bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 977: Mcl-1 levels critically determines the sensitivities of human colon cancer cells to APG1244, a novel Bcl-2 and Bcl-XLinhibitor, that induces Bax- and caspase-8- dependent apoptosis
Authors: Yao Weilong , Sun Shi-Yong 
Published: July 2021

Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide due to its poor prognosis. Most of the patients receive surgical resection when diagnosed as CRC, whereas the recurrence rate is very high. Therefore, additional treatment options, such as targeted therapy, are still urgently needed. The novel BH3 mimetic, APG1244 (a prodrug for APG1252), is a highly potent Bcl-2 and Bcl-XL dual inhibitor and being tested in clinical trials as a potential cancer therapeutic agent. The current study focuses on demonstrating the therapeutic efficacies of APG1244 against colorectal cancer and understanding the underlying mechanisms. A panel of CRC cell lines with different levels of Bcl-2, Bcl-XL and Mcl-1 possessed different sensitivities to APG1244. APG1244 effectively decreased the survival of CRC cell lines, particularly those expressing relative low levels of Mcl-1, with induction of apoptosis. High levels of Mcl-1 in these cell lines were significantly correlated to decreased sensitivity to APG1244. APG1244, when combined with a Mcl-1 inhibitor, synergistically decreased the survival and induced apoptosis of APG1244-insensitive cell lines with high levels of Mcl-1. This combination could further decreased the survival and enhanced apoptosis even in the cell lines with relatively low levels of Mcl-1, whereas enforced expression of ectopic Mcl-1 in these cells abrogated APG1244's effects on decreasing cell survival and inducing apoptosis, which can be reversed by Mcl-1 inhibition. In our study, it appears that APG1244 quickly activated caspase-8 and caspase-3 and induced PARP cleavage with induction of cytochrome C and Smac release from mitochondria. Deficiency of Bax, Smac, Bim or PUMA, but not FADD, in CRC cells protected (BAX-KO) or partially protected cells from APG1244-induced apoptosis, indicating that APG1244 induces Bax-dependent apoptosis. Furthermore, blockage of caspase-8 with a caspase-8 specific inhibitor abolished cleavage of caspase-3 and PARP including attenuation of cytochrome C and Smac release induced by APG1244, suggesting a caspase-8-dependent mechanism. The current study thus demonstrates the potential of APG1244 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with a Mcl-1 inhibitor for CRC treatment, warranting further evaluation in vivo and in the clinic.
Citation Format: Weilong Yao, Shi-Yong Sun. Mcl-1 levels critically determines the sensitivities of human colon cancer cells to APG1244, a novel Bcl-2 and Bcl-XLinhibitor, that induces Bax- and caspase-8- dependent apoptosis [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 977.
Abstract 996: Cold atmospheric plasma therapy selectively targets triple negative breast cancer cells
Authors: Wang Peiyu , Zhou Renwu , Zhou Rusen , Gunter Jennifer , Simpson Fiona , Ostrikov Kostya (Ken) , Richard Derek , Dai Xiaofeng , Thompson Erik (Rik) Walter 
Published: July 2021

Abstract
Background: Cancer cells notoriously escape radiation therapy, chemotherapy, hormonal therapy, and other anti-cancer therapies. Among various breast cancer subtypes, triple negative breast cancers (TNBCs) are known for their poor clinical outcome and dearth of effective targeted therapies due to the absence of druggable receptors. Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment agent that selectively kills basal-like/TN breast cancer cells.
Method: In this study, we used plasma-activated media (PAM) to capture and store the multi-modal chemical species of CAP, which significantly expands the treatment scope and flexibility of plasma medicine as a clinical therapeutic approach. The PAM was diluted into different doses and cells were treated for 12 or 24 hours. The effects of PAM on cell viability and ROS levels in 9 different cell lines; normal cells (MCF-10A and HEK-293T), luminal breast cancer cell lines (MCF-7, T47D, HCC70), and TNBC cell lines (MDA-MB-468, SUM-159PT, SUM-149PT, MDA-MB-231), were assessed.
Results: The results showed that TNBC cells were more highly sensitive, in a dose-dependent manner, to PAM treatment. PAM selectively caused apoptosis of TNBC cell lines compared to luminal lines and had little effect on the normal cell lines. It has been hypothesised that the cancer-selective CAP and PAM cytotoxicity is due in part to reactive oxygen (ROS) and nitrogen species (RNS). Constitutive RONS levels, combined with those present in and/or induced by PAM, can combine to push the cells over a cytotoxic threshold. In support of this, we found a tight correlation (R2=0.7502) between the constitutive ROS level of different cell lines used and their response (cell viability) to 100% PAM treatment, and found that ROS levels selectively increased further in the TNBC&gt;luminal&gt;normal cells in response to PAM. We have also identified a strong synergistic molecular partner that further promotes sensitivity and selectivity of PAM for TNBC cells.
Conclusion: We demonstrated that treatment with PAM promotes apoptosis n cell lines representing the most aggressive TNBC subtype. This discovery opens new TNBC-selective opportunities for simultaneous inhibition of diverse (parallel) cancer development factors through synergistic interactions enabled through plasma activated biochemical media.
Citation Format: Peiyu Wang, Renwu Zhou, Rusen Zhou, Jennifer Gunter, Fiona Simpson, Kostya (Ken) Ostrikov, Derek Richard, Xiaofeng Dai, Erik (Rik) Walter Thompson. Cold atmospheric plasma therapy selectively targets triple negative breast 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 996.
Abstract CT156: Radiologic scoring method to define the therapeutic response and surgical candidacy
Authors: Rahmanuddin Syed , Von Hoff Daniel , Cridebring Derek , Brase Jordyn , Fong Yuman , Motarjem Pejman , Korn Ron , Choong Kevin , Boswell William , Borazanci Erkut 
Published: July 2021

Abstract
Purpose: The purpose of this study is to define the best CT perfusion analytical method for the surgical candidacy of pancreatic cancer patients in Neo-Adjuvant treated clinical trial population. Experimental Design: Study was designed to assess tumor perfusion status. This prospective study involved 24 adult patients with pancreatic adenocarcinoma (PDAC). Inclusion criteria included, patients with histologically or cytologically confirmed resectable, borderline resectable, or locally advanced (unresectable) PDAC. All patients received neoadjuvant therapy (paricalcitol, paclitaxel protein bound, cisplatin and gemcitabine) for up to 6 months Multi-phase CT was performed for most patients on a GE scanner using a standard pancreatic cancer protocol including a pre-injection phase, arterial phase, and porto-venous phase. The iodinated contrast agent Isovue 370 was dosed at 150 cc + 40 cc saline, and injected at a rate of 5 cc/sec into the antecubital vein. Volumetric analysis of images from 24 patients was conducted using 3D imaging software and perfusion scoring assessment was done on each case using 2D and 3D methodology. Regions of interest were drawn to define the volumetric tumor quantification. This work looked at the difference in density between arterial and venous phases, using the Marley equation.
This data was then used to assess treatment response and ultimately whether or not a patient would be a surgical candidate. This surgical candidacy of these patients was defined by the “R” score. Results: The R score defines the number of vessels with tumor involvement. Each vessel that had any amount of tumor involvement was scored with a 1. Any patient with a score of 6 or higher was deemed not eligible for surgery while a score of 5 or less was eligible for surgery. 3D Tumor volumetric assessments were performed for the assessment of the treatment response that linked directly with the tumor perfusion.Conclusion: CT vessel perfusion using the R score method could be helpful to define the surgical candidacy of pancreatic cancer patients along with 3D tumor volumetric quantification.
Citation Format: Syed Rahmanuddin, Daniel Von Hoff, Derek Cridebring, Jordyn Brase, Yuman Fong, Pejman Motarjem, Ron Korn, Kevin Choong, William Boswell, Erkut Borazanci. Radiologic scoring method to define the therapeutic response and surgical candidacy [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 CT156.
Abstract CT212: Expanded phase 1/2a study of PLX8394, a novel next generation BRAF inhibitor in patients with advanced, unresectable solid tumors with alterations in BRAF
Authors: Janku Filip , Sherman Eric , Yaeger Rona , Parikh Aparna , Sullivan Ryan , Feun Lynn , Fuente Macarena De La , Tsai Frank Yung-Chin , Gordon Michael , Allen Carl , Rudoltz Marc S. , Balinski Kathe , Averbuch Steven , Vidne Michael , Tarcic Gabi 
Published: July 2021

Abstract
The authors did not submit an updated abstract. The original abstract should be considered final.
Citation Format: Filip Janku, Eric Sherman, Rona Yaeger, Aparna Parikh, Ryan Sullivan, Lynn Feun, Macarena De La Fuente, Frank Yung-Chin Tsai, Michael Gordon, Carl Allen, Marc S. Rudoltz, Kathe Balinski, Steven Averbuch, Michael Vidne, Gabi Tarcic. Expanded phase 1/2a study of PLX8394, a novel next generation BRAF inhibitor in patients with advanced, unresectable solid tumors with alterations in BRAF [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 CT212.
Abstract CT227: A phase 1 multiple ascending dose study to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of KD033 in subjects with metastatic or locally advanced solid tumors
Authors: Luke Jason J. , Olszanski Anthony J. , Puzanov Igor , Lu Dan , Hackett Adrian , Martomo Stella , Patel Jeegar , Schueller Olivier , Mora Alessandro , Schlitt Miranda L. , Li Linghui 
Published: July 2021

Abstract
Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs). In addition, unlike IL-2, IL-15 does not mediate activation-induced cell death and is expected to have an improved therapeutic index compared to IL-2. KD033 is a fusion antibody molecule generated by combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies to understand the pharmacology, pharmacokinetic (PK) and toxicology properties. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free-IL-15. The increased safety and efficacy of PD-L1-targeted IL-15 observed in pre-clinical studies warranted evaluation of KD033 in humans. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. KD033 is administered as an IV infusion over 30 minutes every 14 days (i.e., a cycle equals 2 weeks). The starting dose of KD033 is 3 µg/kg, with step-up dosing to 12.5 µg/kg in the first cohort of 3 subjects. After the first cohort, the dose escalation will use a standard 3+3 design with planned doses from 25 µg/kg to 600 µg/kg. The dose escalation phase will be followed by one expansion cohort, which will enroll patients who received PD-1/PD-L1 inhibitor but have either progressed or are refractory to therapy. Secondary objectives include characterization of PK and immunogenicity, evaluation of immune correlates that will potentially differentiate the impact of KD033 versus monotherapy as well as investigate IL-15 biology and determine best overall response and duration of response. (NCT04242147)
Citation Format: Jason J. Luke, Anthony J. Olszanski, Igor Puzanov, Dan Lu, Adrian Hackett, Stella Martomo, Jeegar Patel, Olivier Schueller, Alessandro Mora, Miranda L. Schlitt, Linghui Li. A phase 1 multiple ascending dose study to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of KD033 in subjects with metastatic or locally advanced solid tumors [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 CT227.
Abstract LB091: Long-term statin use and risk of colorectal cancer: A prospective cohort study
Authors: Zhang Yin , Chan Andrew T. , Meyerhardt Jeffrey A. , Giovannucci Edward L. 
Published: July 2021

Abstract
Importance Statin use has been examined as a potential chemopreventive strategy against colorectal cancer (CRC), with conflicting findings reported. Prior studies have not been able to investigate this topic with adequate follow-up time. Objective To examine prospectively the association between long-term statin use and CRC risk. Design setting and participants The Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) are large prospective cohorts of US women and men. Participants who were alive and free of cancer at the time when information on their statin use was first assessed were eligible for inclusion (100,300 women and 47,991 men), and were followed for up to 26 years (NHS: 1994-2016; HPFS: 1990-2016). Exposures Overall status and duration of statin use. Main outcome and measures Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for exposures and CRC risk. Results We documented 2,924 incident CRC cases during follow-up. In fully-adjusted analyses, compared to participants who never used statins, longer duration of statin use was associated with higher risk of overall CRC (HR, 95%CI was 1.09, 0.98-1.20 for ever use; 1.06, 0.94-1.19 for 1 to 5 years; 1.10, 0.96-1.27 for 6 to 10 years; 1.10, 0.86-1.41 for 11 to 15 years; 1.56, 1.13-2.16 for &gt;15 years; vs. never users, P=.02 for trend). The risk elevation was driven by proximal colon cancer (1.22, 1.05-1.41 for ever use; 1.17, 0.99-1.39 for 1 to 5 years; 1.21, 0.99-1.48 for 6 to 10 years; 1.27, 0.91-1.78 for 11 to 15 years; 2.22, 1.49-3.30 for &gt;15 years; vs. never users, P&lt;.001 for trend) rather than cancers of distal colon or rectum. The results became more robust in sensitivity analyses among participants with hypercholesterolemia. Conclusion and relevance This study does not support benefit of statin use in CRC chemoprevention. Long-term statin use was associated with increased CRC risk (predominantly driven by proximal colon cancer).
Citation Format: Yin Zhang, Andrew T. Chan, Jeffrey A. Meyerhardt, Edward L. Giovannucci. Long-term statin use and risk of colorectal cancer: A prospective cohort 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 LB091.
Abstract LB117: Identification of novel SOS1-K-Ras disruptors for NSCLC and colon cancers with K-Ras mutation
Authors: Sasmal Sanjita , Ramanathan Anuradha , Boorgu Venkatesham 
Published: July 2021

Abstract
KRAS along with other RAS genes represents the most prevalent oncogene in human cancers. Atypical Ras signaling has been identified in more than 30% of all human cancers with the most common being lung, colon, and pancreatic cancers. In particular, K-Ras has been identified as the most important Ras protein in cancer research, implicated in over 21% of human cancers. Current strategies drug only specific K-Ras mutants, leaving open an unmet need for new agents that can address a broader patient population. A new opportunity is emerging for the development of a therapeutic Pan Ras inhibitor by targeting the upstream guanine nucleotide exchange factor (GEF) protein SOS (Son of sevenless). Disruption of SOS1- K-Ras mutant interaction is a good strategy to inhibit activation of mutant K-Ras. SOS1 inhibition through the protein-protein interaction (PPI) disruption assists in keeping K-Ras in the GDP inactive, rather than its active GTP-bound state. Inhibition of SOS1 results in blockade of the RAS-MEK-ERK pathway and lowering proliferation, in both WT and all mutant Ras forms. Here we discuss our approach to target SOS1 to control aberrant Ras signaling in NSCLC and colon cancers. We report the identification of novel potent SOS1-K-Ras disruptors using the SOS1-K-Ras PPI TR-FRET assay. Multiple series have been identified, with a good SAR trend. We have identified low nanomolar potent compounds that translate to modulation of p-ERK in cell based assays in K-Ras mutant cell lines. These compounds exhibited good ADME properties like solubility and metabolic stability. Further profiling of these compounds is ongoing.
Citation Format: Sanjita Sasmal, Anuradha Ramanathan, Venkatesham Boorgu. Identification of novel SOS1-K-Ras disruptors for NSCLC and colon cancers with K-Ras mutation [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 LB117.
Abstract LB170: HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers
Authors: Lee Chan Gyu , Kim Tae Eun , Hong Sungyoul , Chu Jongwan , Kang Ju Eun , Jeong Hae Min , Shin Young Kee 
Published: July 2021

Abstract
Background: Interferon beta (IFN-β), a promising potent cytokine, has been attracting attention for treatment of cancer. The pleiotropic antitumor effects of IFN-β have been studied, with specific reference to their direct role on cancer cells and indirect action through the immune effector cells. However, its systemic toxicities and poor biophysical properties prevent IFN-β from being widely used for cancer therapy. Since the potential of cytokine therapies are impaired due to dose-limiting systemic toxicities, novel treatment methods should be developed to safely deliver effective drug quantities at the tumor sites. Like antibody-drug conjugates (ADCs), immunocytokine can be attempted to induce cytokine's organ-targeting and alleviate its systemic side effects. Here, we designed recombinant IFN-β mutein immunocytokines that comprise a HER2-targeting antibody and IFN-β mutein, and evaluate the antitumor properties against HER2-positive cancers.Method: A panel of human gastric cancer cell lines was treated with trastuzumab-IFN-β mutein to evaluate direct antitumor effect. In addition, to test the immune cell-mediated antitumor effect, cancer cells were co-cultured with effector cells (e.g. PBMC) in the absence or drug. The antitumor efficacy of trastuzumab-IFN-β mutein in vivo was tested in HER2-positive cancer xenograft models using nude mice or humanized mice. Result: Trastuzumab-IFN-β mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-β mutein alone. Trastuzumab-IFN-β mutein also displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-β mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Moreover, trastuzumab-IFN-β mutein significantly suppress tumor growth in HER2-positive cancer xenograft models. Tumor-infiltration of lymphocytes was enhanced by trastuzumab-IFN-β mutein, implying that the tumor-targeting IFN-β may have an antitumor effect through increased immune response. Conclusion: We have characterized and evaluated the antitumor properties of trastuzumab-IFN-β mutein in HER2-expressing cancers. Since IFN-β activates antitumor immune responses, it is expected to be administered in combination with immunotherapeutic drugs. Therefore, the study suggests that trastuzumab-IFN-β mutein is a promising candidate for the treatment of HER2-positive carcinoma.
Citation Format: Chan Gyu Lee, Tae Eun Kim, Sungyoul Hong, Jongwan Chu, Ju Eun Kang, Hae Min Jeong, Young Kee Shin. HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers [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 LB170.
Abstract LB189: Three-dimensional genome organization maps in normal haematopoietic stem cells and acute myeloid leukemia
Authors: Wang Benny , Kong Lingshi , Babu Deepak , Choudhary Ruchi , Fam Winnie , Tng Jia Qi , Goh Yufen , Liu Xin , Song Fang Fang , Chia Priscella , Chan Ming Chun , An Omer , Tham Cheng Yong , Benoukraf Touati , Yang Henry , Wang Wilson , Chng Wee Joo , Tenen Daniel , Fullwood Melissa J. 
Published: July 2021

Abstract
Many oncogenes, such as MEIS1 and HOXA9, are overexpressed in some but not all cancers. We identified two key epigenetic mechanisms underlying this heterogeneity in oncogene expression in Acute Myeloid Leukemia. Acute Myeloid Leukemia (AML) is a highly lethal blood cancer arising due to aberrant differentiation of haematopoietic stem cells. MEIS1 and HOXA9 regulate stemness-related transcriptional programs in normal haematopoietic stem cells and AML. Here we obtained 3D genome organization maps in the CD34+ haematopoietic stem cells from healthy individuals and individuals with AML. The MEIS1 oncogenic transcription factor is regulated by a Frequently Interacting Region (FIRE). This FIRE is present in normal bone marrow samples, and an AML sample with high MEIS1 levels. However, it is absent in two AML samples that show low MEIS1 levels. CRISPR excision of the FIRE led to loss of MEIS1 and reduced cell growth. Moreover, MEIS1 can bind to the promoter of HOXA9. HOXA9 can also auto-regulate by binding to its own promoter as well as an Acute Myeloid Leukemia-specific super-enhancer that interacts with the HOXA9 promoter via chromatin interactions. The mechanisms elucidated here could be potentially exploited to utilize epigenetic inhibitors to specifically target oncogene expression in cancer.
Citation Format: Benny Wang, Lingshi Kong, Deepak Babu, Ruchi Choudhary, Winnie Fam, Jia Qi Tng, Yufen Goh, Xin Liu, Fang Fang Song, Priscella Chia, Ming Chun Chan, Omer An, Cheng Yong Tham, Touati Benoukraf, Henry Yang, Wilson Wang, Wee Joo Chng, Daniel Tenen, Melissa J. Fullwood. Three-dimensional genome organization maps in normal haematopoietic stem cells and acute myeloid leukemia [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 LB189.