bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2204: Novel FAK/ALK/ROS1 inhibitor APG-2449 synergizes with osimertinib in preclinical xenograft models of EGFR-mutant NSCLC
Authors: Wang Guangfeng , Fang Douglas D. , Min Ping , Tao Ran , Tang Chunyang , Gu Shoulai , Rui Li , Li Jiajun , Wang Jingwen , Wu Miaoyi , Li Yingfeng , Chen Dingxiong , Zhang Fei , Lian Kejie , Zhang Feifei , Wang Lvcheng , Xu Rongcheng , Yang Dajun , Zhai Yifan 
Published: August 2019

Abstract
Focal adhesion kinase (FAK) plays an important role in cell migration, growth factor signaling, cell cycle progression and cellular survival. It had been shown that FAK and SRC family kinases were able to sustain downstream AKT and MAPK signaling under continuous EGFR inhibition driven by osimertinib (AZD9291), a mutant-selective third-generation EGFR inhibitor. Incomplete inhibition of AKT and MAPK was consistently observed even under increased concentrations of osimertinib and led to acquired resistance to osimertinib, implicating the need of combination therapy with FAK/SRC inhibitors to enhance antitumor activity of osimertinib and overcome its resistance. APG-2449 is a novel oral active small-molecular inhibitor that targets FAK, ALK and ROS1. In this study, we investigated the effect of combination treatment with APG-2449 and osimertinib using NSCLC NCI-H1975 cells carrying EGFRL858R/T790M mutation and an osimertinib-resistant patient-derived xenograft (PDX) model carrying EGFRT790M/19del/C797S mutation. In vitro, the combination treatment with APG-2449 and osimertinib synergistically inhibited the proliferation of NCI-H1975 cells. In vivo, APG-2449 significantly enhanced antitumor activity of osimertinib in NCI-H1975 xenograft models, leading to complete or partial tumor regression. More profound antitumor activity of this combination was also demonstrated in the osimeritinib-resistant PDX model in comparison with single agents. In term of mechanism, the combination arm significantly suppressed the on-target phosphorylation of EGFR, FAK and SRC, as well as AKT and ERK in NCI-H1975 xenografts. Collectively, these results suggest that addition of APG-2449 to osimeritinib may enhance antitumor activity and suppress the development of resistance in NSCLC.
Citation Format: Guangfeng Wang, Douglas D. Fang, Ping Min, Ran Tao, Chunyang Tang, Shoulai Gu, Li Rui, Jiajun Li, Jingwen Wang, Miaoyi Wu, Yingfeng Li, Dingxiong Chen, Fei Zhang, Kejie Lian, Feifei Zhang, Lvcheng Wang, Rongcheng Xu, Dajun Yang, Yifan Zhai. Novel FAK/ALK/ROS1 inhibitor APG-2449 synergizes with osimertinib in preclinical xenograft models of EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2204.
Abstract 2206: Anti-tumor activity of infigratinib, a potent and selective inhibitor of FGFR1, FGFR2 and FGFR3, in FGFR fusion-positive cholangiocarcinoma and other solid tumors
Authors: Li Gary , Krook Melanie , Roychowdhury Sameek , Avogadri Francesca , Ye Yining , Moran Susan 
Published: August 2019

Abstract
Abnormal expression and constitutive activation of receptor tyrosine kinases, such as ALK, ROS1 and TRK, as a result of gene rearrangements have been clinically validated as therapeutic targets for cancer. Recently, fusions involving the FGFR family, especially FGFR1, FGFR2 and FGFR3, have been identified in diverse solid tumors such as cholangiocarcinoma, glioblastoma, bladder, lung, breast, thyroid and prostate cancers. FGFR fusions are oncogenic drivers that ligand-independently activate the receptor kinases and their downstream signaling pathways, leading to uncontrolled cell proliferation and invasion.
Infigratinib (BGJ398) is an oral and selective inhibitor of FGFR. At biochemical and cellular levels, infigratinib selectively inhibits the activity of FGFR1, FGFR2 and FGFR3 with low nM potency, while sparing FGFR4, VEGFR2 and other kinases. In FGFR fusion-positive xenograft models, including cell line-derived and patient-derived models representing diverse tumor histologies, infigratinib treatment leads to significant tumor growth inhibition and regression at clinically achievable exposure levels. The anti-tumor effect of infigratinib is accompanied by inhibition of downstream signaling pathways and induction of tumor apoptosis.
Clinically, in an open-label phase II trial, infigratinib demonstrated a cORR of 39.3% in FGFR2 fusion-positive cholangiocarcinoma patients who had received one or fewer prior chemotherapy regimens. Additionally, RECIST responses were achieved in non-cholangiocarcinoma solid tumors tested positive for FGFR fusions.
In conclusion, the available preclinical and clinical data demonstrate the potential of infigratinib as an effective treatment for patients with FGFR fusion-positive tumors, regardless of the fusion partners or the origin of tissue. On the basis of these data there is a clear rationale for performing tumor-agnostic clinical trials in molecularly defined cancers to maximally benefit patients with serious and life-threatening diseases.
Citation Format: Gary Li, Melanie Krook, Sameek Roychowdhury, Francesca Avogadri, Yining Ye, Susan Moran. Anti-tumor activity of infigratinib, a potent and selective inhibitor of FGFR1, FGFR2 and FGFR3, in FGFR fusion-positive cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2206.
Abstract 2209: Novel therapeutic agents for RET-driven cancers, which is highly potent and selective inhibitor to RET kinase
Authors: Li Hua , Jo SeoHyun , Do Woomi , Kim Hyunkyung , Kim Hwan , Seo Kyung-ah , Oh Ji-hoon , Choi Jieun , Ahn Jaeyoung , Son Jung Beom , Kim Nam Doo 
Published: August 2019

Abstract
The rearranged during transfection (RET) tyrosine kinase is mostly altered by fusion and it makes RET as a attractive therapeutic target for medullary thyroid cancer and non-small cell lung cancer (NSCLC). Multi-kinase inhibitors (mKIs) such as cabozantinib and vandetanib expressed poor tolerability and limited efficacy due to off-target kinase inhibitory activity in academia and clinical cases. As for selective RET inhibitor, compounds such as BLU-667 and LOXO-292 are under development, currently in clinical trials. We are currently developing potent and selective RET inhibitors to address unmet medical needs for RET-driven cancers. Our team has validated its high potency and selectivity via kinase profiling and in-vitro assay results. We also anticipate our compound to overcome certain mutation, such as V804M. Our compounds strongly suppress phosphorylation of RET in tumor cells with various RET fusions and mutations by inhibiting proliferation at below 10 nM. This potency result is higher than those of other mKIs with RET inhibitory activity. The inhibitory concentration of our compounds to VEGFR2 is more than dozens of fold compared with RET. In addition, our compounds reveal low cytotoxicity in Ba/F3 naïve cells in the 1 µM concentration. These findings lead us to conclude that our compounds can be potent and highly selective inhibitors of RET kinase, a potential novel therapeutic agents for RET-driven cancers.
Citation Format: Hua Li, SeoHyun Jo, Woomi Do, Hyunkyung Kim, Hwan Kim, Kyung-ah Seo, Ji-hoon Oh, Jieun Choi, Jaeyoung Ahn, Jung Beom Son, Nam Doo Kim. Novel therapeutic agents for RET-driven cancers, which is highly potent and selective inhibitor to RET kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2209.
Abstract 2247: Platinoid-induced MHCI antigen presentation enables checkpoint inhibitor responsiveness
Authors: Bastian Ingmar Niels , Li Weihua , Phung Qui , Fisch Kathleen , Lill Jennie , Karin Michael , Shalapour Shabnam 
Published: August 2019

Abstract
Many cancers are refractory to immune checkpoint therapy (ICT), but the causes of ICT resistance remain unknown. Despite low mutational burden, hepatocellular carcinoma (HCC) responds to PD-1 blockade, but prostate cancer (PCa) does not. RNA-seq analysis revealed that, unlike HCC, PCa cells poorly express MHC-I molecules and components of the MHC-I antigen processing and presentation machinery. We found that treatment of PCa cells and other tumor types with platin-based drugs, especially low dose Oxaliplatin, led to a pronounced upregulation of MHC-I molecules and their antigen generating and loading machinery. Most importantly, Oxaliplatin synergistically potentiated the effect of exogenous IFNγ; a conclusion based on two cumulative observations. First, ATAC-seq analyses revealed that Oxaliplatin activates MHC machinery through different pathways compared to well-known IFNγ signaling. Second, Oxaliplatin upregulates IFNγR2 expression in cancer cells. Induction of IFNγR2, which was needed for Oxaliplatin-potentiation of ICT-induced tumor rejection in vivo, depended on NF-κB signaling. Induction of IFNγR2, which was needed for Oxaliplatin-potentiation of ICT-induced tumor rejection in vivo, depended on NF-κB signaling. Moreover, we found that Oxaliplatin activates histone acetyltransferases (HATs) which alter chromatin structure of genes encoding MHC-I complex components, thereby enabling recruitment of a diverse array of activating transcription factors.
Our data indicates that combining ICT with an appropriate low dose platinoid chemotherapeutic agent is useful in reinvigorating the immune response to tumors that have escaped immune destruction due to MHC-I downregulation and do not respond to single agent therapy.
Citation Format: Ingmar Niels Bastian, Weihua Li, Qui Phung, Kathleen Fisch, Jennie Lill, Michael Karin, Shabnam Shalapour. Platinoid-induced MHCI antigen presentation enables checkpoint inhibitor responsiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2247.
Abstract 226: Optimization of folate receptor alpha-targeting tunable drug conjugates
Authors: Sigler Sara C. , Gupta Vinayak , Nguyen Hanh N. , Rood Michael K. , Wanner Jutta , Werner Doug S. 
Published: August 2019

Abstract
We have integrated a family of innovative technologies with an aligned set of properties into Tunable Drug Conjugates (TDCs). TDCs are made up of a targeting moiety (e.g. small molecules, peptides, antibodies or antibody fragments), combined with our proprietary Silicon-based linkers (SiLinkers) and novel Payload Cassette (PC) designs which allow for delivery of multiple payloads, preferentially Conditionally Active Payloads (CAPs). CAPs are cytotoxic moieties which cannot readily permeate into normal cells due to their charged state at physiological pH of 7.4; however, at the more acidic pH of the endosome or the tumor microenvironment, the charge is neutralized enabling the CAP to readily permeate into and accumulate within the cancer cells. Our goal is to establish a beneficial Therapeutic Index (TI) and dosing flexibility by creating TDCs around a rapid payload release/rapid systemic clearance approach. Therefore, SiLinker/CAP constructs are designed to concentrate payload in the targeted tumor cell and associated tumor microenvironment while minimizing systemic payload release and rapidly clearing the parent TDC. Folate Receptor alpha (FRα) is overexpressed in multiple cancers, most notably, ovarian, endometrial, and NSCLC. Our optimized FRα-targeting TDCs use folic acid as the ligand and deliver various triple- and hexa-CAP cassettes. The various CAPs were selected from different target classes in order to allow for optimized treatment of different cancer types. We will present comparative cellular data, in vivo xenograft studies in KB, OV90 and IGROV1 models, as well as DMPK parameters of our lead FRα-TDCs. Using our triple- and hexa-PCs, we have achieved cures in in vivo xenograft studies which were durable and lasted even after treatment was stopped. We also demonstrate that in vivo our hexa-PC shows superior efficacy compared to our triple-PC in the moderate FRα expressing models. Based on our data, we believe that the combined properties of our innovative CAP-TDCs and rapid payload release/rapid systemic clearance approach will further increase TI, differentiate from other Drug Conjugates, and ultimately provide a compelling addition to existing Drug Conjugate technologies.
Citation Format: Sara C. Sigler, Vinayak Gupta, Hanh N. Nguyen, Michael K. Rood, Jutta Wanner, Doug S. Werner. Optimization of folate receptor alpha-targeting tunable drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 226.
Abstract 2263: Ceramide mimetics regulation of tumor cell response to immune checkpoint inhibitor immunotherapy
Authors: Redd Priscilla S. , Lu Chunwan , Klement John D. , Ibrahim Mohammed , Yang Dafeng , Payne Daniela , Lebedyeva Iryna , Liu Kebin 
Published: August 2019

Abstract
Programmed cell death-1 (PD-1) is an immunosuppressive receptor expressed on T cells upon activation. Once interacting with its ligand, programmed death ligand-1 (PD-L1), the PD-1:PD-L pathway curbs T cell activation and thereby serves as a natural protection mechanism against autoimmunity. However, this pathway has been hijacked by cancer cells in order to evade the immune system. This interface has already been recognized as an effective target for cancer therapy leading to the development of immune checkpoint inhibitor (ICI) immunotherapy. Blocking the PD-1:PD-L axis unleashes T cells from suppression to maintain their effector function against tumor cells. ICI has durable efficacy in many types of cancer; however, colorectal cancer, except for the approximately 4% microsatellite-instable (MSI) colorectal cancer, stands out as one of the few human cancers that does not respond to ICI immunotherapy. One potential mechanism that these tumor cells may be using is resisting cell death, making them insensitive to apoptosis induction by T cells. Ceramide, the central metabolite of the sphingolipid metabolism pathway, plays a critical role in many cell signaling processes, and one of its most prevalent roles can be seen in cell death. Our lab has developed five novel ceramide mimetics (IG4, IG7, IG14, IG17, and IG19) which function to sensitize tumor cells to apoptosis and enhance T cell-mediated cell death. We have previously shown that these ceramide mimetics significantly increase FasL-induced apoptosis by perforin-deficient cytotoxic T lymphocytes. Using the murine colon carcinoma cell line CT26, we show that the ceramide mimetics induce tumor cell death in a dose-dependent manner. Interestingly, the ceramide mimetics appear to be functioning by different mechanisms in vitro. Still, we report here that these five ceramide mimetics exhibit tumor suppression activity in a colon tumor mouse model in a dose-dependent manner in vivo. Also, ceramide mimetic IG19 significantly increased the efficacy of anti-PD-1 mAb immunotherapy in suppressing colon tumor development in vivo. Our data thus indicate that ceramide mimetics are potential effective enhancers for ICI immunotherapy in colon cancer.
Citation Format: Priscilla S. Redd, Chunwan Lu, John D. Klement, Mohammed Ibrahim, Dafeng Yang, Daniela Payne, Iryna Lebedyeva, Kebin Liu. Ceramide mimetics regulation of tumor cell response to immune checkpoint inhibitor immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2263.
Abstract 2309: Chimeric antigen receptor T-cell therapy targeting glypican-1 in pancreatic cancer
Authors: Li Nan , Li Dan , Ren Hua , Torres Madeline , Ho Mitchell 
Published: August 2019

Abstract
Pancreatic cancer is the fourth most common cause of death from cancer in the US, with a 5-year overall survival of 8.5%. While immunotherapy with chimeric antigen receptor (CAR) T cells has shown promise in certain hematological malignancies, their efficacy for solid tumors including pancreatic cancer remains elusive. Thus, laboratory research is urgently needed to identify and validate a new target of CAR T-cell therapy for patients with pancreatic cancer. In this study, we made CAR T cells that recognize glypican-1 (GPC1), a cell surface heparan sulfate proteoglycan protein that is overexpressed in pancreatic cancer. We isolated two GPC1-specific antibodies; the mouse monoclonal antibody HM2 that binds the C-lobe of GPC1 close to the cell surface, and the camel single domain antibody D4 that recognizes a conformational epitope in the protein core of GPC1. The transduction efficiencies of CAR (HM2) and CAR (D4) in primary T cells were 86% and 58%, respectively. GPC1-overexpressing KLM1 cells (2B9) and GPC1-overexpressing A431 cells (H8) were efficiently lysed by both CAR T cells in dose-dependent manners. By contrast, minimal cell lysis was observed in GPC1-negative cell line A431. In the presence of GPC1-positive tumor cells, greater amount of TNF-α, IFN-γ and IL-2 were produced by GPC1-specific CAR T cells than mock-transduced T cells. Although both CAR T cells showed similar cytolytic activity in vitro, CAR (D4) T cells induced 2-4 times more cytokines than CAR (HM2) T cells when co-cultured with GPC1-postive tumor cells. Notably, both GPC1-targeted CAR T cells demonstrated potent antitumor efficacy in a peritoneal dissemination xenograft mouse model. Our findings indicate that GPC1-targeted CAR T cell therapy could be a new approach for treating pancreatic cancer.
Citation Format: Nan Li, Dan Li, Hua Ren, Madeline Torres, Mitchell Ho. Chimeric antigen receptor T-cell therapy targeting glypican-1 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2309.
Abstract 231: Optimizing lysosomal activation of antibody-drug conjugates (ADCs) by incorporation of novel cleavable dipeptide linkers
Authors: Salomon Paulin , Harris Luke , Reid Emily E. , Maloney Erin K. , Wilhelm Alan J. , Miller Michael L. , Chari Ravi V. , Keating Thomas A. , Singh Rajeeva 
Published: August 2019

Abstract
Peptides constitute a major linker class in antibody-drug conjugates (ADCs), designed to connect antibodies to cytotoxic drug molecules. An optimal linker for an ADC should be stable in circulation and be cleaved efficiently in lysosomes upon binding and internalization of the ADC in target cells, releasing drug molecules that exit lysosomes and inhibit key cellular functions. Previous studies have focused on a limited selection of peptide linkers and specific biochemical tools, such as a cathepsin B cleavage assay, leading to the selection of a valine-citrulline dipeptide linker with a p-aminobenzyloxycarbonyl (PABC) spacer, which is now often used in candidate ADCs.
In this study, we screened a panel of dipeptide linkers for efficient lysosomal proteolysis. Dipeptide linkers bearing different amino acids (typically both L, with D used as a control) were synthesized with a fluorogenic leaving group, 7-amino-4-methylcoumarin, which provided a convenient model system for screening of peptide cleavage using lysosomal extracts from cancer cells as well as several individual cathepsins. The linkers were also tested for stability in mouse, rat, cynomolgus, and human plasma.
Based on these screens, we identified several novel, previously unreported peptide linker designs and incorporated them into ADCs bearing a DNA-alkylating indolinobenzodiazepine (IGN) payload. These ADCs with different peptide linkers were assayed for in vitro cytotoxicity in multiple cancer cell lines, in vivo efficacy in human tumor xenograft models in mice, and ex vivo plasma stability. In addition, we measured the impact of peptide linkers on the kinetics of proteolytic processing of ADCs in cancer cell lines. We observed that several dipeptide linker designs were superior in rates of lysosomal processing compared to a reference standard L-Ala-L-Ala dipeptide linker.
Citation Format: Paulin Salomon, Luke Harris, Emily E. Reid, Erin K. Maloney, Alan J. Wilhelm, Michael L. Miller, Ravi V. Chari, Thomas A. Keating, Rajeeva Singh. Optimizing lysosomal activation of antibody-drug conjugates (ADCs) by incorporation of novel cleavable dipeptide linkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 231.
Abstract 2315: Alteration of tumor metabolism by CD4+ T cells leads to TNF-α-dependent intensification of oxidative stress and tumor cell death
Authors: Ding Zhichun , Habtetsion Tsadik , Zhou Gang 
Published: August 2019

Abstract
The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathionedepletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy.
Citation Format: Zhichun Ding, Tsadik Habtetsion, Gang Zhou. Alteration of tumor metabolism by CD4+ T cells leads to TNF-α-dependent intensification of oxidative stress and tumor cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2315.