bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 604: Combination of the Aurora A inhibitor TAS-119 and adavosertib results in synergistic c-Jun-mediated cell death in head and neck and lung cancers
Authors: Lee Jong Woo , Yang Cindy , Burtness Barbara 
Published: September 2020

Abstract
Head and neck squamous cell carcinomas (HNSCC) account for more than 800,000 cases annually worldwide. Human papillomavirus (HPV)-negative HNSCC mainly harbor disruptive mutations in TP53 and/or CDKN2A tumor suppressor genes, which are associated with refractoriness to treatment as well as poor prognosis and survival. Synthetic lethal approaches hold promise for such patients. Cancers with TP53/CDKN2A mutations lose the G1/S checkpoint, and foster a dependence on the G2/M checkpoint as the primary mechanism to repair the resulting accumulation of genomic instability, thus creating a vulnerability that can potentially be exploited with synthetic lethal targeted therapy. We have previously demonstrated in HPV-negative HNSCC patients that elevation in expression of Aurora kinase A (AURKA), a crucial mitotic regulator, is correlated with worse outcome. Combined inhibition of AURKA and WEE1, a G2/M checkpoint kinase, resulted in a synergistic anti-tumor effect in HNSCC in vitro and in vivo. Upon these findings, we confirmed synergy in testing the more specific AURKA inhibitor, TAS-119 in HNSCC and lung cancers harboring TP53 mutations, and explored mechanisms of cell death. TAS119 and adavosertib combination treatment synergistically suppressed cell viability, clonogenic cell survival, anchorage-independent cell growth in soft agar and oncosphere formation relative to vehicle and single-agent treatment in HNSCC FaDu and CAL27 cells, and lung cancer NCI-H520 and NCI-H358 cells bearing TP53/CDKN2A mutations. Of note, this synergistic anti-tumor effect was not seen in normal human tracheobronchial epithelial cells, predicting a favorable therapeutic index. Furthermore, combination treatment accelerated an accumulation of mitotic catastrophe with mitotic arrest, and led to apoptotic cell death. Mechanistically, combination TAS-119 and adavosertib in HNSCC cells drastically augmented DNA damage and phosphorylation of c-Jun (Ser 63) as demonstrated by kinase array and western blotting, indicating an activation of c-Jun-mediated pro-apoptotic genes. In vivo, this combination demonstrated a synergistic suppressive effect on tumor growth in FaDu xenografts compared with either vehicle or single-agent treatment. Taken together, these results support the promise of further clinical evaluation of AURKA inhibitor in combination with WEE1 inhibitor as a novel and effective treatment for HNSCC and lung cancer patients with TP53/CDKN2A mutations.
Citation Format: Jong Woo Lee, Cindy Yang, Barbara Burtness. Combination of the Aurora A inhibitor TAS-119 and adavosertib results in synergistic c-Jun-mediated cell death in head and neck and lung cancers [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 604.
Abstract 6055: Discovery of epitope-selective anti-CD25 targeting therapeutic antibodies for effective Treg cell depletion in cancer using a novel AI/ML based platform
Authors: Gip Phung , Li Bing , Estelles Angeles , Daino-Laizure Hanako , Gurinovich Oleg , Zalicki Piotr , Hauser Kevin , Taguchi Alex , Barrett Christian , Morin Andrew , Willis Jordan , Srinivasan Mohan , Bright Isaac , Greving Matt 
Published: September 2020

Abstract
Therapeutic antibodies have contributed significantly to better clinical outcomes across multiple tumor types. However, there is still unmet clinical need in cancers with an immunosuppressive and stroma rich tumor microenvironment (TME). One key limitation in early antibody discovery is immunodominance - an evolutionary bias toward specific epitopes that steer antibody selection away from potentially high-efficacy epitopes. Our integrated computational and laboratory approach to antibody discovery enabled us to build focused epitope embodiments of structural epitopes. These epitope embodiments, called Meso-scale Engineered Molecules (MEMs), are used in antibody selection to steer hits toward intended epitopes. CD25 (IL2Rα) is highly expressed on regulatory T-cells (Tregs) that drive immunosuppression in the TME. Depletion of Tregs can restore anti-tumor T effector (Teff) function in the TME, by increasing the Teff/Treg ratio, especially when combined with checkpoint-inhibitors. Using our epitope-selective antibody discovery platform, we built MEMs that embody eight CD25 structural epitopes outside the CD25:IL-2 interface. Through in vitro selection, several high-affinity (median KD = 25 nM) anti-CD25 antibodies from each of the eight intended CD25 epitopes were identified and confirmed to be on epitope by cross-blocking assays and in-epitope alanine mutations. Several conventional- and epitope-selective anti-CD25 clones were converted to human IgG1 and tested in in vitro assays. As a result, these antibodies bound specifically to CD25+ cells, preserve IL-2 signaling via pSTAT5 assays and elicited potent ADCC activity using human effector cells, superior to benchmark antibodies. These studies show that our integrated computational and laboratory platform improves the antibody discovery process, producing clones with biological function and improved therapeutic efficacy.
Citation Format: Phung Gip, Bing Li, Angeles Estelles, Hanako Daino-Laizure, Oleg Gurinovich, Piotr Zalicki, Kevin Hauser, Alex Taguchi, Christian Barrett, Andrew Morin, Jordan Willis, Mohan Srinivasan, Isaac Bright, Matt Greving. Discovery of epitope-selective anti-CD25 targeting therapeutic antibodies for effective Treg cell depletion in cancer using a novel AI/ML based platform [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 6055.
Abstract 6057: Discovery of a novel function for USP7 inhibitors: Reprogramming the tumor microenvironment
Authors: Jacq Xavier , Jurisic Anamarija , Daubriac Julien , Lobb Ian T. , Wappett Mark , Cranston Aaron , Sung Peggy , Gavory Gerald , O'Dowd Colin , Harisson Tim 
Published: September 2020

Abstract
During the transition from healthy tissue to cancer and metastasis, the tumor microenvironment (TME) initiates crucial changes that licenses the progression from primary tumors to aggressive and metastatic disease. Our understanding of the specific factors and molecular mechanisms underpinning these transitions in the TME is critical for influencing the potency and scope of existing cancer therapy strategies but is still evolving and subject to substantial and widespread investigations. Here we uncover a novel molecular mechanism actioned by fibroblasts in the TME to modulate the secretion of the vascular endothelial growth factor (VEFG) via the hypoxia-inducible transcription factor (HIF1α). Utilizing primary human cells co-culture systems in combination with highly potent and selective USP7 inhibitors, we demonstrate that the deubiquitinating enzyme USP7 modulates the stability of HIF1α in primary human fibroblasts and secreted VEGF levels in primary fibroblasts as well as cancer-associated fibroblasts. This USP7-mediated modulation of VEGF secretion in the TME does not occur in cancer cells, immune cells or endothelial cells, rather it is restricted to the fibroblastic compartment. Importantly, the modulation of VEGF secretion by USP7 in fibroblasts is not mediated via the Mdm2 axis: Mdm2 antagonists are unable to recapitulate the VEGF modulation in fibroblasts. Knock-down of USP7 in primary fibroblasts validates the phenotype obtained with potent and selective USP7 inhibitors. In line with their effects on the TME in primary cell cultures, potent, selective USP7 inhibitors demonstrated tumour growth inhibition in vivo in a syngeneic cancer xenograft model that does not respond to USP7 inhibitors in vitro. Collectively, our studies reveal a molecular mechanism whereby USP7 inhibition leads to TME reprogramming mediated by an increased destabilization of HIF1α leading to reduced levels of VEGF in the TME and improved anti-tumor activity. Our results support further investigations of combination of a USP7 inhibitor with immune checkpoint inhibitors, as well as other TME modulating agents.
Citation Format: Xavier Jacq, Anamarija Jurisic, Julien Daubriac, Ian T. Lobb, Mark Wappett, Aaron Cranston, Peggy Sung, Gerald Gavory, Colin O'Dowd, Tim Harisson. Discovery of a novel function for USP7 inhibitors: Reprogramming the tumor microenvironment [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 6057.
Abstract 6061: NR2F1 limits dissemination of early cancer mammary epithelial cells
Authors: Sosa Maria Soledad , Kale Nupura , Shrivastava Nitisha , Rodriguez-Tirado Carolina , Carlini Maria , Ji Jiayi , Bravo-Cordero Javier 
Published: September 2020

Abstract
Cancer cells have been found to disseminate during very early and sometimes asymptomatic stages of tumor progression. At secondary organs, early disseminated cancer cells (eDCCs) can enter a non-proliferative state for prolonged periods of time. Intriguingly, eDCCs also carry metastasis- initiating capacity. However, the mechanisms by which these early cancer cells complete all steps of metastasis including metastasis-initiating capacity are unknown. Here we report that the orphan nuclear receptor and lineage commitment regulator NR2F1 serves as an early barrier to early dissemination propelled by HER2 signaling. NR2F1 loss of function in HER2 early cancer cells induced cell motility, loss of E-cadherin junctions, disorganized laminin-V deposition, decreased β-catenin membrane localization and increased micro-invading cells with CK14+/CK18 phenotype. Importantly, upon NR2F1 depletion in HER2 early cancer acini, TWIST, ZEB1 and PRRX1 levels were upregulated. Our findings reveal a previously unrecognized function of NR2F1 as a suppressor of dissemination during early stages of breast tumor progression. Thus, therapies that restore and activate NR2F1 function might limit early dissemination and metastatic outgrowth.
Citation Format: Maria Soledad Sosa, Nupura Kale, Nitisha Shrivastava, Carolina Rodriguez-Tirado, Maria Carlini, Jiayi Ji, Javier Bravo-Cordero. NR2F1 limits dissemination of early cancer mammary epithelial 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 6061.
Abstract 6096: Bladder cancer microbiome and its association with chemoresponse
Authors: Ginwala Rashida , Nachman Erika , Peri Suraj , Franklin Jodie , Greathouse Leigh , Ingersoll Molly , Kutikov Alexander , White James R. , Abbosh Philip H. 
Published: September 2020

Abstract
Background: The microbiome is widely known to cause cancer, modify its behavior, and alter the way therapies interact with tumors. Despite the urinary microbiome being one of the most clinically significant microbiomes in human health, is one of the least well-described.
Results: To begin to annotate the urinary microbiome present in bladder cancers, we analyzed raw sequencing data from the Cancer Genome Atlas (TCGA) from 116 tumors (duplicates from 22 tumors), 22 adjacent normal bladder tissues, and 99 blood samples to identify reads originating from known microbiota. Twenty-seven viral and bacterial species were found to be enriched in the tumor samples. Bacterial species such as B. thetaiotamicron, A. mucinaphila and Bifidobacterium spp. with known positive association with immune checkpoint blockade therapy against CTLA-4 and PD-L1 were frequently found in these tumor samples. We also found sex-specific enrichment of genera such as Lactobacillus and Prevotella in female bladder cancer patients which also are prevalent in the normal female genitourinary tract. A. prevotii and F. magna were also enriched in females. We also found a correlation between Prevotella and TCGA subtypes III and IV (basal expression subtypes), suggesting a link between enrichment of certain microbial species and bladder cancer subtypes. Finally, single sample gene set enrichment analysis using the Hallmark and KEGG gene sets revealed the association of Mycoplasma with the Hallmark DNA repair gene set and with the KEGG pyrimidine metabolism pathway that can be further studied to ascertain its effects on DNA damaging chemotherapeutic agents. To corroborate these findings, we performed 16S metagenomics from urine pellets of 40 bladder cancer patients undergoing radical cystectomy on a prospective clinical trial (NCT02968732). We found one predominant genus consistent with prior urinary metagenomics studies in samples from most of the patients. Thirty eight of the 58 genera identified in the TCGA analyses were also present in these urine samples. Further correlation with response to clinical metadata is ongoing.
Conclusions: Description of the bladder cancer microbiome is the first step in approaches to manipulate it for therapeutic gain.
Citation Format: Rashida Ginwala, Erika Nachman, Suraj Peri, Jodie Franklin, Leigh Greathouse, Molly Ingersoll, Alexander Kutikov, James R. White, Philip H. Abbosh. Bladder cancer microbiome and its association with chemoresponse [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 6096.
Abstract 6116: Role of secretory factors from obese-derived omentum in supporting ovarian cancer progression
Authors: Waters Jennifer , Robinson Mikella , Gilbert Samuel F. , Alexander Logan J. , House Carrie D. 
Published: September 2020

Abstract
Ovarian cancer is the most lethal gynecological malignancy in the United States, with a known predilection for metastasizing to the omentum, a sheet of fatty peritoneal tissue that encloses the abdomen. This finding coincides with some evidence that ovarian cancer is more aggressive in the obese setting with worse overall survival. While it has been shown that ovarian cancer cells invade towards adipocytes in vitro, the mechanism by which they support formation of secondary tumors is not well understood. We hypothesize that soluble factors enriched in the obese setting are activating signaling pathways in tumor cells to drive migration and proliferation. To evaluate this hypothesis we co-cultured primary human omental adipocytes derived from obese female donors with ovarian cancer cell lines and profiled secretory factors (cytokines and adipokines) responsible for increasing tumor initiation in vivo and clonogenicity, proliferation, and drug resistance in vitro. Secretion of cytokines IL-6, IL-8, and CCL2 by adipocytes is enhanced when co-cultured with ovarian cancer cells. A subcutaneous tumor model showed that low dilutions of ovarian cancer cells require adipocytes for engraftment and tumor formation. A transplantation assay showed that ovarian cancer cells require the presence of adipocytes for sustained tumor-initiation capacity. Studies are underway to investigate adipocyte-secreted factors in this process. Our findings highlight the role of adipocytes in the ovarian tumor microenvironment and uncover signaling factors that may enhance ovarian cancer progression. Understanding these processes will enable the design of more effective therapies for treating ovarian cancer.
Citation Format: Jennifer Waters, Mikella Robinson, Samuel F. Gilbert, Logan J. Alexander, Carrie D. House. Role of secretory factors from obese-derived omentum in supporting ovarian cancer progression [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 6116.
Abstract 6139: Sex-dependent development of anal squamous cell carcinoma in Kras-mutant mice
Authors: Walcheck Morgan , Noel Jessica , Nukaya Manabu , Matkowskyj Kristina , Ronnekleiv-Kelly Sean 
Published: September 2020

Abstract
A historical over-reliance on male animals in research studies has clouded sex differences in pathologic diseases. This led to a mandate from the NIH requiring the use of both male and female animals in preclinical studies. Our study began with the aim to evaluate both sexes of KC mice (LSL-KrasG12D/+; Pdx1-Cre), a standard pre-clinical model for pancreatic ductal adenocarcinoma (PDAC). This was because previous characterization of this model to advanced age (9-12 months) only included males, and evaluating both sexes was an essential foundation for subsequent studies of PDAC progression. Twenty-eight KC mice have been evaluated, comprised of 15 males and 13 females. KC mice developed the expected pancreatic cancer pre-cursor lesions called PanINs (100% PanIN1, 7% PanIN 2 and 7% PanIN 3) and PDAC (14%) at an established time point (age 9 months). Surprisingly, female KC mice developed anal lesions, a finding that has not previously been described. Histopathologic analysis demonstrated anal squamous cell carcinoma (SCC), with all 13 KC females developing anal SCC compared to 0/15 in KC males and 0/83 control mice (Table 1). Genotyping for activated Kras mutation confirmed the presence of KrasG12D, indicating Pdx1 expression (Pdx1-Cre) in the anal tumor tissue. To understand the distinct sex differences and connection to sex-dependent steroids (estrogen and testosterone), female mice were ovariectomized (n = 5) and males castrated (n = 6). Remarkably, while 5/5 females developed anal SCC (i.e. unchanged phenotype), 6/6 males developed anal SCC, a stark contrast to the absence of tumor development in non-castrated KC males. This suggests a novel mechanism in which Kras driven anal SCC tumor development is suppressed through testosterone / dihydrotestosterone (DHT) exposure. Follow-up studies will focus on the mechanism by which testosterone or DHT suppresses Kras-driven anal SCC formation. These findings may ultimately have therapeutic implications for the subset of patients with Kras-mutant anal SCC.
Table 1:Characterization and Incidence of Anal SCC TumorsGroupMouseAnal SCC IncidenceControlC57Bl6 Male (n=12)0/12 (0%)ControlC57Bl6 female (n=11)0/11 (0%)ControlKrasG12D/+ Female (n=9)0/9 (0%)ControlKrasG12D/+ Male (n=18)0/18 (0%)ControlPDX1-Cre male (n=10)0/10 (0%)ControlPDX1-Cre Female (n=23)0/23 (0%)KC MiceKC Male (n=15)0/15 (0%)KC MiceKC Female (n=13)13/13 (100%)Study KC MiceCastrated KC Male (n=6)6/6 (100%)Study KC MiceOvariectomized KC Female (n=5)5/5 (100%)
Citation Format: Morgan Walcheck, Jessica Noel, Manabu Nukaya, Kristina Matkowskyj, Sean Ronnekleiv-Kelly. Sex-dependent development of anal squamous cell carcinoma in Kras-mutant mice [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 6139.
Abstract 6171: High throughput screening identified new radiosensitizers which inhibit DNA damage repair pathway
Authors: Tamari Keisuke , Li Zhihao , Matsutani Hideki , Seo Yuji , Takahashi Yutaka , Minami Kazumasa , Isohashi Fumiaki , Ogawa Kazuhiko 
Published: September 2020

Abstract
Radiotherapy (RT) plays a crucial role in the treatment of cervical cancer. However, the efficacy of existing radiosensitizers in clinical applications is limited. The aim of this study was to established an efficient method of identifying new radiosensitizers and to investigated the specific mechanisms when used in combination with RT. An effective platform for radiosensitizers discovery was created based on high-throughput screening (HTS) technology. We established an automated and powerful HTS approach to identify potent radiosensitizers from the LOPAC1280 chemical library. We used the Geldanamycin for validation of our HTS method, which had been known as a radiosensitizer for cervical cancer cells. Z'-score of our HTS platform was 0.6. From 1280 compounds, we identified four hit compounds. Among them, we found Dihydroouabain (DHO) and Ro90-7501 which have not been previously known as radiosensitizers. Clonogenic survival assay showed that DHO and Ro90-7501 significantly enhanced radiosensitivity in cervical cancer cells. Western blot analysis showed that DHO inhibited the phosphorylation of Chk1, and Ro90-7501 inhibited the phosphorylation of ATM. These results indicated that DHO and Ro90-7501 inhibited DNA damage response pathway. In conclusion, we established the HTS method for radiosensitizer screening, and found DHO and Ro90-7501 as new radiosensitizers targeting DNA damage repair pathway.
Citation Format: Keisuke Tamari, Zhihao Li, Hideki Matsutani, Yuji Seo, Yutaka Takahashi, Kazumasa Minami, Fumiaki Isohashi, Kazuhiko Ogawa. High throughput screening identified new radiosensitizers which inhibit DNA damage repair pathway [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 6171.
Abstract 6177: Triple negative breast cancer patients treated with radiation therapy: Improvement in survival and local control with adjuvant chemotherapy compared to neoadjuvant chemotherapy
Authors: Nittala Mary R. , Mundra Eswar K. , Packianathan Satya , Mehta Divyang , Smith Maria L. , Woods William C. , McKinney Shawn , Craft Barbara S. , Vijayakumar Srinivasan 
Published: September 2020

Abstract
Purpose: The objective of this study is to evaluate local control and survival rates of node negative triple negative breast cancer patients (TNBCs) treated with radiotherapy (RT) in our institution.
Methods: This is a retrospective analysis of 67 TNBCs (2007 - 2017) at an academic state institution who underwent lumpectomy and /or mastectomy (surgery) followed by adjuvant irradiation to median total dose of 50 Gy (range 40.5-50.40 Gy). Chemotherapy was administered in a neoadjuvant (31) or adjuvant setting (36). For all 67 TNBCs, local control (LC), overall survival (OS) and disease free survival (DFS) were estimated using the Kaplan-Meier method. The significance of survival variables were analyzed using the Cox univariate and multivariate proportional hazards model. A p-value of less than 0.05 was considered statistically significant. The SPSS 24.0 software was used for data analysis.
Results: The baseline characteristics of all 67 TNBCs were measured with median follow up of 58 months (range 10-142 months). Patients were stratified into two groups (neoadjuvant chemotherapy-RT (31) vs. adjuvant chemotherapy-RT (36)). The median rates for LC, DFS and OS were 27 % vs. 68 % (p= 0.001), 27.2% vs. 63.2 % (p= 0.034), and 63.4% vs. 92.5% (0.001) respectively. On Cox multivariate analysis, patients who received adjuvant chemotherapy were associated with statistically improved significant LC (p= 0.002) and OS (p=0.005). The variables included were: ethnicity (p=0.251), age (p=0.984), BMI (p=0.032), lump boost (p=0.300), TNM (p=0.162) and tumor grade (p=0.336).
Conclusion: Among TNBC patients undergoing RT, adjuvant chemotherapy appears to be better than neoadjuvant chemotherapy in determining the clinical outcomes.
Citation Format: Mary R. Nittala, Eswar K. Mundra, Satya Packianathan, Divyang Mehta, Maria L. Smith, William C. Woods, Shawn McKinney, Barbara S. Craft, Srinivasan Vijayakumar. Triple negative breast cancer patients treated with radiation therapy: Improvement in survival and local control with adjuvant chemotherapy compared to neoadjuvant chemotherapy [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 6177.