of KMTase activity we observe in biochemical assays. These inhibitors also bind to the NSD1 and NSD3 SET domains in cells and exhibit potent anti-proliferative effects against leukemia cells containing NUP98-NSD1 and breast cancer cells with high levels of NSD3 expression. In summary, we present novel irreversible inhibitors of NSD1 and NSD3 KMTase activity which represent important chemical probes that can be used to investigate the therapeutic potential of targeting NSD family member catalytic activity in cancers.
Citation Format: Christina Howard, Sergei Zari, Shuangjiang Li, Huang Huang, EunGi Kim, Se Ra Park, Trupta Purohit, Hongzhi Miao, Xiaotian Zhang, Caroline Nikolaidis, Hao Li, Juliano Ndoj, HyoJe Cho, Jolanta Grembecka, Tomasz Cierpicki. Targeting NSD family histone methyltransferase activity with irreversible inhibitors [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 3274.
Abstract 3325: ERK inhibitor increases cancer stem cell population in NSCLC through Slug-Mediated epithelial-to-mesenchymal transition
Authors: Cai Shurui , Li Na , Bai Xuetao , Banerjee Ananya , Kousalya Lavudi , Wang Qi-en 
Published: June 2022

Abstract
The aberrant activation of the Mitogen-activated protein kinase pathway (MAPK/ERK pathway) has been found to play an important role in many cancers including non-small-cell lung cancer (NSCLC). Multiple inhibitors targeting this pathway have been developed to treat cancer patients harboring the aberrant MAPK pathway genes. ERK inhibitors (ERKi) have been shown to be effective in a variety of solid-tumor malignancies, but like other MAPK inhibitors, they rarely confer complete and durable responses. Therefore, it is important to define the mechanism underlying potential tumor relapse following ERKi treatment. In this study, we found that ERKi treatment expanded the cancer stem cell (CSC) population in various NSCLC cell lines and a NSCLC patient-derived xenograft (PDX) harboring aberrant MAPK signaling. Such expansion of the CSC population is mainly caused by enhanced epithelial-to-mesenchymal transition (EMT)-mediated cancer cell dedifferentiation. Mechanistically, we revealed that ERK inhibition induces EMT via pSTAT3-mediated upregulation of EMT-transcription factor Slug. Specifically, we found that ERK inhibition increased phosphorylation of STAT3 at Y705, which further increased the expression of miR-204. Increased miR-204 then downregulated expression of SPDEF, a transcriptional repressor of Slug, thereby derepressing Slug expression. Moreover, we found that a low expression of Slug is necessary for maintaining stemness properties of CSCs. Thus, ERKi treatment-increased Slug must be downregulated to allow these cells to fully acquire stemness, and this process is mediated by a Slug-miR-200c negative feedback loop. Finally, we demonstrated that the JAK/STAT pathway inhibitor Ruxolitinib can block the ERK inhibitor-induced EMT and CSCs expansion, providing a feasible combination inhibitor approach for treating NSCLC patients. Overall, these studies provide a better understanding of the tumor relapse following ERKi treatment, and define the role of Slug in de novo production of CSCs and their maintenance.
Citation Format: Shurui Cai, Na Li, Xuetao Bai, Ananya Banerjee, Lavudi Kousalya, Qi-en Wang. ERK inhibitor increases cancer stem cell population in NSCLC through Slug-Mediated epithelial-to-mesenchymal transition [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 3325.
Abstract 3358: Targeting p63 isoforms in cancer to restore their anti-tumorigenic activity
Authors: Ozdemir E. Sila , Gomes Michelle , Fischer Jared 
Published: June 2022

Abstract
p63 plays a central role in limb formation and epithelial differentiation. p63, reported to correlate with cancer formation, is rarely mutated in cancers. Different p63 isoforms can have anti-tumorigenic or pro-tumorigenic activity. TA isoforms act as tumor suppressor by promoting cell death, while deltaN isoforms are strong driver for squamous/squamous-like cancers including lung, head and neck, cervical, skin and pancreas. A large number of tumors are addicted to deltaN isoforms. Furthermore, cancer associated p53R175H mutant gains ability to interact with TAp63 isoforms and inhibit their anti-tumorigenic function, while indirectly promoting tumorigenic function of deltaN isoforms. However, the exact mechanism of p53R175H-p63 interaction is unclear. The changes in the balance of p63 isoform activity are likely to be crucial to understanding the transition between normal cell and tumor formation. Here, we modelled p53R175H-p63 complex using homology modelling, flexible/unbiased docking and molecular dynamics simulations. Moreover, we used our models to design peptides to disrupt p53R175H-p63 interaction and restore anti-tumorigenic function of TAp63 isoforms. Also, we studied deltaN isoform oligomerization and designed peptides to inhibit their oligomerization to reduce their tumorigenic activity. We showed that some of our peptides promoted cell death in a p63 enriched cancel cell line. We characterized our peptides performing kinetic binding assays to validate binding of our peptides to their designated targets. In this study, our computational and experimental analyses presented a detailed model for the p53R175H-p63 interaction. We also provided a framework for potential therapeutic peptides to outweigh the balance in the advantage of anti-tumorigenic p63 activity.
Citation Format: E. Sila Ozdemir, Michelle Gomes, Jared Fischer. Targeting p63 isoforms in cancer to restore their anti-tumorigenic 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 3358.
Abstract 340: The Hu2G10 tumor-selective anti-Trop-2 monoclonal antibody targets the cleaved-activated Trop-2 and shows therapeutic efficacy against multiple human cancers
Authors: Alberti Saverio , Trerotola Marco , Guerra Emanuela 
Published: June 2022

Abstract
Trop-2 is a transmembrane glycoprotein that transduces a calcium signal and activates growth-signaling networks that converge on Akt, ERK, Cyclin D1, NFkB (1). We discovered that Trop-2 cleavage by ADAM10 is an activator switch for induction of cancer growth and metastatic diffusion (2). This cleavage causes a spatial rearrangement of the extracellular portion of Trop-2 and exposes protein sites that would normally be inaccessible.We devised a strategy to obtain monoclonal antibodies (mAbs) capable of recognizing these cancer-exposed sites.Most Trop-2-targeted approaches are based on anti-Trop-2 mAbs that recognize a single immunodominant epitope poised between the globular and stem regions. Such mAbs have limited therapeutic index.We removed the immunodominant epitope by deletion mutagenesis. To optimize breadth of immune response, mice were immunized with target proteins produced in cells with different end-glycosylation patterns, including tumor cells, insect, yeast, bacterial cells. Screening for cancer-specific mAbs were performed by cell-based ELISA assays, ELISA assays on recombinant target proteins, bio-layer interferometry, flow cytometry and fluorescence microscopy on cleaved, wild-type and glycosylation-site mutagenized Trop-2. mAbs were obtained that efficiently bound Trop-2 expressing cancer cells and were able to inhibit cell growth in vitro. We humanized the 2G10 mAb as the IgG1 Hu2G10 antibody with an affinity for recombinant, cancer-specific, cleaved Trop-2 that is several orders of magnitude higher than for the wtTrop-2. In vivo the naked Hu2G10 antibody was effective at inhibiting the growth of breast, colon, ovary and prostate cancers. In the ADC setting Hu2G10 drove high anticancer effectiveness with unprecedented specificity, for best-in-class anticancer therapy. (1) E. Guerra et al., The Trop-2 signalling network in cancer growth. Oncogene 32, 1594-1600 (2013).(2) M. Trerotola et al., Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia 23, 415-428 (2021).
Citation Format: Saverio Alberti, Marco Trerotola, Emanuela Guerra. The Hu2G10 tumor-selective anti-Trop-2 monoclonal antibody targets the cleaved-activated Trop-2 and shows therapeutic efficacy against multiple human 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 340.
Abstract 3444: Administration of anti-CD40 enhances local and systemic antitumor efficacy of radiotherapy in allograft tumor model of a check-point blockade resistant melanoma
Authors: Pandey Sanjay , Chavez Claudia G. , Basu Indranil , Minn Andy , Guha Chandan 
Published: June 2022

Abstract
Resistance to immune checkpoint therapy develops in a subset of patients after initial response. Therefore, we hypothesized that defective antigen presentation contributes to immune resistance, and a sequential therapy comprising of ablative radiation therapy (RT) and agonist αCD40 antibody can reprogram the tumor-infiltrating myeloid and dendritic cells for effective in-situ tumor antigen presentation and activation of T cells. Palpable B16-F10-Res499 tumors in C57BL/6 mice, resistant to the systemic effects of RT and αCTLA-4 blockade, were treated with 3 fractions of 20Gy (RT) followed by agonist αCD40 antibody (3x100μg). Tumor growth, survival, and anti-tumoral immune memory after rechallenge was monitored. Mice were sacrificed on Day 16 post-RT, and immune cells from irradiated tumors and draining lymph nodes (DLN) were analyzed using flow cytometry. There was complete tumor regression and enhanced anti-tumoral immune memory in RT+αCD40-treated animals. In a dual tumor model, combination therapy significantly delayed abscopal tumor growth by 64% on D30 (p&lt;0.0001). When compared to unirradiated or tumors treated with RT alone, there was a significant increase in cell surface expression of co-stimulatory molecules (CD80, CD86, CD40 and 4-1BBL) and TNF-α, and iNOS in the CD103+ DCs and myeloid cells (p&lt;0.05) indicating a reprogramming of antigen presentation and co-stimulatory function in MDSCs. There was an increase in CD8+ T cells with reduced CD4/CD8 ratio (p&lt;0.01) in abscopal tumors and DLN in the RT+αCD40 group. Combination treatment enhanced the frequency of proliferating Ki67+ (p&lt;0.001) and IFNγ+ (p&lt;0.01) CD8 T cells and an increase in the Ki67+ high GRZ+ (granzyme secreting) population in the pool of early exhausted cells (PD1intEOMESlow). Interestingly CD8 depletion by anti-CD8 only partially reversed the effect of the combination group. Furthermore, αCD40 showed an increase in the CD11b+Ly6C population in the tumors. Also, Ly6C depletion completely reversed the effect of the IR+anti-CD40 treatment.
Conclusion: Combination of ablative RT, followed by αCD40 therapy, overcame immune resistance in murine melanoma by enhancing systemic anti-tumoral immunity, abscopal effects, survival, and anti-tumoral immune memory. The immunomodulatory effects of αCD40 are dependent upon Ly6C+ cells and partially on CD8+ T cells.
Citation Format: Sanjay Pandey, Claudia G. Chavez, Indranil Basu, Andy Minn, Chandan Guha. Administration of anti-CD40 enhances local and systemic antitumor efficacy of radiotherapy in allograft tumor model of a check-point blockade resistant melanoma [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 3444.
Abstract 3465: Efficacy of concomitant application of Tumor Treating Fields (TTFields), temozolomide and lomustine in glioblastoma cancer cells in vitro
Authors: Fishman Hila , Monin Roni , Dor-On Eyal , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: June 2022

Abstract
Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Newly diagnosed GBM (ndGBM) is treated with adjuvant temozolomide (TMZ), however, more than 50% of patients do not respond to therapy. Tumor Treating Fields (TTFields) therapy concomitant with maintenance TMZ was approved by the FDA in 2015 and represents a major advance in treatment of patients with ndGBM. Recently, lomustine (CCNU) together with TMZ demonstrated improved overall and progression-free survival following resection and radiochemotherapy in patients with ndGBM. Accordingly, the current study aimed to examine the effect of concomitant application of TTFields with TMZ and CCNU in GBM cells.
Methods: GBM cells (U-87 MG and LN229) were treated for 72 h with TTFields at a frequency of 200 kHz and an intensity of 1 V/cm RMS using the inovitro system. Efficacy of combining TTFields with TMZ and/or CCNU was tested by measuring cell survival, clonogenic potential, overall effect (multiplicity product of cytotoxicity and clonogenicity), and apoptosis induction.
Results: Combination of TMZ and TTFields resulted in increased cytotoxicity compared with each treatment alone. The cytotoxic effect resulting from co-application of CCNU with TTFields suggested a synergistic interaction between the two modalities. The clonogenic, overall, and apoptotic effects of TMZ and CCNU were also enhanced following co-treatment with TTFields. The triple combination of TTFields with both TMZ and CCNU was more efficacious than TMZ/CCNU or TTFields separately.
Conclusions: The current research suggests potential benefits for the treatment of GBM using concomitant application of TTFields with TMZ/CCNU.
Citation Format: Hila Fishman, Roni Monin, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Efficacy of concomitant application of Tumor Treating Fields (TTFields), temozolomide and lomustine in glioblastoma cancer cells in vitro [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 3465.