bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 417: Identification of next-generation EGFR degraders to treat non-small cell lung cancer (NSCLC) patients
Authors: Ki Dong Hyuk , Nam Joonwoo , Kim Eunjung , Choi Hunmi , Kim Chulwon , Kim Jiyeon , Jin Jimmy , Kang Sang-Uk , Han Wooseok 
Published: June 2022

Abstract
Although EGFR-targeted tyrosine kinase inhibitors (TKIs) developed over a couple of decades have made great progress in the treatment of EGFR-mutant driven NSCLC, patients are at great risk to their lives due to drug resistance caused by constantly emerging EGFR mutations. Targeted protein degraders (TPDs), also known as heterobifunctional protein degraders or PROteolysis TArgeting Chimeras (PROTACs), have drawn great attention as a new modality to overcome drug resistance by achieving selective degradation of disease-causing proteins, like an EGFR mutant protein, which are required for the survival and proliferation of various malignant tumor cells. Therefore, we have developed a series of EGFR mutant degraders using BBT-176, a 4th generation EGFR TKI developed by Bridge BioTherapeutics, and novel EGFR inhibitors as warheads which are expected not only to treat various EGFR mutated NSCLC including C797S but also to delay drug resistant-mechanisms by further mutations in the EGFR TKI target site.
We synthesized a set of heterobifunctional degraders applying Cyrus BiFx Degrader (CBD) library platform containing different types of linkers and E3 ligase binders. DC50 (half-maximal degradation concentrations) values of the EGFR degraders were obtained in multiple human EGFR mutant NSCLC cell lines, where C-2051, C-2482, and C-4383 showed excellent EGFR degradation potency (DC50 = 7-25 nM, Dmax at 100 nM = 80-97%) with high selectivity against WT EGFR. Among those compounds, C-4383 was potent in cell viability assays with EGFR mutant HCC827 (Del19) and NCI-H1975 (L858R, T790M) cell lines showing a range of GI50 values from 77 to 81 nM at 72 h of compound exposure. By contrast, the compound was much less potent in A549 cells harboring wild-type EGFR (GI50 value at 72 h of treatment, 4.2 μM). We also performed proteomic analysis of C-4383 in H1975 cells resulting that EGFR was the most degraded protein with no off-target events at 100 nM (Dmax dose). A PK study of C-4383 in rats showed good exposure with moderate CL when administered intravenously (CL = 8.51 mL/min/kg, AUC = 5911 ng•h/mL).
In summary, we identified heterobifunctional degraders using a 4th generation EGFR inhibitor, BBT-176, that are active in EGFR mutant NSCLC cells harboring single or C797S-containing multiple mutations. We are currently making our efforts on the improvement of physicochemical properties of EGFR mutant targeted heterobifunctional compounds.
Citation Format: Dong Hyuk Ki, Joonwoo Nam, Eunjung Kim, Hunmi Choi, Chulwon Kim, Jiyeon Kim, Jimmy Jin, Sang-Uk Kang, Wooseok Han. Identification of next-generation EGFR degraders to treat non-small cell lung cancer (NSCLC) patients [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 417.
Abstract 4172: rhIL-7-hyFc (efineptakin alpha; NT-I7) enhances the anti-tumor response when combined with anti-TIGIT or anti-VEGF
Authors: Baek Seungtae , Im Sun-Kyoung , Lee Minji , Ji Mankyu , Kim Miyoung , Lee Kwang-Hoon , Choi Yun Hee , Kim Won Tae , Choi Donghoon 
Published: June 2022

Abstract
rhIL-7-hyFc (efineptakin-alfa; NT-I7) is a potent T cell amplifier, with a homodimeric interleukin-7 (IL-7) fused to the hybridizing IgD/IgG4 immunoglobulin domain. Previous work has shown that in mice, NT-I7 dramatically increases tumor-infiltrating CD8+ T cells while reducing the frequency of PD-1+ CD8+ T cells in the tumor. There is also significant expansion of Central Memory (CM)-phenotype CD8+ T cells (CD62L+CD44+) in the tumor and tumor draining lymph node. Here, we investigated the anti-tumor effect of NT-I7 in combination with two different T cell suppressor blockades; anti-TIGIT (YH29143) and anti-VEGF (Aflibercept) in MC38 tumor-bearing mice. NT-I7 was administered by intramuscular injection with the first dose of either YH29143 or Aflibercept. YH29143 or Aflibercept was administered every 3 days for 3 total doses, via intraperitoneal or intravenous route, respectively. The combination of NT-I7 with either T cell suppressor blockade enhanced the anti-tumor response. Surprisingly, NT-I7 combined with YH29143 increased the frequency of PD-1+TCF-1+TOX-CD39- stem-like CD8+ T cells in the draining lymph node. The combination also dramatically increased the frequency of CD62L-CD44+ effector memory CD8+ T cells in the tumor. Surprisingly, NT-I7 combined with YH29143 increased the frequency of PD-1+TCF-1+TOX-CD39- stem-like CD8+ T cells in the draining lymph node. In addition, Aflibercept reduced the expression of TOX in PD-1+ CD8+ T cells in the tumor. Our data suggests that NT-I7 can be applied in combination with other immunotherapies such as anti-TIGIT or anti-VEGF to enhance the anti-tumor response.
Citation Format: Seungtae Baek, Sun-Kyoung Im, Minji Lee, Mankyu Ji, Miyoung Kim, Kwang-Hoon Lee, Yun Hee Choi, Won Tae Kim, Donghoon Choi. rhIL-7-hyFc (efineptakin alpha; NT-I7) enhances the anti-tumor response when combined with anti-TIGIT or anti-VEGF [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 4172.
Abstract 4175: Combining a novel MEK inhibitor with immunomodulation to promote an anti-tumor response
Authors: Dong Lauren , Choi Hyejin , Budhu Sadna , Schulze Isabell , Verma Svena , Mehanna Nezar , Rosen Neal , Merghoub Taha , Wolchok Jedd 
Published: June 2022

Abstract
To enhance the therapeutic scope of MEK inhibitors (MEKis), we aim to develop new strategies to extend their usage to MEKi resistant RAS mutant cancers, which represent an unmet clinical need. CH5126766 (CKI27) binds the allosteric site of MEK to inhibit its kinase activity but is novel due to its interaction with MEK S218 and 228, which blocks their phosphorylation by RAF. CKI27 bound MEK binds to RAF and cannot be released by phosphorylation, thus becoming a dominant negative inhibitor of RAF activation. This prevents the induction of MEK phosphorylation observed with other MEKis. Although this results in more potent tumor control, CKI27 is also capable of inhibiting T cell function because the MAPK/ERK pathway is activated downstream of T cell receptor signaling. We aim to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. We observed that CKI27 increased MHC expression on tumor cells and improved T cell mediated killing. Yet, CKI27 also decreased T cell proliferation, activation, and cytolytic activity. Intermittent administration of CKI27 allowed T cells to recover and partially relieved these inhibitory effects. Further combination with agonist antibodies anti-OX40 and GITR completely alleviated T cell inhibition and increased combination efficacy with immune checkpoint blockade antibody anti-CTLA-4. We also observed an increase in proliferation and T cell activation markers in LLC tumor bearing mice treated with the combination of CKI27, anti-GITR, and anti-CTLA-4. Understanding the immunomodulatory effects of combining CKI27 with immunotherapy will elucidate the mechanism behind this increased efficacy. This will allow us to make more informed decisions in dosing regimens, overcoming resistance, and generating long-term immune responses in future clinical trials treating patients with RAS mutant cancers.
Citation Format: Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Nezar Mehanna, Neal Rosen, Taha Merghoub, Jedd Wolchok. Combining a novel MEK inhibitor with immunomodulation to promote an anti-tumor response [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 4175.
Abstract 4231: Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment
Authors: Liu Arthur J. , Curran Michael A. 
Published: June 2022

Abstract
Pancreatic cancer patients remain largely unresponsive to single agent immune checkpoint blockade (ICB) therapy. This refractory state originates from PDAC’s unique immunosuppressive microenvironment that is densely populated by suppressive myeloid cells, exhibits poor vascularity, and is highly hypoxic. We previously showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) reduces intratumoral hypoxia through a tissue remodeling process, initiates tumor vasculature reorganization, and sensitizes aggressive, spontaneous murine models of prostate cancer to ICB. In a clinical trial testing the combination of Evofosfamide with cytotoxic T-lymphocyte-associated protein (CTLA-4) blockade (NCT03098160) a subset of metastatic, immune checkpoint blockade refractory patients showed prolonged progression free survival. While these studies highlight hypoxia reduction as therapeutically tractable, we lack complete understanding of the contribution of the tumor vasculature to hypoxia reduction therapy, as well as the downstream consequences of hypoxia reduction on the cellular composition of the tumor microenvironment and the responsiveness to immunotherapy.
We used a transplantable, orthotopic pancreatic tumor model derived from Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre mice and a syngeneic prostate tumor model to study tumor responses to hypoxia-reduction, anti-angiogenic therapy, and combination immunotherapy.
We find that Evofosfamide with anti-VEGFR-2 (DC101) significantly extends mouse survival. Combination therapy reduces intratumoral hypoxia, improves vessel integrity, and increases intratumoral DNA damage. In response to the improved metabolic microenvironment, CD8 T cells gain enhanced effector function and lose expression of exhaustion-associated features. Like other anti-angiogenic regimens, combination Evofosfamide and DC101 leads to an increased frequency of PD-L1 expressing cells within the tumor, however blockade of PD-1 failed to prolong survival. Bulk-tumor RNA sequencing and tumor infiltrating lymphocyte analysis implicates immature myeloid cells as mediators of resistance. Re-education of the infiltrating myeloid stroma with CD40 agonist could improve responses to hypoxia-reducing, anti-angiogenic therapy. Put together, these data indicate that targeted hypoxic reduction with anti-angiogenic therapy remodels the pancreatic tumor microenvironment. In this setting, CD40 agonist over PD-1 blockade provides an additive benefit in prolonging mouse survival.
Citation Format: Arthur J. Liu, Michael A. Curran. Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment [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 4231.
Abstract 4245: QL301, a PD-L1 dependent 4-1BB agonist with enhanced preclinical anti-tumor efficacy and minimal liver toxicity
Authors: Gu Shenda , Tang Irene , Mihardja Shirley , Prior Wei Wei , Tran Hieu V. , Chan Allan , McClain Anna , Kurtzman Aaron , Chen Shihao , Luo Youguang , Kang Xiaoyan , Wu Xiaoran , Zheng Qingmei , Jia Guodong 
Published: June 2022

Abstract
4-1BB (CD137, TNFRSF9) is a potent co-stimulatory receptor found on T and NK cells. Activation of 4-1BB requires receptor clustering, which is naturally mediated by the endogenous trimeric 4-1BB ligand. Cross-linking via agnostic monoclonal antibodies can also activate 4-1BB but has generally resulted in unwanted side effects, mainly liver toxicity. To address the shortcomings of 4-1BB agonists, we have developed QL301, a PD-L1 x 4-1BB bispecific antibody that conditionally activates 4-1BB only when concurrently engaged to PD-L1, an immune checkpoint mediator elevated in the immuno-suppressive tumor microenvironment. The IgG1 backbone of QL301 was mutated to eliminate Fc gamma receptor-dependent functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), thereby preventing depletion of effector immune cells and non-specific activation of 4-1BB through Fc gamma receptor binding. In addition, QL301 blocks the suppressive interaction of PD-1 with PD-L1. Therefore, through a combination of 4-1BB agonism and PD-L1 blockade, QL301 provides both a co-stimulatory signal and the release of a suppressive signal to reinvigorate anti-tumor immune response. In vitro, QL301 induced robust cytokine release and expansion of CD8+ T cells conditional on the presence of tumor or antigen presenting cells expressing PD-L1. In xenograft and transgenic mice models, QL301 had potent anti-tumor effect that was superior to PD-L1 monoclonal antibodies. Tumor regression correlated with the expansion of CD8+ T cells. In addition, QL301 potentiated tumor cell killing mediated by an EGFR targeted CD3 bispecific antibody, providing a basis for combination therapy. In non-human primates, QL301 was well tolerated up to 30 mg/kg. There was no chronic elevation of serum AST and ALT levels, and histopathology analysis showed minimal inflammation of liver tissue. A phase 1 clinical trial to evaluate the safety, tolerability, and early efficacy of QL301 is currently ongoing.
Citation Format: Shenda Gu, Irene Tang, Shirley Mihardja, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Aaron Kurtzman, Shihao Chen, Youguang Luo, Xiaoyan Kang, Xiaoran Wu, Qingmei Zheng, Guodong Jia. QL301, a PD-L1 dependent 4-1BB agonist with enhanced preclinical anti-tumor efficacy and minimal liver 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 4245.
Abstract 4256: YH012, a novel bispecific anti-HER2 and TROP2 antibody-drug conjugate, exhibits potent antitumor efficacy
Authors: Shang Chengzhang , Yang Liu , Zhang Jiyong , Han Yanfei , Li Zhuolin , Han Zhenyan , Li Jun , Meng Ying , An Gao , Yang Hao , An Wenqian , Chen Lei , Charpentier John 
Published: June 2022

Abstract
Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) are among the most promising and fastest growing classes of next-generation antibody therapeutics for cancer therapy. The strategy of targeting dual tumor-associated antigens (TAAs) with a BsAb offers several advantages, such as improved efficacy due to synergistic effects, increased target cross-linking and internalization, increased tumor cell specificity and reduced side effects in normal tissues. HER2 is an established therapeutic target for approximately 20% of breast cancers, and its overexpression has been observed in a variety of other solid tumors. Trop-2 is another ideal tumor-associated target overexpressed on a wide variety of solid tumors. Co-expression of HER2 and TROP2 has been found in a number of tumors including gastric, colorectal, bladder and breast cancers. Therefore, co-targeting these TAAs using bispecific antibodies has clinical potential. YH012 is a novel first-in-class bispecific antibody-drug conjugate targeting HER2-TROP2 (HER2-TROP2-ADC), which contains a novel fully human bispecific anti-HER2/TROP2 antibody conjugated with Monomethyl auristatin E (MMAE) via a protease-cleavable linker. The anti-HER2/TROP2 BsAb showed increased endocytosis activity compared with its parental mAbs in tumor cells co-expressing HER2/TROP2, whereas the monovalent HER2 or TROP2 antibodies showed reduced internalization. As expected, YH012 showed increased in vitro potency of cell killing compared to the monovalent HER2/TROP2-ADC. These results suggest that YH012 increases the selectivity of payload delivery demonstrating the beneficial effects of targeting dual TAAs using BsAb-ADC. Moreover, YH012 showed robust anti-tumor efficacy in multiple cell line-derived none-small cell lung cancer (NSCLC) and gastric xenografts. Treatment with YH012 showed sustained tumor growth inhibition, which is more pronounced than the effects of the parental mAb-ADCs and monovalent ADCs. These preclinical data suggest that YH012 could potentially benefit patients with tumors co-expressing HER2 and TROP2 through improved drug selectivity and efficacy. Further investigations on the antitumor activity and safety profile of YH012 are ongoing in dogs.
Citation Format: Chengzhang Shang, Liu Yang, Jiyong Zhang, Yanfei Han, Zhuolin Li, Zhenyan Han, Jun Li, Ying Meng, Gao An, Hao Yang, Wenqian An, Lei Chen, John Charpentier. YH012, a novel bispecific anti-HER2 and TROP2 antibody-drug conjugate, exhibits potent antitumor efficacy [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 4256.
Abstract 461: Mixed supervision to improve the classification and localization: Coherence of tumors in histological slides
Authors: Tourniaire Paul , Ilie Marius , Hofman Paul , Ayache Nicholas , Delingette Hervé 
Published: June 2022

Abstract
With the growing standardization of Whole Slide Images (WSIs), deep learning algorithms have shown promising results for the automated classification and localization of tumors. Yet, it is often difficult to train such algorithms, as they usually require careful detailed annotations from expert pathologists, which are tedious to produce. This is why in general only slide-level labels are accessible while annotations of small regions (or tiles) are limited. With only slide-level information, it is difficult to obtain accurate predictions of the localization of pathological tissues inside a slide, despite reaching good slide-level classification. Besides, existing algorithms show limited consistency between slide- and tile-level predictions, leading to difficult interpretation in case of healthy tissue. Using the attention-based multiple instance learning framework, we propose to combine slide-level labels on all slides with tile-level labels on a small fraction (e.g. 20%) of slides within a histology dataset to improve both classification and localization performances. With this mixed supervision of slides, we aim to enforce a better consistency between slide- and tile-level labels. To this end, we introduce an attention-based loss function to further guide the model’s attention on discriminative regions inside tumorous slides, and display an equal attention among all tiles of normal slides. On the Camelyon16 dataset, we reached precision and recall scores as high as 0.99 and 0.85 respectively with an AUC of 0.93 on the competition test set, using only 50% of the slides with tile-level annotations in the training set. Experiments using various proportions of fully annotated slides in the training set show promising results for an improved localization of tumors and classification of slides. In this work, we showed that using a limited amount of fully annotated slides we can improve both the classification and localization performances of an attention-based deep learning model. This increased consistency and performances should help pathologists to better interpret the algorithm output and to focus on suspicious regions in probable tumorous slides.
Citation Format: Paul Tourniaire, Marius Ilie, Paul Hofman, Nicholas Ayache, Hervé Delingette. Mixed supervision to improve the classification and localization: Coherence of tumors in histological slides [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 461.
Abstract 479: The role of diffusion in molecular networks: Diffusion coefficients in describing the development of cancer
Authors: Garimella Narayana 
Published: June 2022

Abstract
To study and forecast the developments of cancers, the molecular networks, compositional fluctuations, diffusion in networks and altogether the biological processes resulting at cellular and intracellular levels, are highly important. Focusing on diffusion coefficients as the translational biomarkers to quantify the nucleation and growth of tumors and cancers has potential advantages. Because, diffusion coefficients act as guiding tools in preventing or treating the cancers and associated adversities. Collectively the biological, pharmacological and toxicological indicators during and prior to the course of cancer are taken as measures for the data over specific distances of the molecules to determine diffusion coefficients. Because, multiple mechanisms are simultaneously responsible in altering the compositions. In this work, the mass transportation in both healthy individuals and cancer patients are taken into account to compare and contrast the initiation and spread of cancers in the light of immunology and immunotherapy. Measurements through incoherent motion diffusion-weighted imaging (IVIM-DWI) and echo planar magnetic resonance (MR) imaging are applied in determining the diffusion parameters. Diffusion coefficients were within the ranges of 0.1 to 5 X 10-3 mm2/sec. Perfusion played important role in quantifications. Magnitudes of diffusion coefficients are used to forecast biological prevalence and to develop prevention and treatment therapeutics.
Citation Format: Narayana Garimella. The role of diffusion in molecular networks: Diffusion coefficients in describing the development of 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 479.
Abstract 490: De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens
Authors: Weiskittel Taylor , Correia Cristina , Ung Choong , Zhang Cheng , Li Hu 
Published: June 2022

Abstract
Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline which collects potent disease gene cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo which enable us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of notorious cancer drivers TP53 and PIK3CA fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations, and that rarely mutated genes such as XPO1 and PLEKHA1 have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies which were highly varied across patients demonstrating the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals.
Citation Format: Taylor Weiskittel, Cristina Correia, Choong Ung, Cheng Zhang, Hu Li. De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens [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 490.