bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 852: Index-based dietary patterns and risk of pancreatic ductal adenocarcinoma: Results from the NIH-AARP Diet and Health Study
Authors: Julián-Serrano Sachelly , Reedy Jill , Robien Kim , Stolzenberg-Solomon Rachael 
Published: July 2021

Abstract
Background: There is limited-suggestive evidence for individual dietary components, and few studies have examined whether dietary patterns are associated with pancreatic cancer risk.
Objective: We examined the associations between five established index-based dietary quality patterns and pancreatic ductal adenocarcinoma (PDAC) risk in middle aged and older US adults.
Methods: The Healthy Eating Index (HEI)-2015, Alternative HEI-2010 (AHEI-2010), alternate Mediterranean diet (aMED), and two Dietary Approaches to Stop Hypertension (DASH) scores (Fung et al. and Mellen et al.) were calculated using responses from a food frequency questionnaire data from 535,398 (315,780 men and 224,044 women) NIH-AARP Diet and Health Study participants aged 51-70 years at baseline (1995-1996). Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for PDAC risk according to each dietary pattern quintile. Covariates included in multivariable models were age, sex, smoking, body mass index, diabetes, and energy intake.
Results: During follow-up though 2011 (15.5 years median), 3,137 incident PDAC cases were identified. Participants with the highest adherence scores compared to those with the lowest adherence scores for each dietary pattern (Q5 versus Q1), had a significantly lower risk of PDAC, except for AHEI-2010: HRs (95% CIs) for HEI-2015 [0.84 (0.75, 0.94)], aMED [0.82 (0.73, 0.93)], DASH-Fung [0.86 (0.77, 0.96)], DASH-Mellen [0.86 (0.77, 0.99)] and AHEI-2010 [0.93 (0.83, 1.04)]. Sex-stratified analyses showed stronger results in men for the HEI-2015 [0.78 (0.68, 0.90)], DASH-Fung [0.78 (0.67, 0.91)], and DASH-Mellen [0.82 (0.71, 0.95)] indices. Only the aMED score remained statistically significantly associated with PDAC risk in women [0.76 (0.63, 0.92)]. Tests for interaction by sex were not significant (P-values &gt; 0.07).
Conclusions: In this analysis of dietary patterns and PDAC, we observed a 14-24% lower cancer risk with greater adherence to index-based dietary quality patterns. Our findings support the hypothesis that adherence to dietary recommendations such as the Dietary Guidelines for Americans, Harvard's Healthy Eating Plate, the Mediterranean Diet and the DASH diet may reduce the risk of developing PDAC
Citation Format: Sachelly Julián-Serrano, Jill Reedy, Kim Robien, Rachael Stolzenberg-Solomon. Index-based dietary patterns and risk of pancreatic ductal adenocarcinoma: Results from the NIH-AARP Diet and Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 852.
Abstract 925: Introduction to the preclinical profile of SYD1875, a novel site-specifically conjugated duocarmycin-based 5T4-targeting antibody-drug conjugate
Authors: Groothuis Patrick , Jacobs Danielle , Berentsen Kim , van der Vleuten Monique , Coumans Ruud , Elgersma Ronald , Blomenrohr Marion , van den Dobbelsteen Diels , Beusker Patrick , Ubink Ruud , van der Lee Miranda , Dokter Wim H.A. 
Published: July 2021

Abstract
5T4 is an oncofetal antigen with low expression in healthy tissues which is frequently overexpressed in different tumor types. Despite its overexpression in various malignancies and its association with poor prognosis, there are currently no marketed drugs that target this tumor antigen. We developed a novel antibody-drug conjugate (ADC), named SYD1875, comprising a humanized, HC41-cysteine-engineered IgG1 monoclonal antibody directed against 5T4, site-specifically conjugated to a proprietary cleavable synthetic duocarmycin-based linker-drug (vc-seco-DUBA). SYD1875 showed sub-nanomolar binding affinity to human and cynomolgus 5T4, rapid internalization, and induction of both target- and bystander-mediated cell killing. SYD1875 showed superior in vitro cytotoxicity and in vivo activity compared to A1-mcMMAF -also known as PF-6263507-, a 5T4-targeting ADC that is no longer in clinical development. A single dose of SYD1875 induced strong anti-tumor activity in patient-derived xenograft models of multiple tumor types with low, moderate and high 5T4 expression. The GLP toxicity study in cynomolgus monkey showed an acceptable toxicity and PK profile. A first-in-human dose-finding trial was initiated to evaluate safety and explore efficacy (NCT04202705).
Citation Format: Patrick Groothuis, Danielle Jacobs, Kim Berentsen, Monique van der Vleuten, Ruud Coumans, Ronald Elgersma, Marion Blomenrohr, Diels van den Dobbelsteen, Patrick Beusker, Ruud Ubink, Miranda van der Lee, Wim H.A. Dokter. Introduction to the preclinical profile of SYD1875, a novel site-specifically conjugated duocarmycin-based 5T4-targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 925.
Abstract 948: Preclinical evaluation of VEGF Ang2 bispecific nanobody BI836880 in patient-derived xenograft models of nasopharyngeal carcinoma
Authors: Wong Eric Chi , Lam Gigi , Wong Connie , Lam Rachel C. , Lo Kwok Wai , Hui Edwin Pun , Chan Anthony Tak , Ma Brigette B. 
Published: July 2021

Abstract
BI836880 is a humanized bispecific nanobody directed against angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF)-derived peptides, with selective and potent antiangiogenic and antineoplastic activities. It comprises of blocking domains that bind to Ang2 and VEGF and prevents Ang2- and VEGF-mediated signalling; thus, inhibits both angiogenesis and tumour cell proliferation. Tumor angiogenesis contributes to progression of nasopharyngeal cancer (NPC) and VEGF/receptor inhibitors agents have activity in NPC patients. In this study, the preclinical activity of a novel VEGF/Ang-2 bi-specific nanobody, BI836880, was evaluated in two NPC-PDX models - Xeno-2117 and Xeno-666. The effect of BI836880 on tumor growth was compared with the control, bevacizumab - an anti-VEGF antibody which has been evaluated in NPC patients. Tumor-bearing mice were randomized into three groups: vehicle control, 15mg/kg bevacizumab (b.i.w) and 15mg/kg BI836880 (b.i.w.). Drug was administered by intraperitoneal injection and the treatment duration was four weeks. Tumor sizes and body weights were monitored by caliper and balance, respectively.
The results showed that BI836880 was very well tolerated in mice, with no signs of stress and loss of weight observed during the treatment. At day 14, the mean tumor volumes of BI836880, bevacizumab vs vehicle control was 264.5±36.0, 290.0±32.4 vs 697.38±88.4 mm3 in Xeno-666 (p&lt;0.001, BI836880 vs control), and 293.5±39.3, 319.6±37.6 vs 1016.8±107.6 mm3 in Xeno-2117 (p&lt;0.0001, BI836880 vs control), respectively. Angiogenesis marker CD34 was analyzed by IHC staining and the microvessel densities were calculated by Image J. The results showed that BI836880 could significantly reduce the numbers of microvessels to a comparable extent as bevacizumab in NPC model. In addition, BI836880 had increased the tumor internal necrotic area by 118.7% compared to vehicle control in Xeno-2117 (p=0.0148), but the effect was insignificant in Xeno-666 (p=0.5467).
In conclusion, BI836880 can inhibit NPC growth to an extent that is comparable to bevacizumab, further investigation in combination with cytotoxic or immunotherapeutic agents are warranted.
Citation Format: Eric Chi Wong, Gigi Lam, Connie Wong, Rachel C. Lam, Kwok Wai Lo, Edwin Pun Hui, Anthony Tak Chan, Brigette B. Ma. Preclinical evaluation of VEGF Ang2 bispecific nanobody BI836880 in patient-derived xenograft models of nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 948.
Abstract 971: Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation
Authors: Foley Kevin P. , Ye Long , Wang Mingkai , Ying Chenghao , Yin Wei , Zhang Lingjie , Ying Weiwen 
Published: July 2021

Abstract
The HSP90 chaperone mediates folding of many important client proteins and mutated oncoproteins, but can also direct its substrates towards degradation by the ubiquitin-proteasome system. Further, in tumor tissues, HSP90 complexes are in a highly activated state relative to normal tissues, which results in HSP90-binding small molecule compounds displaying unique tumor-selective pharmacokinetics. In order to take advantage of these attributes of HSP90 to degrade the transcription factor BRD4 in a tumor-selective fashion, hetero-bifunctional small molecule compounds were synthesized, termed chaperone-mediated protein degraders (CHAMPs), that chemically induced proximity between BRD4 and HSP90. In vitro, treatment of MV-4-11 leukemia cells with a BRD4-CHAMP compound resulted in formation of a BRD4:CHAMP:HSP90 ternary complex and subsequent proteasome-dependent BRD4 degradation and inhibition of cell proliferation. CHAMPs were identified that induced selective degradation of BRD4 and displayed only minimal effects on other HSP90-regulated client proteins. While BRD4 is a known HSP90 client protein, non-HSP90 clients such as mutated KRAS could also be degraded using this approach. In vivo, in the MV-4-11 mouse xenograft model, a selective BRD4-CHAMP compound displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues, with its tumor concentration remaining above the in vitro cytotoxicity EC50 value for at least 7 days following a single dose. This resulted in greater than 90% and prolonged degradation of BRD4 in tumors, as well as decreased expression of the BRD4-regulated MYC gene. Treatment with BRD4-CHAMP at its MTD resulted in dramatic tumor regressions after a single dose and the majority of tumors were undetectable following 3 weekly doses. In contrast, daily dosing of a clinical stage pan-BET inhibitor at its MTD resulted in stable to progressive disease, indicating that BRD4-CHAMP has a greatly improved therapeutic index in this model. CHAMP technology has a number of advantages relative to other targeted protein degradation approaches, such as PROTAC, including an improved safety margin due to selective accumulation in tumor tissues.
Citation Format: Kevin P. Foley, Long Ye, Mingkai Wang, Chenghao Ying, Wei Yin, Lingjie Zhang, Weiwen Ying. Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 971.
Abstract CT134: A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC)
Authors: Gold Kathryn A. , Sacco Assuntina , Bykowski Julie , Daniels Gregory , Pittman Emily , Messer Karen , Chen Ruifeng , Cohen Ezra 
Published: July 2021

Abstract
Background: Checkpoint inhibitors have activity in RM HNSCC, but response rates to single agent therapy are low. Combination therapy may improve outcomes. We aimed to study a novel combination of palbociclib (P) and cetuximab (C) with the PD-L1 inhibitor avelumab (A) in RM HNSCC. Methods: Eligible patients (pts) with RM HNSCC received P in combination with A 10 mg/kg IV every 2 wks and C 400 mg/m2 IV x 1, then 250 mg/m2 weekly. The starting dose of P was 75 mg PO daily on days 1 to 21 of a 28 day cycle. The 3+3 dose escalation design included planned doses of P 100 mg and P 125 mg, with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included response rate and progression free survival (PFS). Results: As of 10/15/20, 12 pts have been treated in 3 cohorts: P 75 mg PO daily (3 pts), 100 mg PO daily (3 pts), and 125 mg PO daily (6 pts). Median age was 56 yo, 92% were male, with 58% p16+, 25% p16-, 17% p16 unknown. One DLT was observed in cohort 3: a grade 3 infusion reaction related to C. The RP2D was P 125 mg, with A and C at standard doses. Other grade 3 AEs were leukopenia (4 pts), neutropenia (4 pts), acneiform rash (2 pts), cellulitis (1pt), increased WBC (1pt). One pt had grade 4 leukopenia. There were no grade 5 AEs. Tx related AEs occurring in &gt; 30% of pts were: acneiform rash (11pts), fatigue (10pts), mucositis (7pts), dry skin (6 pts), decreased WBCs (5 pts), paronychia (5 pts), nausea (5pts), hypomagnesemia (4pts). Response rate by RECIST 1.1 was 42% (3 CRs, 2PRs); median duration of response has not been reached. Median PFS was 6.5 m. Reasons for discontinuation were disease progression (8 pts), pt choice (1 pt). 3 patients remain on therapy (after 20, 15, and 9 months). Conclusions: The combination of APC was well tolerated in patients with RM HNSCC; no unexpected toxicities were seen. The RP2D is A 10 mg/kg every 2 wks, C 400 mg/m2 x 1 then 250 mg/m2 wkly, and P 125 mg daily, 3 wks on, one wk off. Promising response rates were seen, and several pts have had durable responses. These data support further development of this combination. Biomarker analyses on tissue and blood are ongoing. NCT03498378.
Citation Format: Kathryn A. Gold, Assuntina Sacco, Julie Bykowski, Gregory Daniels, Emily Pittman, Karen Messer, Ruifeng Chen, Ezra Cohen. A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT134.
Abstract LB074: Chymostatin, a cathepsin L inhibitor, inhibits lung cancer cell proliferation and COVID-19 Mpro in vitro
Authors: Yarla Nagendra Sastry , Pathuri Gopal , Terzyan Simon , Zhang Yuting , Singh Anil , Scotti Marcus T. , Madka Venkateshwar , Rao Chinthalapally V. 
Published: July 2021

Abstract
Lung cancer patients are more vulnerable to COVID-19 infection. Treatment of patients with lung cancer during the current COVID-19 pandemic is challenging and development of drugs for COVID-19 and lung cancer is urgently needed. Cathepsin L plays key role in lung cancer progression, invasion and more so, endocytosis of SARS-Cov-2 virus into the lung epithelial cells. Importantly, patients with KrasG12V mutation show agreessive disease and high-resistance to chemotherapy due to over-expression of Cathepsin L. Thus, Cathepsin L is a common target for lung cancer and COVID-19 infection. Chymostatin is a known cathepsin L inhibitor, here we screened it for dual inhibition of COVID-19 Mpro and lung cancer patients with COVID-19. In vitro COVID-19 Mpro fluorometric assay was performed to evaluate its inhibitory efficacy by chymostatin. Chymostatin showed dose-dependent inhibition of COVID-19 Mpro activity with IC50 of 15.81 µM (P&lt;0.0001). Isothermal titration calorimetry based binding studies determined that chymostatin strongly bound to COVID-19 Mpro (KD=22.45 µM). CD spectrum analysis demonstrated that chymostatin (10 µM)-induced changes in the secondary structure of COVID-19 Mpro. A unit cell crystal parameter COVID-19 Mpro co-crystalized with chymostatin (a = 49.926 Å, b = 108.71 Å, c = 56.49 Å, α = 90.0°, β = 102.7553°, γ = 90.0°; unit cell volume: 299.03 Ao) was determined using X-ray diffractometer. Molecular docking studies demonstrated that chymostatin interacts with active site amino acids (Cys145). Pro-apoptotic effect of chymostatin was evaluated on human H441 lung cancer cells and mouse lung normal epithelial cells using Annexin V/propidium iodide staining. Chymostatin did not show any cytotoxicity on normal mouse lung epithelial cells up to 100 µM, where as it inhibited proliferation of human H441 lung cancer cells (KrasG12V mutant) with IC50 of 1.2 µM. In conclusion, preliminary in vitro studies demonstrated that naturally occurring cathepsin L inhibitor chymostatin is a SARS-CoV-2 Mpro inhibitor and exhibited anticancer activity against lung cancer cells. The results of the study warranted detailed studies to develop as drugs for lung cancer patients during COVID-19 pandemic (supported by VPR-PHF, the University of Oklahoma Health Sciences Centre for financial support through COVID-19 seed grant program).
Citation Format: Nagendra Sastry Yarla, Gopal Pathuri, Simon Terzyan, Yuting Zhang, Anil Singh, Marcus T. Scotti, Venkateshwar Madka, Chinthalapally V. Rao. Chymostatin, a cathepsin L inhibitor, inhibits lung cancer cell proliferation and COVID-19 Mpro in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB074.
Abstract LB097: MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells
Authors: Chen Meikuang , Gao Yuan , Yu Dihua , Hung Mien-Chie 
Published: July 2021

Abstract
Gemcitabine is one of the current first-line chemotherapy agents in pancreatic cancer treatment. However, the response rate of pancreatic cancer patients to gemcitabine treatment is lower than 20%. Among the potential targeted therapies for pancreatic cancer patients, PARP inhibitor (Olaparib) has been approved by the U.S. Food and Drug Administration for maintenance treatment of metastatic pancreatic adenocarcinoma patients with germline BRCA-mutation. Taking advantages of the high oxidative stress in most pancreatic cancer cells, therapeutic agents that enhance the burden of oxidative DNA damages in these cancer cells can be introduced in novel treatment strategies. Because c-MET overexpression positively correlates with poor prognosis in pancreatic cancer, and our previous studies show that oxidative stress induced-nuclear c-MET phosphorylates PARP1 to reduce oxidative DNA damages, we focused on developing novel treatment strategies by combining c-MET inhibitors (crizotinib and tivantinib) with either gemcitabine or olaparib. In this study, we found that gemcitabine induced nuclear accumulation of c-MET, and that tivantinib reduced c-MET mediated PARP1 phosphorylation in both BxPC-3 and L3.6pl pancreatic cancer cell lines. We also found that combination of tivantinib with either gemcitabine or Olaparib induced more DNA damages than the single agent treatments. Further, we demonstrated the synergistic effects of c-MET inhibitors combined with gemcitabine or Olaparib in pancreatic cancer cell lines, suggesting that combining c-MET inhibitor with PARP inhibitor or gemcitabine is a novel and rational therapeutic strategy for pancreatic cancer treatment.
Citation Format: Meikuang Chen, Yuan Gao, Dihua Yu, Mien-Chie Hung. MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB097.
Abstract LB174: Discovery and preclinical characterization of INCA00186, a humanized monoclonal antibody antagonist of CD73, as a cancer immunotherapy
Authors: Stewart Shaun , Buonpane Rebecca , Zhou Jing , Hansbury Michael , Smith Michael , Wang Hui , Lu  , Su Bin , Awdew Rahel , Huang Cheng-Yen , Kulkarni Ashwini , Harvey Shane , Mondal Arpita , Wang Steve , Stevens Christina , Pratta Michael , Behshad Elham , Fanuka Alexandra , Ren Xiaodi , Koblish Holly , Nastri Horacio , Mayes Patrick 
Published: July 2021

Abstract
In the tumor microenvironment, dying cells release ATP which gets converted to AMP by CD39. AMP is subsequently converted to immunosuppressive adenosine by the extracellular 5'-nucleotidase CD73. CD73 is linked to the cell surface by a GPI-anchor and can be released into the plasma as soluble CD73. In order to lower extracellular levels and reverse the immunosuppressive activity of adenosine in the tumor microenvironment, an antibody was researched and discovered that antagonizes CD73 function. INCA00186 is a humanized monoclonal antibody that binds and inhibits CD73 function. INCA00186 binds human and cynomolgus CD73 with sub-nanomolar affinity, and inhibits CD73 enzymatic activity in a manner that is non-competitive for AMP binding. In functional studies, INCA00186 restored effector T cell proliferation in the presence of high concentrations of AMP. In the human A375 melanoma tumor model in CD34+ humanized NSG mice, INCA00186 decreased levels of cell surface CD73, displayed high receptor occupancy on tumor cells, and decreased CD73 activity in ex vivo assays of tumor homogenates. In the human MDA-MB-231 breast tumor model in CD34+ humanized NSG mice, INCA00186 decreased intratumoral adenosine concentrations. In combination with the novel A2A/A2B adenosine receptor antagonist INCB106385, INCA00186 synergistically restored effector T cell activity as measured by interferon gamma (IFNγ) production in the presence of high concentrations of AMP. In the human MDA-MB-231 breast tumor model in CD34+ humanized NSG mice, combination treatment with INCA00186 and INCB106385 controlled tumor growth significantly better than monotherapies. In summary, the data presented in this study demonstrates that INCA00186 is a potent CD73 antagonist and effectively attenuates adenosine induced immunosuppression in the tumor microenvironment. INCA00186 demonstrated anti-tumor immunity alone and, to a greater extent, in combination with the A2A/A2B adenosine receptor antagonist INCB106385.
Citation Format: Shaun Stewart, Rebecca Buonpane, Jing Zhou, Michael Hansbury, Michael Smith, Hui Wang, Lu, Bin Su, Rahel Awdew, Cheng-Yen Huang, Ashwini Kulkarni, Shane Harvey, Arpita Mondal, Steve Wang, Christina Stevens, Michael Pratta, Elham Behshad, Alexandra Fanuka, Xiaodi Ren, Holly Koblish, Horacio Nastri, Patrick Mayes. Discovery and preclinical characterization of INCA00186, a humanized monoclonal antibody antagonist of CD73, as a cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB174.