bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 97: Mechanisms of action and regulation of the progranulin/EphA2 axis in mesothelioma
Authors: Ventura Elisa , Buraschi Simone , Williams Stephen J. , Belfiore Antonino , Iozzo Renato V. , Giordano Antonio , Morrione Andrea 
Published: June 2022

Abstract
Mesothelioma is an aggressive tumor with very poor prognosis. The limited availability of therapeutic options for mesothelioma patients suggests the need for a better understanding of mesothelioma biology and the identification of novel therapeutic targets. Progranulin is a pluripotent growth factor whose dysregulation is implicated in several human pathologies including cancer. The pro-tumorigenic activity of progranulin depends on the activation of its functional receptor EphA2. Indeed, in bladder cancer, progranulin promotes EphA2 phosphorylation at Ser897 and triggers EphA2 oncogenic action resulting in increased tumor cell migration, invasion and in vivo tumor growth. Both progranulin and EphA2 are expressed in mesothelioma, with progranulin promoting tumor angiogenesis in a VEGF-independent manner and EphA2 being often mutated or overexpressed. However, in mesothelioma, the potential functional interaction between progranulin and EphA2 is unexplored. Using a panel of mesothelioma cell lines covering all mesothelioma subtypes, we observed increased levels of phosphorylated EphA2 at Ser897 when compared to immortalized normal mesothelial cells, and the levels of phosphorylation positively correlated with progranulin expression. Progranulin-dependent activation of EphA2 in mesothelioma cells promoted the activation of the MAPK and AKT pathways and ERK1/2-dependent EphA2 phosphorylation at Ser897. Transient depletion of progranulin by siRNA approaches as well as GRN gene knock-out by CRISP/Cas9 strategies in mesothelioma cells reduced the activation of the AKT signaling pathway and inhibited the migratory and invasive capabilities of progranulin-depleted cells when compared to parental cells, suggesting that the progranulin/EphA2 axis is oncogenic in mesothelioma. However, EphA2 genetic ablation resulted in an increased basal activation of AKT and MAPK and in progranulin-evoked EphA2-independet AKT/MAPK activation, indicating that alternative membrane receptors might compensate for EphA2 loss and sustain progranulin action in mesothelioma. Using several pharmacological and genetic approaches, we uncovered a role for EGFR and FAK in compensating for EphA2 loss by triggering progranulin-dependent oncogenic signaling in mesothelioma, highlighting a complex functional cross-talk between EphA2, EGFR and FAK in mediating progranulin-dependent tumorigenesis. Thus, these results suggest the need for combinatorial therapeutic approaches to blunt progranulin oncogenic action in mesothelioma.
Citation Format: Elisa Ventura, Simone Buraschi, Stephen J. Williams, Antonino Belfiore, Renato V. Iozzo, Antonio Giordano, Andrea Morrione. Mechanisms of action and regulation of the progranulin/EphA2 axis in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 97.
Abstract 972: MMR-deficiency is the most prominent genetic feature of prostate cancer metastases organotropism
Authors: Vis Daniel , Palit Sander , Corradi Marie , Lolkema Martijn , Mehra Niven , Cuppen Edwin , Wessels Lodewyk FA , Bernards Rene , Zwart Wilbert , van der Heijden Michiel S. , Bergman Andries M. 
Published: June 2022

Abstract
Prostate cancer (PCa) is the most prevalent, non-cutaneous, cancer in men in the Western world. Disease confined to the prostate can be cured, but metastatic disease cannot. PCa metastases are found in bone, lymph-nodes, liver and other visceral organs (visceral), in decreasing order of frequency. After an initial response to androgen receptor directed therapy, metastatic disease will inevitably recur as metastatic castration resistant prostate cancer (mCRPC), which is hallmarked by high morbidity and mortality. Since it is previously established, that the site of metastasis correlates with prostate cancer survival, we need a better understanding of metastatic organotropism. Therefore, we took advantage of the largest Whole Genome Sequencing (HiSeq X Ten system using the paired-end sequencing protocol) data set of mCRPC metastases to date. Molecular profiling of 326 metastases (Bone: 105, Lymph-node: 149, Liver: 49, Visceral: 23) revealed genetic determinants associated with organ-specific metastasis. First, we assessed differential occurrence of mutations in genes associated with targetable pathways. RB1 alteration were enriched in liver (35%) and in visceral metastases (30%), while lower rates were found in bone (10%) and lymph-nodes (13%)(Fisher exact test, p: 0.012). Analysis of aggregated pathway alteration data revealed a trend for increased frequency of alterations in the DNA repair and PI3K pathways in lymph node vs. bone metastases (p: 0.066 and 0.066, respectively). Next, we explored differential tumor mutational burden (TMB) between the sites. A higher TMB was observed in liver and visceral metastases compared to bone and lymph node metastases, while there was no difference between liver and visceral. The increased TMB in liver and visceral samples was associated with an MMR-deficiency mutational signature. Alterations in MSH6, MLH1 and POLD3 characterized a significant proportion of high TMB liver metastases, whereas high TMB visceral metastases predominantly showed MSH2 and POLD1 alterations.In conclusion: Our findings implicate high TMB/MMR-deficiency is a characteristic feature of liver and visceral PCa metastases, potentially impacting disease progression. Moreover, since response to immune check-point inhibitors is associated with high TMB, our findings might direct choice of therapy.
Citation Format: Daniel Vis, Sander Palit, Marie Corradi, Martijn Lolkema, Niven Mehra, Edwin Cuppen, Lodewyk FA Wessels, Rene Bernards, Wilbert Zwart, Michiel S. van der Heijden, Andries M. Bergman. MMR-deficiency is the most prominent genetic feature of prostate cancer metastases organotropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 972.
Abstract 982: A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma
Authors: Alchahin Adele Mirna , Mei Shenglin , Tsea Ioanna , Hirz Taghreed , Kfoury Youmna , Dahl Douglas , Wu Chin-Lee , Subtelny Alexander O. , WU Shulin , Scadden David T. , Shin John H. , Saylor Philip J. , Sykes David B. , Kharchenko Peter V. , Baryawno Ninib 
Published: June 2022

Abstract
Introduction: Renal cell carcinoma, particularly the clear cell histological subtype (ccRCC), is the most common kidney cancer in adults, accounting for 75-85% of all cases. When it is localized to the kidney, it is often cured with surgical resection or thermal ablation. One quarter of the patients have evidence of metastatic disease at the time of diagnosis, and in this setting ccRCC still is a highly lethal disease with few effective treatment options. In this study we used single-cell RNA-sequencing to characterize tumor cell clonality, metastatic signatures and the tumor microenvironment in ccRCC at the single-cell level.
Methodological approach: Here we took advantage of fresh patient samples that included treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. We used single cell RNA sequencing (10X Genomics, Chromium 3’ v2 kit, 10x Genomics), that was analyzed with PAGODA and CONOS.
Summary of new unpublished data: Our analysis revealed a distinct transcriptional signature that predicts metastatic potential and patient survival was disclosed through the single-cell analysis. In-depth exploration of the supporting stromal cells displayed a phenotype of vascular remodeling within the endothelial cells. The fibroblasts showed a proliferative signature that was associated with poor survival. An in silico cell-to-cell interaction analysis highlighted the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets.
Conclusions: Our discoveries in ccRCC provide complementary biological insights, specifically in the interplay between tumor cells and their microenvironment in ccRCC. We demonstrate important biological insights into ccRCC biology including: (1) identification of a distinct metastatic signature that predicts survival outcome, (2) discovery of a proximal tubule cell population that may represent the ccRCC cell of origin, and (3) a detailed exploration in the immunosuppressive environment and the stromal alterations in treatment-naïve patients. In addition, we stress potential therapeutic targets for further evaluation in preclinical models.
Citation Format: Adele Mirna Alchahin, Shenglin Mei, Ioanna Tsea, Taghreed Hirz, Youmna Kfoury, Douglas Dahl, Chin-Lee Wu, Alexander O. Subtelny, Shulin WU, David T. Scadden, John H. Shin, Philip J. Saylor, David B. Sykes, Peter V. Kharchenko, Ninib Baryawno. A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 982.
Abstract 998: Extracellular proximity labeling (ePL) as a tool to identify protein-protein interactions in the tumor microenvironment
Authors: Gurung Sadeechya 
Published: June 2022

Abstract
The extracellular matrix (ECM) is a dynamic niche that is extensively reshaped in the development of the tumor microenvironment (TME). Our current understanding of ECM function and dynamics is largely informed by identification of protein-protein interactions (PPIs) using co-immunoprecipitation (co-IP) techniques that may miss transient and weak/unstable interactions. Recent advances in proximity labeling techniques have greatly expanded the interactome networks of numerous intracellular proteins, however these tools have yet to be extended to study PPIs in the ECM. We have recently optimized a systematic approach to identify PPIs in the ECM using fusion constructs of the biotinylating enzymes, BioID2 and TurboID, with the widely expressed matrix regulator TIMP2. BioID2 and TurboID offer differing reaction kinetics that may provide complimentary information on extracellular PPIs (ePPIs). Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs) are crucial regulators of ECM structure and composition. TIMPs are widely expressed multifunctional proteins that serve to promote ECM homeostasis that is often perturbed in many cancers and chronic disorders. Although biochemical data suggests that TIMPs are promiscuous proteins, the TIMP interactome is poorly defined. We have optimized a protocol for the identification of ePPIs for the TIMP family of proteins. Fusion constructs equipped with a promiscuous biotin ligase (BioID2/TurboID) fused to the N- or C-terminal of full length TIMP2 were packaged into retroviral vectors for cellular delivery. Cells were exposed to the extracellular proximity labelling (ePL) fusion proteins and processed in our optimized analysis pipeline. ePPIs were identified via streptavidin pulldown and proteomic techniques. We present our optimized ePL pipeline and show that this technique is an effective tool for the identification of novel ePPIs for multiple extracellular targets.
Citation Format: Sadeechya Gurung. Extracellular proximity labeling (ePL) as a tool to identify protein-protein interactions in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 998.
Abstract CT035: Safety, preliminary efficacy and pharmacodynamic (PD) analysis of maveropepimut-S, intermittent low-dose cyclophosphamide and pembrolizumab in patients with advanced, metastatic bladder cancer
Authors: Rixe Olivier , Castonguay Vincent , Conter Henry , Chalas Eva , Desai Pratibha , Squillante Christian , MacDonald Lisa A. , Conlon Rebekah , Bramhecha Yogesh , Hirsch Heather , Graff Jeremy R. , Fiset Stephan 
Published: June 2022

Abstract
Background: Maveropepimut-S (MVP-S) is a novel immunotherapeutic that educates a specific CD8 T cell response to the cancer antigen, survivin, to orchestrate immune-mediated elimination of survivin-expressing cancer cells. Specifically, MVP-S is a lipid-in-oil formulation of the DPX delivery platform, incorporating five survivin-specific immunogenic peptides, the innate immune stimulant, polydIdC, and a CD4 T cell helper peptide. In prior clinical studies, MVP-S and intermittent low-dose cyclophosphamide (CPA) elicited confirmed clinical responses (both partial and complete by RECISTv1.1) and induced a robust, durable survivin-specific CD8 T cell response. Moreover, the combination with pembrolizumab appeared to be well tolerated in solid tumors and lymphomas. The purpose of this phase 2 study is to explore whether this combination may be safe and effective in advanced, metastatic bladder cancer patients, both naïve to, and previously treated with, immune checkpoint inhibitors.
Results: Seventeen (17) subjects were treated with the combination of MVP-S, CPA and pembrolizumab. Subjects received an average of 3 prior lines of therapy with 13/17 (76.4%) having previously received an anti-PD1/L1. Seven subjects progressed on or after anti-PD1/L1 as last line of therapy prior to entering the trial. The combination was well-tolerated, with majority of AEs being grade 1 or grade 2. Five (5) out of 17 subjects showed response: 3 subjects with PR (unconfirmed) and 2 with CR (confirmed). Three of these, including the 2 CRs, had progressed on anti-PD-1/L1. Long-term clinical benefit has been observed in several subjects (one patient is still on treatment after 17 months) and coincides with an increase in detectable survivin-specific T cells in peripheral blood.
Conclusion: Preliminary data suggest that MVP-S/CPA and pembrolizumab is a well-tolerated combination and shows encouraging preliminary clinical activity in the treatment of advanced or metastatic bladder cancer patients, including patients who have progressed on prior anti-PD-1/L1 therapy.
Citation Format: Olivier Rixe, Vincent Castonguay, Henry Conter, Eva Chalas, Pratibha Desai, Christian Squillante, Lisa A. MacDonald, Rebekah Conlon, Yogesh Bramhecha, Heather Hirsch, Jeremy R. Graff, Stephan Fiset. Safety, preliminary efficacy and pharmacodynamic (PD) analysis of maveropepimut-S, intermittent low-dose cyclophosphamide and pembrolizumab in patients with advanced, metastatic bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT035.
Abstract CT206: EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, started enrollment for its phase I first-in-human study
Authors: Gomez roca Carlos , Cassier Philippe , Mandron Marie , Estrabaut Myriam , Delesque-Touchard Nathalie , Smith Adam C. , Klawitter Amy , Gentry Leesa , Fons Pierre , Paillasse Michael R. , Davenne Lise , Fitzgerald Michael , Garner James , Delord Jean-Pierre 
Published: June 2022

Abstract
Introduction: EVT801 is a highly selective, orally available VEGFR3 inhibitor that strongly inhibits angiogenesis without inducing hypoxia, considered one of the main causes of cancer-associated immunosuppression. EVT801 has shown compelling single agent efficacy in multiple in vivo models. In addition, combination of EVT801 and Immune Checkpoint Therapy (ICT) agents shows additive effects, and thus holds promise for combination treatment without induction of hypoxia-induced-immunosuppression. A phase I clinical trial is underway.
Methods: The phase I trial will consist of two sequential stages. During the first stage, EVT801 will be administered to patients with advanced solid tumors in a multiple ascending dose study using an accelerated 3+3 design (1 patient per dose until grade 2 toxicities are observed) in up to 48 patients in 8 dose levels. The primary objective is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Stage 2 will focus on validation of this RP2D in two 6-patient cohorts diagnosed with soft tissue sarcoma or renal cell carcinoma. These patients will participate in intensive analyses involving several biomarkers to better understand the pharmacological activity of the drug. A potential third stage, consisting of a multiple ascending dose evaluation of the combination of EVT801 with immuno-oncology drugs, may be added to the ongoing trial, pending further technical discussions with physicians and regulators. In addition to conventional measures of safety, tolerability, efficacy, and pharmacokinetics, the phase I study will employ a rich suite of histological, immunological, and radiological biomarkers to provide early insights into the activity of EVT801.
Citation Format: Carlos Gomez roca, Philippe Cassier, Marie Mandron, Myriam Estrabaut, Nathalie Delesque-Touchard, Adam C. Smith, Amy Klawitter, Leesa Gentry, Pierre Fons, Michael R. Paillasse, Lise Davenne, Michael Fitzgerald, James Garner, Jean-Pierre Delord. EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, started enrollment for its phase I first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT206.
Abstract CT233: A phase 3, single-arm study of CG0070 in subjects with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG)
Authors: Uchio Ed , Lamm Donald , Shore Neil , Bivalacqua Trinity , Kamat Ashish , Tyson Mark , Anderson Paul , Grandi Paola , Burke James 
Published: June 2022

Abstract
IntroductionCG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG (J Urol. 2012;188:2391-7; Urol Oncol. 2018;36(10):440-7). This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC.Methods110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x1012 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 months (m) may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response.ResultsThe primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response.ConclusionThe study an ongoing trial, currently enrolling in the United States, Japan, South Korea, Australia, and Taiwan.Refs. Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, Aimi J, Lerner S, Yeung AW, Kazarian T, Maslyar DJ, McKiernan JM. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer.
Citation Format: Ed Uchio, Donald Lamm, Neil Shore, Trinity Bivalacqua, Ashish Kamat, Mark Tyson, Paul Anderson, Paola Grandi, James Burke. A phase 3, single-arm study of CG0070 in subjects with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT233.
Abstract CT512: A technology-based intervention using computers and mobile devices: To improve symptom experience of Asian American breast cancer survivors
Authors: Im Eun-Ok , Kim Gayeong , Jin Ruiqi , Choi Mi-Yong , Paul Sudeshna , Chee Wonshik 
Published: June 2022

Abstract
Purpose: Especially with the COVID19 pandemic, the necessity of technology-based interventions using computers and mobile devices has increased in cancer survivorship management including symptom management. However, little is known about the effectiveness of a technology-based intervention in improving symptom experience of racial/ethnic minorities including Asian American breast cancer survivors. The purpose of this study was to examine the efficacy of a technology-based intervention in improving symptom experience of Asian American breast cancer survivors.
Methods: This study was conducted as a part of an ongoing randomized clinical trial among 199 Asian American breast cancer survivors. The technology-based intervention included three sub-ethnic specific social media sites, interactive online educational sessions, and online resources. Both groups (intervention and control groups) used the American Cancer Society’s website on breast cancer, and only the intervention group used the technology-based intervention. Only the data collected using the questionnaire on background characteristics and health/disease status and the Memorial Symptom Assessment Scale-Short Form (MSAS) were analyzed for this study. The data were analyzed using separate intent-to-treat growth curve models.
Results: While both groups reported decreases in symptom scores from the pre-test to post 3-months (p&lt;.01), the intervention group had larger decreases in symptom scores compared with the control group (p&lt;.01). There existed significant group * time interactive effects on the Global Distress Index (β = - 0.234), the Physical Symptom Distress scores (β = -0.266), the psychological symptom distress scores (β = - 0.212c), the total number of symptoms (β = -0.261), and the total symptom distress scores ( β = -0.261).
Conclusions: The findings of this study clearly indicated symptom improvement among Asian American breast cancer survivors by a technology-based intervention using computers and mobile devices. Further studies with diverse racial/ethnic minorities are warranted to confirm the effectiveness of technology-based interventions in improving symptom experience of cancer survivors across different types of cancer.
Citation Format: Eun-Ok Im, Gayeong Kim, Ruiqi Jin, Mi-Yong Choi, Sudeshna Paul, Wonshik Chee. A technology-based intervention using computers and mobile devices: To improve symptom experience of Asian American breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT512.