tbuckley/cabot-search huggingface dataset:
Abstract 4852: CBLC functions as a novel therapeutic target to enhance the efficacy of paclitaxel on EGFR wild-type lung adenocarcinoma by downregulating AURKA
Authors: Shiao-Ya Hong, Yu-Rung Kao, Yi-Ping Lin, Meng-Hsuan Lee, Jyun-Yi Wu, Cheng-Wen Wu
Journal: Cancer Research (2020)

Abstract Patients with lung adenocarcinoma harboring driver genes can be treated with target therapies, such as tyrosine kinase inhibitors for epithelial growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) inhibitors for ALK gene rearrangements, and so on. However, a large portion of lung adenocarcinoma patients, especially for those with wild-type EGFR, still do not have valid target therapies in clinics. The CBL family proteins (CBL, CBLB, and CBLC) are E3 ubiquitin ligases of protein tyrosine kinases (PTKs), including EGFR, hepatocyte growth factor receptor (MET), and SRC proto-oncogene (SRC). It has been reported that the K63-linkaged ubiquitination mediated by CBL can negatively regulate activated EGFR (aEGFR) signaling through lysosomal degradation. Previously, we discovered that CBLC, unlike CBL, possesses an oncogenic function and positively regulates aEGFR stability through polyubiquitination via K6 and K11 linkages. The CBLC-mediated conjugation of polyubiquitin promotes aEGFR preferentially recycled back to the plasma membrane, or trafficked to the cell nucleus, leading to the sustained activation of EGFR signaling in lung adenocarcinoma. Aside from aEGFR dysregulation, we recently found that CBLC assumes a novel role in positively regulating the expression of Aurora kinase A (AURKA), which contributes to tumor development by promoting cell proliferation, metastasis, epithelial-mesenchymal transition, and drug resistance. In lung adenocarcinoma cells with wild-type EGFR, CBLC knockdown significantly reduced cell viability, delayed cell cycle progression and increased apoptotic death. Our study also showed that CBLC knockdown in EGFR wild type cells was associated with increased sensitivity to paclitaxel, probably through downregulating AURKA. Taken together, these findings indicated that CBLC may play a role in promoting cell cycle progression and may be a novel therapeutic target to enhance the efficacy of paclitaxel on EGFR wild-type lung adenocarcinoma. Citation Format: Shiao-Ya Hong, Yu-Rung Kao, Yi-Ping Lin, Meng-Hsuan Lee, Jyun-Yi Wu, Cheng-Wen Wu. CBLC functions as a novel therapeutic target to enhance the efficacy of paclitaxel on EGFR wild-type lung adenocarcinoma by downregulating AURKA [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4852.
Abstract 4302: Molecular profile of KRAS G12C-mutant non-small-cell lung cancer and colorectal cancer in Brazilian patients
Authors: Bianca Mendes Souza, Laura Rabelo Leite, Sabrina A. Parma, Natália P. Lopes, Frederico S. Malta, Luiz Henrique Araujo, Maíra C. Freire
Journal: Cancer Research (2020)

Abstract Background: Cancer is one of the leading causes of death and one of the main barriers to increasing life expectancy worldwide. The development of therapeutic strategies directly targeting mutant oncogenes, such as EGFR and BRAF, has resulted in substantial benefits for patients with a variety of cancers. KRAS is one of the most frequently mutated oncogenes, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) from Brazilian patients tested in a clinically-certified laboratory. Methodology: 4,842 NSCLC patients were tested for KRAS, NRAS, EGFR and BRAF mutations by next generation sequencing (NGS), while 4,815 CRC patients were tested for KRAS and NRAS mutations, by pyrosequencing, between 2017 and 2019 Results and Discussion: From the 4,842 NSCLC samples tested, KRAS G12 mutations were identified in 1013 cases (20.9%) and, 336 of these (6.9% of total) were KRAS G12C. Additionally, from 4,815 CRC samples tested, KRAS G12 mutations were identified in 1633 cases (33.9%), and 166 of these (3.4% of total) were KRAS G12C. In the literature, KRAS G12C has been reported in 14 to 16% of all lung adenocarcinomas, and 5% of colorectal adenocarcinomas. Our data illustrate a relevance of this mutation in a significant number of patients and highlight an opportunity for targeted therapy. Some studies characterizing lung cancers have indicated that KRAS mutations, including KRAS G12C, are mutually exclusive with other known oncogenic driver mutations in NSCLC. However, in the current analysis, we identified 30 cases of NSCLC harboring multiple mutations, such as KRAS G12C mutations co-existing with EGFR, BRAF or NRAS mutations. This finding is probably due to the multiclonal presentation in selected cases. Conclusions: A relatively high number of patients may present with KRAS G12C-mutant cancers in Brazil, indicating the relevance of identifying such cases for targeted therapy. Further studies will deepen the analysis of clonality and heterogeneity in this cohort. Citation Format: Bianca Mendes Souza, Laura Rabelo Leite, Sabrina A. Parma, Natália P. Lopes, Frederico S. Malta, Luiz Henrique Araujo, Maíra C. Freire. Molecular profile of KRAS G12C-mutant non-small-cell lung cancer and colorectal cancer in Brazilian patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4302.
Five-Year Follow-up of First 11 Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure
Authors: Kohsaku Numa, Kojiro Imai, Morio Ueno, Koji Kitazawa, Hiroshi Tanaka, John D. Bush, Satoshi Teramukai, Naoki Okumura, Noriko Koizumi, Junji Hamuro, Chie Sotozono, Shigeru Kinoshita
Journal: Ophthalmology (2020)

To report the safety and efficacy of a novel cell injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions via the report of the long-term 5-year postoperative clinical data from a first-in-humans clinical trial group.Prospective observational study.This study involved 11 eyes of 11 patients with pseudophakic endothelial failure conditions who underwent hCEC injection therapy between December 2013 and December 2014.All patients underwent follow-up examinations at 1 week, 4 weeks, 12 weeks, and 24 weeks and 1 year, 2 years, 3 years, 4 years, and 5 years after surgery. Specific corneal endothelial cell parameters (i.e., corneal endothelial cell density [ECD], coefficient of variation of area, and percentage of hexagonal cells) and central corneal thickness, best-corrected visual acuity (BCVA) on a Landolt C eye chart, and intraocular pressure (IOP) were recorded.The primary outcome was the change in central ECD after cell injection therapy, and the secondary outcome was corneal thickness, BCVA, and IOP during the 5-year-postoperative follow-up period.At 5 years after surgery, normal corneal endothelial function was restored in 10 of the 11 eyes, the mean ± standard deviation central corneal ECD was 1257 ± 467 cells/mm2 (range, 601-2067 cells/mm2), BCVA improved significantly in 10 treated eyes, the mean visual acuity changed from 0.876 logarithm of the minimum angle of resolution before surgery to 0.046 logarithm of the minimum angle of resolution after surgery, and no major adverse reactions directly related to the hCEC injection therapy were observed.The findings in this study confirmed the safety and efficacy of cultured hCEC injection therapy for up to 5 years after surgery.
Abstract 4227: Safety of dendtritic cell and cytokine-induced killer(DC-CIK) cell based immunotherapy in patients with solid tumor: A large retrospective study in China
Authors: Shuo Wang, Jun Ren
Journal: Cancer Research (2020)

Abstract Background: Adoptive T cell therapy especially cytokine-induced killer cell and dendric cell treatment (DC-CIK) alone or combined with chemotherapy had significantly improved patient survival time. Although some side effects studies were briefly reported in some articles. However, systematic assessment of the adverse side effects for DC-CIK therapy, especially combined with chemotherapy has not been reported. Patients and Methods: Totally 1099 consecutive patients (2054 trail cycles) enrolled in DC-CIK treatment trials at Beijing Shijitian hospital between August 2012 and August 2018 were retrospectively reviewed, and applying Common Terminology Criteria for Adverse Events version 4.0 [CTCAE v4.0] standards to definite adverse effects (AE). Result: The 370 patients (34%)/ 815 cycles enrolled in our trail combined with chemotherapy. In total, there were 548(cases)/870(cycles) had AEs. The AE class mainly composed of Neurological 34 cycles (4%), Musculoskeletal 28 cycles (3%), Immunopathies 5 cycles(1%), Hematological 521 cycles(60%), General disorders and Administration site conditions 224 cycles(26%), Gastrointestinal 209 cycles(24%), Skin 15 cycles(2%), Metabolism and Nutrition disorders 119 cycles(14%). AE class of the Gastrointestinal (vomiting P=0.025), Nutrition disorders (anorexia P=0.016) and Hematological (anemia P&amp;lt;0.0001, leukopenia P&amp;lt;0.0001) appears in the DC-CIK treatment were mainly correlated with combined with chemotherapy. Multiple logistic regression analysis suggests that no matter whether DC-CIK was combined with chemotherapy, multi-line treatment was more prone to nausea, anorexia, fatigue, anemia and leukopenia than the first-line treatment. However, correlation analysis verified that increasing cycles of only DC-CIK treatment could reduce the incidence rate of fatigue (P=0.001), anorexia (P&amp;lt;0.0001) and anxiety (P=0.01). Conclusion: Most of the adverse side effects that occur during autologous DC-CIK treatment were associated with combined or previously applied chemotherapeutic treatment, which also indicates that autologous DC-CIK anti-tumor therapy was safe. At the same time, the application of DC-CIK alone treatment could also reduce the occurrence rate of some side effects. Citation Format: Shuo Wang, Jun Ren. Safety of dendtritic cell and cytokine-induced killer(DC-CIK) cell based immunotherapy in patients with solid tumor: A large retrospective study in China [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4227.
Abstract 376: Intravital microscopy reveals HER2-dependent and -independent effects of myeloid cells on the single-cell biodistribution of trastuzumab
Authors: Ran Li, Ralph Weissleder, Miles A. Miller
Journal: Cancer Research (2020)

Abstract Advents in single-cell profiling have revealed that tumor tissues are highly heterogenous, and this cell-to-cell heterogeneity can greatly affect therapeutic efficacy. This is especially true for monoclonal antibody (mAb) therapies that exhibit variability in both delivery and action within solid tumors. Moreover, recent studies have highlighted the importance of tumor microenvironment in determining mAb responses. Yet, it has been traditionally difficult to analyze the kinetics of mAb biodistribution and delivery at a single-cell resolution, as well as how mAb interacts with tumor-associated stromal cells in vivo. To address these issues, we developed a high-resolution intravital microscopy (IVM) pipeline to study single-cell pharmacokinetics and pharmacodynamics of mAb in a tumor consists of cancer cells with variable target expression. We applied this imaging strategy to track the in vivo binding of trastuzumab (Tzm), a HER2-targeting mAb, to fluorescently-labeled HER2 in the heterogenous tumor microenvironment. We observed efficient binding of Tzm to HER2+ cancer cells, and the amount of Tzm on cancer cells correlated with HER2 expression level. We also discovered a large accumulation of Tzm in tumor-associated macrophages (TAMs). Time-lapse IVM imaging further revealed an increase in Tzm uptake in TAMs over the period of 72 hrs, with concomitant decrease in Tzm level on the HER2+ cancer cells. Further controlled experiments demonstrated that the baseline ability of TAMs to take up Tzm was not dependent on HER2 expression in the surrounding cancer cells, yet HER2 over-expression can increase the levels of Tzm in TAMs. All in all, these results revealed crucial roles that tumor-associated stromal cells play in mAb delivery and action. They also demonstrated the utility of IVM in dissecting mAb behaviors in heterogenous tumor microenvironment, which can significantly impact our understanding of mAb treatment efficacy. Citation Format: Ran Li, Ralph Weissleder, Miles A. Miller. Intravital microscopy reveals HER2-dependent and -independent effects of myeloid cells on the single-cell biodistribution of trastuzumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 376.
Abstract 3289: The status of the tumor microenvironment changes dynamics of the balance of CD8+ T cells and Treg cells in renal cell carcinoma
Authors: Daisuke Sugiyama, Tomoaki Muramatsu, Yoichi Kobayashi, Naoto Sassa, Shoichi Maruyama, Momokazu Goto, Yoshiki Akatsuka, Hiroyoshi Nishikawa
Journal: Cancer Research (2020)

Abstract Immune checkpoint inhibitors (ICIs) are widely applied into the clinic based on their remarkable clinical effectiveness. Tumor mutation burden (TMB) and PD-L1 expression in the tumor microenvironment (TME) have been shown to be correlated with clinical responses of ICIs. In contrast, immunosuppressive cells, especially regulatory T (Treg) cells, in the TME are thought to be associated with the resistance to ICI therapy. In this study, we investigated the role of Treg cells in the TME in renal cancer (RCC). We have previously reported that the RCCs can be classified into three groups based on the frequency of CD3+CD4+CD45RA+FoxP3highcells; effector/activated Treg (eTreg) cells: high: &amp;gt; 10%, moderate: &amp;gt; 5%, and low: &amp;gt; 0%, and high frequency of eTreg cells were correlated with the higher expression of PD-1, LAG-3, TIM-3 by CD8+ T cells. Based on the findings, we further investigated the frequency and phenotypes of Treg cells in the TME. We first compared flow cytometry analysis with immunohistochemistry analysis in the frequency of Treg cells. The frequency of Treg cells in the TME was well-correlated with FCM and IHC analyses. Then, the detailed phenotypes of tumor-infiltrating eTreg cells was examined. eTreg cells harbored high expression of activation markers such as TIGIT and CTLA-4, but low-moderate expression of exhausted molecules such as PD-1 and LAG-3. These data implicate that CD8+ T cells are exhausted, whereas Treg cells are activated in the TME. The clinical benefits by ICI therapy for RCC could be associated with the balance of CD8+ T cells and Treg cells. We are now analyzing the detailed mechanism controlling the balance to identify biomarkers of ICI therapy and to develop novel effective cancer immunotherapies. Citation Format: Daisuke Sugiyama, Tomoaki Muramatsu, Yoichi Kobayashi, Naoto Sassa, Shoichi Maruyama, Momokazu Goto, Yoshiki Akatsuka, Hiroyoshi Nishikawa. The status of the tumor microenvironment changes dynamics of the balance of CD8+ T cells and Treg cells in renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3289.
Abstract 6591: Antibody-based redirection of meditope-CAR T cells selectively kill antigen bearing tumor cells
Authors: Yi-Chiu Kuo, Jeremy D. King, Cheng-Fu Kuo, Victor Kenyon, Miso Park, Wen-Chung Chang, Lawrence Stern, Christine E. Brown, John C. Williams
Journal: Cancer Research (2020)

Abstract Adoptive T cell transfer of engineered T cells with a chimeric antigen receptor (CAR) can harness the patients' immune system to recognize a specific antigen and redirect T cells to target disease. Conventional CAR T cells, however, are specific to a single antigen. While remarkably effective, antigen escape, due in part to the heterogeneous nature of a tumor, renders these CAR T cells ineffective. In order to address the disadvantage of conventional CAR T cells, we developed a switchable CAR T cell system. Specifically, we replaced the antigen-binding domain of a conventional CAR with a meditope and used meditope-enabled monoclonal antibodies (memAbs) to alter antigen specificity. As the T cell decoration is similar to how a bike rack is used to transport bicycles on cars, we have coined the technology a Fabrack. To fully examine our switchable CAR T cell system, Fabrack CAR Jurkat-NFAT-Luc cells were established to quantitate T cell activation through NFAT-regulated luciferase expression. Multiple memAbs with unique antigen specificity were combined with the Fabrack CAR Jurkat cells and target tumor cells and demonstrated the feasibility, specificity and robustness of the in vitro system. Next, native human T cells transduced with Fabrack showed dramatic tumor-killing effect when coupled with an antigen specific memAb. The engaged Fabrack T cells proliferated with remarkably increased CD107a and IFNγ, indicating functional activation of T cells. Live cell imaging demonstrated selective killing of target cells in the presence of corresponding memAbs. Furthermore, tumor burden in immunocompromised mice with OVCAR3 xenografts was largely reduced when mice were treated with Fabrack T cells and memAbs. Collectively, these studies suggest the feasibility of switchable CAR T cell and support further development for future clinical use in cancer immunotherapy. Citation Format: Yi-Chiu Kuo, Jeremy D. King, Cheng-Fu Kuo, Victor Kenyon, Miso Park, Wen-Chung Chang, Lawrence Stern, Christine E. Brown, John C. Williams. Antibody-based redirection of meditope-CAR T cells selectively kill antigen bearing tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6591.
Abstract 2885: Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window
Authors: Ryan Lyski, Lauren Bou, Margo Zaval, Kim Emmerton, Nicole Okeley, Jessica Simmons, Francisco Zapata, David Ortiz, Erica McKinney, David Meyer, Maureen Ryan, Peter Senter, Scott Jeffrey
Journal: Cancer Research (2020)

Abstract In efforts to bring forward antibody-drug conjugate (ADC) technologies that complement vedotin and enable new clinical-stage ADCs, we have investigated compounds that interact with topoisomerase 1, an enzyme involved in the unwinding of DNA. In connection with this, we developed a highly active and well-tolerated camptothecin drug-linker technology, in which the lead molecule consists of 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT) attached to a protease-cleavable valine-lysine-glycine (VKG) tripeptide linker unit. A hydrophilic and discrete polyethylene glycol unit was included to improve the properties of the drug-linker, enabling high ADC drug-loading, and reducing the propensity for aggregation. A VKG-AMDCPT ADC, with 8 drug-linkers/mAb (DAR8), displayed a pharmacokinetic profile coincident with parental unconjugated antibody, with a high degree of stability against retro-Michael reaction deconjugation. ADCs based on the VKG-AMDCPT were broadly active against cancer cells in vitro, and in mouse xenograft models, giving tumor regressions and complete responses with a single ≤3 mg/kg dose. These included both solid and hematologic tumor models, and models of bystander killing activity and multidrug resistance. A non-binding DAR8 ADC was well-tolerated in rats at 60 mg/kg, q7dx4. The VKG-AMDCPT drug-linker can be prepared from available materials in eight high-yielding steps, and this drug-linker is being employed in the anti-CD30 ADC, SGN-CD30C; an investigational new drug application is planned for 2020. Citation Format: Ryan Lyski, Lauren Bou, Margo Zaval, Kim Emmerton, Nicole Okeley, Jessica Simmons, Francisco Zapata, David Ortiz, Erica McKinney, David Meyer, Maureen Ryan, Peter Senter, Scott Jeffrey. Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2885.
Abstract 5790: An epigenome-wide gene-age interaction analysis reveals opposite effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients
Authors: Li Su
Journal: Cancer Research (2020)

Abstract Introduction: Aging has become a global public health concern. The number of elderly lung cancer patients increased and elderly comprise the majority (81%) of non-small cell lung cancer (NSCLC) patients. DNA methylation is a potential prognostic biomarker for NSCLC, while it is also associated with aging. However, whether the association between DNA methylation and NSCLC survival is modified by aging is not known. Methods: After quality control procedures, we used a two-stage study design to identify DNA methylation-age interaction that associated with overall survival (OS) for early-stage adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients from four international collaborating study centers. In the discovery phase, we investigated the interaction effect in LUAD and LUSC using Cox proportional hazards model, adjusted for covariates. We confirmed the significant interactions with Bonferroni adjusted P ≤ 0.05 were further confirmed in the validation phase using The Cancer Genome Atlas (TCGA) database. Results: A total of 1,230 LUAD and LUSC patients were eligible for the study and 311,981 DNA methylation loci were evaluated. There were 613 (NLUAD = 492 and NLUSC = 121) patients in the discovery phase, and 617 (NLUAD = 332 and NLUSC = 285) patients in the validation phase, respectively. We identified one LUAD-specific CpG probe cg14326354PRODH, the effect on OS was significantly modified by age (HRinteraction = 0.989; 95% CI: 0.986-0.994; P = 9.18 × 10−7). The effect of DNA methylation on OS was different in young and elderly patients (young: HR = 2.44; 95% CI: 1.26-4.72; P = 8.34 × 10−3; elderly: HR = 0.58; 95% CI: 0.42-0.82; P = 1.67 × 10−3). Low methylation level benefited elderly LUAD patients. Moreover, there was an antagonistic interaction between low methylation of cg14326354PRODH and elder age (HRinteraction = 0.21; 95% CI: 0.11-0.40; P = 2.20 × 10−6). Conclusion: Low methylation of cg14326354PRODH may benefit the survival of elderly LUAD patients, providing new insight into only age-specific prediction, but also potential methylation-specific drug targeting. Citation Format: Li Su. An epigenome-wide gene-age interaction analysis reveals opposite effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5790.