bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 328: LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry
Authors: Kim Hyejung , Guerra Emanuela , Baek Eunji , Jeong Yeojin , You Hyogeun , Yu Byeongjun , Jang Taeik , Saverio Alberti , Chung Chul-Woong , Park Changsik 
Published: June 2022

Abstract
LCB84 is a human Trop-2-targeting antibody drug conjugate (ADC) composed of monomethyl auristatin E (MMAE) as payload and the Hu2G10 (by Mediterranea Theranostic) humanized IgG1 antibody that selectively targets the ADAM10-activated Trop-2 protein selectively expressed in transformed cancer cells (1). LCB84 was prepared using ConjuAll࣪, a proprietary site-directed conjugation technology of LegoChem Biosciences, which incorporates a conjugation ‘handle’ joined by enzymatic prenylation to a specifically engineered recognition sequence (CaaX) on antibody light chains. This conjugation handle facilitates simple versatile chemical conjugation to the linker-payload. A proprietary plasma-stable cleavable linker that is recognized and cleaved by a cancer-associated lysosomal enzyme, β-glucuronidase, was used to enable efficient and traceless payload release in a cancer-specific manner. LCB84 has been evaluated for anti-tumor activity and showed superior anticancer efficacy in triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), gastric cancer and non-small cell lung cancer (NSCLC) cell line-derived xenograft (CDX) models compared to the ADC competitors Trodelvy and DS-1062. The LCB84 treatments were well tolerated, with no changes in body weight compared to control animals, for all dosing groups. LCB84 has robust cross-reactivity against primate Trop-2, which allows rigorous toxicity studies in monkeys. Remarkably, preliminary toxicity studies using cynomolgus monkeys showed that LCB84 is well tolerated, with calculated therapeutic index (TI, MTD/MED) of ~30 for single dosing and ~40 for repeat dosing. In conclusion, LCB84 is highly effective against Trop-2-positive CDX models in mice at doses that are well tolerated in mice and in primate models. Use of this proprietary plasma-stable cancer-selective linker technology and the Hu2G10 anti-Trop-2 monoclonal antibody that targets cancer-activated Trop-2 has led to a greatly improved next generation ADC for the treatment of various Trop-2-positive solid cancers including TNBC, PDAC, NSCLC and gastric cancer.
Citation Format: Hyejung Kim, Emanuela Guerra, Eunji Baek, Yeojin Jeong, Hyogeun You, Byeongjun Yu, Taeik Jang, Alberti Saverio, Chul-Woong Chung, Changsik Park. LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry [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 328.
Abstract 3308: Chemoradiation sensitization effect of PARPi in non-small cell lung cancer
Authors: Ye Rui , Wang Kaile , Qiao Yawei , Xiao Zhenna , Yan Yun , He Jianzhong , Li Nan , Wang Yifan , Hu Min , Bai Shanshan , Sei Emi , Navin Nicholas , Lin Steven 
Published: June 2022

Abstract
Chemoradiation (CRT) is widely used to treat locally advanced non-small cell lung cancer (NSCLC) patients, but only around 30% of patients achieve pathological complete response. Here, we utilized an in vitro high-content clonogenic survival screening method to identify CRT sensitizers from the NCI Cancer Therapy Evaluation Program (CTEP) portfolio. Talazoparib (PARPi) was identified among the top candidates to show potent CRT sensitization effects in both KRAS mutant and TP53 mutant NCSLC cell lines. We validated the CRT sensitization effect of PARPi on lung tumors in vivo with cell line xenografts mouse models. To further investigate alterations in the tumor microenvironment (TME) induced by PARPi, we utilized syngeneic mouse models and showed that the combination of radiotherapy, PARPi, and PD-L1 blockade achieved superior tumor control effects. By applying single cell RNA sequencing technologies to the mouse tumors, we found that PARPi combined with CRT or immunotherapy significantly reprogrammed the tumor cells and TME, resulting in the increase of tumor-infiltrating T cells which elicit potent tumor control effects. Our data showed that PARPi sensitizes NSCLC tumors to CRT and immunotherapy through a combination of tumor-intrinsic and extrinsic phenomenon.
Citation Format: Rui Ye, Kaile Wang, Yawei Qiao, Zhenna Xiao, Yun Yan, Jianzhong He, Nan Li, Yifan Wang, Min Hu, Shanshan Bai, Emi Sei, Nicholas Navin, Steven Lin. Chemoradiation sensitization effect of PARPi in non-small cell lung 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 3308.
Abstract 3349: In-silico analysis identifies the unique role of the ADRB2-USP20 axis in T cell lymphoma
Authors: Tiwari Rajan Kumar , Kumar Ajay 
Published: June 2022

Abstract
T cell lymphoma represents an aggressive subgroup of lymphoma having a poor prognosis. Many factors, including psychological stress, define the onset/progression of the disease. Although psychological stress can cause several health problems, preclinical and clinical reports regarding its role in cancer have been mixed. Therefore, in this study, we sought to determine the role of psychological stress hormone in the progression of T cell lymphoma and provide a mechanistic framework of activity. Initially, we used the cBioportal and performed expression analysis of genes involved in stress pathways with large-scale cancer genomics TCGA datasets having nearly 10071 patient samples. Through a series of in-silico investigations, we identified Adrenoceptor Beta 2 (ADRB2), a key mediator of stress, highly expressed in T cell lymphoma compared to other tumors.Furthermore, the expression of ADRB2 was not gender-specific and equally represented in both males and females. String analysis further identified the interaction of ADRB2 with Ubiquitin carboxyl-terminal hydrolase 20 (USP20), which directly regulates Hypoxia-inducible factor 1-alpha (HIF1-A) and ADRB2. This regulation could lead to enhanced glucose metabolism to support T cell lymphoma growth and progression. Collectively, our in-silico findings suggest that psychological stress releases hormones that could modulate T cell lymphoma proliferation through the ADRB2-USP20 axis. Ongoing preclinical studies with stress hormones will be presented to provide undescribed mechanisms of their protumorigenic activity through the ADRB2-USP20 axis and their role in regulating cancer-specific metabolism. We sought to determine the role of psychological stress hormone These studies will provide an opportunity to learn the involvement of stress hormones in cancer progression and provide a framework for developing a novel approach for stress management during cancer.
Citation Format: Rajan Kumar Tiwari, Ajay Kumar. In-silico analysis identifies the unique role of the ADRB2-USP20 axis in T cell lymphoma [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 3349.
Abstract 335: c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning
Authors: Howard Caleigh , Wiley Shu , Dong Wenzhao , Mendiola Andrea , Partridge Veronica , LeMar Sara , Amador Paul , Chaudhary Amit K. , Dekker Joseph D. , Zhao Jay , Durland Ross , Iberg Aimee 
Published: June 2022

Abstract
Engineered toxin bodies (ETBs) are next-generation immunotoxins that harbor an antibody-derived targeting domain and a cytotoxic payload derived from Shiga-like toxin-1 catalytic subunit A (SLTA). SLTA has been engineered to reduce innate immunogenicity and therefore increase the safety of ETBs whilst retaining potent cytotoxic properties. When targeted via a binding domain, SLTA is internalized and routes to the cytosol leading to irreversible ribosome inactivation and ultimately cell death.
ETBs have been developed to treat a wide variety of cancers, including breast, lymphoma, multiple myeloma and PD-L1 positive solid tumors. This technology holds promise for non-oncology indications as well, particularly as a targeted and non-genotoxic conditioning regimen for hematopoietic stem cell (HSC) ablation to prepare patients for autologous stem cell transplant.
c-KIT (CD117) is a well-known marker of hematopoietic stem and progenitor cells and is overexpressed in a high percentage of certain cancers including GIST, SCLC and AML. While tyrosine kinase inhibitors such as imatinib are effective therapies for c-KIT mutant GIST, resistance often occurs by the development of secondary mutations in the intracellular signaling domains. Thus, c-KIT represents a potential ETB target for both oncological and HSC transplant conditioning indications. Here we present data highlighting the in vitro potency and efficacy of CD117-targeting ETBs on cancer cell lines as well as on primary human CD34+ HSCs. CD117-targeted ETBs demonstrate exquisite specificity in vitro by killing only target positive CD34+ cells at picomolar potency while sparing the progenitors that lack CD117 expression. However, relatively low CD117 receptor levels on CD34+ HSCs prevent complete killing in vitro, limiting the observed efficacy. To overcome this challenge, an additional cytotoxic payload was conjugated to the ETB molecule to capitalize on ETBs’ unique internalization and routing properties to deliver a secondary mechanism of action. ETB-drug conjugates (ETB-DCs) exhibited improved cytotoxicity in vitro, especially in CD117-low target cells. Moving forward, we plan to explore both the ETB and the ETB-DC therapeutic index in vivo with a series of CD117+ tumor efficacy and HSC depletion models.
Citation Format: Caleigh Howard, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Sara LeMar, Paul Amador, Amit K. Chaudhary, Joseph D. Dekker, Jay Zhao, Ross Durland, Aimee Iberg. c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning [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 335.
Abstract 341: Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma
Authors: Wen Hui-Ju , Crawford Howard 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and will become the 2nd leading cause of cancer related death in the United States within the next 10 years. Lack of early symptoms and a poor response to current therapies make PDAC the deadliest of all major cancers. PDAC is characterized by a dense fibroinflammatory stroma which is composed of fibroblasts and immune cells and has been implicated to influence tumor progression and therapeutic outcome. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, systemic inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. Tumor regression was observed in the mice treated with MEDI3622 and was accompanied by high infiltration of cytotoxic T cells and low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). In addition, activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways, were reduced by MEDI3622. These results demonstrate a pronounced anti-tumor effect by ADAM17 blockage and indicate ADAM17 as a therapeutic target of pancreatic cancer.
Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal 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 341.
Abstract 3422: Combined treatment with interleukin-4 receptor-targeted cytotoxic peptide and PD-L1-blocking peptide efficiently induces immunogenic cell death of tumor cells and activates T-cell activity
Authors: Park Nawon , Lee Byungheon , Lee Hyunsu 
Published: June 2022

Abstract
Immune checkpoint blockade therapy has provided clinical benefit to some patients with advanced cancer including melanoma and non-small cell lung cancer. However, many patients still fail to respond to single immune checkpoint blockade therapy. The need for combination therapies to increase anti-tumor responses is becoming important. Interleukin-4 receptor (IL4R) is frequently overexpressed in various cancer types and promotes tumor cell survival. PD-L1, a well-known immune checkpoint, is up-regulated in malignant tumors and inhibits T-cell activity. In this study, we aimed at a combination therapy using an IL4R-targeted cytotoxic peptide and PD-L1-blocking peptide. To target IL4R-high tumor cells, we exploited IL4RPep-1-KLA composed of IL4RPep-1, an IL4R-binding peptide, and (KLAKLAK)2, a cytotoxic peptide. IL4RPep-1-KLA induced necrosis as well as apoptosis of IL4R-expressing tumor cells and increased the secretion of CRT, HMGB1, and ATP, well-known markers of immunogenic cell death (ICD). Flow cytometry analysis showed that the conditioned medium of tumor cells treated with IL4RPep-1-KLA enhanced the expression of CD86 and CD80 on dendritic cells, suggesting the activation and maturation of dendritic cells through ICD. Sequential treatment with IL4RPep-1-KLA followed by PD-L1Pep-2, a PD-L1-blocking peptide, during the co-culture of tumor cells and CD8+ T-cells activated T-cell activity including T-cell proliferation and cytokine secretion more efficiently than single treatment with IL4RPep-1-KLA or PD-L1Pep-2, or simultaneous treatment. These results suggest that sequential, combined treatment with the IL4R-targeted cytotoxic peptide and PD-L1-blocking peptide can induce ICD of tumor cells and maturation of dendritic cells and subsequently activate T-cells. This treatment is a promising strategy for cancer immunotherapy.
Citation Format: Nawon Park, Byungheon Lee, Hyunsu Lee. Combined treatment with interleukin-4 receptor-targeted cytotoxic peptide and PD-L1-blocking peptide efficiently induces immunogenic cell death of tumor cells and activates T-cell 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 3422.
Abstract 3450: Impact of model inaccuracy on dose estimation in TTFields therapy
Authors: Marciano Tal , Zeevi Oshrit , Bomzon Zeev 
Published: June 2022

Abstract
Introduction: Tumor Treating Fields (TTFields) is a modality for treating Glioblastoma (GBM). A recent study combining clinical data and simulations demonstrated that the simulation-based dose estimation at the tumor level is directly correlated with patient survival (Ballo M, et al. Int J Radiat Oncol Biol Phys. 2019;104(5):1106-1113). This study highlights the importance of computer-modelling based TTFields treatment planning in the clinic. Performing such planning in a meaningful manner requires an understanding about how inaccuracies in the patient model influence calculated TTFields distributions. In this study we show the effect of local perturbations in the model, errors in tumor segmentation, and inaccuracy in the patient head model on TTFields dose estimation.
Methods: Computational studies were performed with Sim4Life software. 1) Local model uncertainty outside of tumor region: To create defects in the models, conductive spheres with varying conductivities and radii were placed into the model’s brains at different distances from the tumor. Virtual transducer arrays were placed on the models, and delivery of TTFields numerically simulated. The error in the electric field induced by the defects as a function of defect conductivity, radius, and distance to tumor was investigated. 2) Tumor segmentation uncertainty: For illustrating segmentation errors in tumors and necrotic cores, layered spheres with various conductivities and radii were placed in different head locations. Tumor conductivity uncertainty was defined as (σ-σref)/σref where σref = 0.24 S/m is the standard tumor conductivity and σ is the varied conductivity over the tumor. The normalized tumor radius was calculated when each of the varied radii was normalized to the results obtained by all the other combinations.
Results: The results show that that when a defect of radius R is placed at a distance, d, from the tumor that is larger than seven times R, the error is below 1% regardless of the defect conductivity.
Conclusions: Our models and results show the impact of uncertainty in segmentation of the tumor or other tissue distant from it on the TTFields dose estimation. These results could serve as a guideline for model creation and tissue segmentation that would lead to optimal dose estimation in TTFields treatment planning.
Citation Format: Tal Marciano, Oshrit Zeevi, Zeev Bomzon. Impact of model inaccuracy on dose estimation in TTFields therapy [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 3450.
Abstract 3459: Patient derived gliomaspheres exhibit HA concentration dependent invasiveness in 3D hydrogels
Authors: Safarians Gevick , Solomon Itay , Sohrabi Alireza , Seidlits Stephanie 
Published: June 2022

Abstract
Hyaluronic acid (HA) is a highly abundant glycosaminoglycan within the central nervous system. In glioblastoma (GBM), interactions with HA mediate tumor cell invasion. An improved knowledge of the biological underpinnings of HA-dependent GBM cell migration can facilitate the development of efficacious therapeutics. To better study how HA in the tumor matrix affects invasion, we have developed a tunable, 3D culture system in which to study gliomaspheres (GSs) of patient-derived tumor cells. Photopolymerization (365 nm for 15 seconds) of GSs suspended in a solution 0.025 w/v% lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), thiolated 4-arm poly-ethylene glycol (20 kDa, Laysan Bio), 8-arm poly-ethylene glycol-norbornene (20 kDa, Laysan Bio), thiolated peptides containing an ‘RGD’ amino acid motif, and either 0.10, 0.25, 0.50, or 0.75 w/v% of thiolated HA (700 kDa average molecular weight, Lifecore Biomedical) yielded 3D hydrogels of varying HA concentrations and similar mechanical properties. Relative invasive capacity, quantified by shape factor (deviation from circularity) and migration length (maximum extension length of processes from the GS periphery), differed across patient lines and was independent of their Cancer Genome Atlas (TCGA) classification as either mesenchymal or proneural. Hydrogels with higher amounts of HA (&gt;0.25% w/v) generally enhanced invasion as compared to low HA (0.10 w/v%) hydrogels. In certain cell lines, a biphasic relationship between HA concentration and migration was observed, in line with previous reports of CD44 expression and migration. Moreover, inhibition of the CD44-Ezrin-Actin axis, using NSC668394, reduced migratory activity in hydrogels with higher HA (&gt;0.25% w/v), while slightly increasing invasion in hydrogels with low HA (0.10 w/v%). In sum, results demonstrate the use of a matrix-mimetic, 3D hydrogel system in which to study GBM invasion through the local extracellular matrix.
Citation Format: Gevick Safarians, Itay Solomon, Alireza Sohrabi, Stephanie Seidlits. Patient derived gliomaspheres exhibit HA concentration dependent invasiveness in 3D hydrogels [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 3459.
Abstract 3517: Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor activity
Authors: Lee Jacob S. , Toy Pamela , Min-Oo Gundula , Lee Tony , Salvo Patrick , Belzile JeanPhilippe , Clancy Sheila , Nazareno Jonathan , Xu Mengshu , Xing Weimei , Giacomini Marilyn , Santos Rex , Stapleton Lance , Wang Adele , Juric Vladislava , Mitchell Scott A. , Kuhne Michelle 
Published: June 2022

Abstract
Hematopoietic progenitor kinase 1 (HPK1, mitogen-activated kinase kinase kinase kinase 1 [MAP4K1]), a cytosolic STE20 ser/thr kinase from the germinal center family of kinases, regulates the function of diverse immune populations including T cells, B cells, and dendritic cells. In T cells, activated HPK1 regulates T cell receptor (TCR) signaling by phosphorylating the adaptor protein SLP76 on Ser376, which induces the association of SLP76 with 14-3-3 proteins. This SLP76/14-3-3 complex leads to its disassociation from the TCR signalosome, resulting in reduced downstream TCR signaling. The kinase activity of HPK1 is necessary for its regulatory function as mice expressing a mutant kinase-inactive HPK1 demonstrate enhanced T cell activity and superior tumor growth control compared to their WT counterparts. Here we describe a highly potent, selective and orally bioavailable small molecule inhibitor of HPK1 which displays sub-nanomolar HPK1 inhibition, good selectivity against MAP4K family members and oral bioavailability in preclinical animal models. Pharmacological inhibition of HPK1 kinase activity with Gilead’s HPK1 inhibitor compound demonstrates robust inhibition of pSLP76 S376 with concomitant enhancement in T cell activation, proliferation and effector function in in vitro assays. These immune enhancing effects translate into in vivo preclinical tumor models, where treatment with Gilead’s HPK1 inhibitor compound results in heightened T cell activation and effector function and enhanced tumor growth control both as a single agent and in combination with PD-1 blockade. In summary, our data show that Gilead’s HPK1 inhibitor compound is expected to be a selective, orally bioavailable HPK1 inhibitor with potential to combine with checkpoint inhibitors and other immuno-oncology agents.
Citation Format: Jacob S. Lee, Pamela Toy, Gundula Min-Oo, Tony Lee, Patrick Salvo, JeanPhilippe Belzile, Sheila Clancy, Jonathan Nazareno, Mengshu Xu, Weimei Xing, Marilyn Giacomini, Rex Santos, Lance Stapleton, Adele Wang, Vladislava Juric, Scott A. Mitchell, Michelle Kuhne. Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor 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 3517.