bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 413: WT RAS signaling is an essential therapeutic target in RAS mutated cancers
Authors: Sealover Nancy E. , Kortum Robert L. 
Published: June 2022

Abstract
Single-agent targeting of RAS-mutated cancers using RAF/MEK/ERK or PI3K/AKT pathway inhibitors is ineffective; blocking one pathway relieves negative feedback control of RTK signaling and hyperactivates parallel effector pathways. While combined MEK and PI3K inhibition is effective in preclinical models, toxicity of this combination prevents its clinical use. Alternative strategies for treating RAS-mutated cancers are essential. Therapeutics directly targeting mutated RAS proteins have the potential to spare normal cellular function thereby lessening overall toxicity. Unfortunately, direct RAS inhibition as a monotherapy does not fully block RAS effector signaling. RAS proteins show differential activation of RAF and PI3K pathways: KRAS potently activates RAF but poorly activates PI3K, whereas HRAS potently activates PI3K but poorly activates RAF. Further, mutant RAS inhibition relieves negative feedback controls leading to rapid hyperactivation of RTK−WT RAS signaling. A more comprehensive understanding of the interplay between mutant RAS and RTK−WT RAS signaling is essential to developing rational therapeutic approaches to treat RAS-mutated cancers. We found that WT RAS enhanced mutant RAS-driven transformation by activating RAS effectors poorly engaged by mutated RAS. Further, inhibition of RAS effectors activated poorly by mutant RAS synergized with and limited resistance to mutant HRAS and KRAS inhibitors. The mutant HRAS inhibitor tipifarnib blocked PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cancer cell lines; covalent KRASG12C inhibitors blocked MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cell lines. Synergy between inhibitors of mutant RAS and RAS effectors was dependent on intact RTK/WT RAS signaling and was lost in both RASless or SOSless MEFs. Upstream of RAS, the RASGEFs SOS1 and SOS2 showed unique and overlapping functions to promote mutant RAS-driven transformation. SOS1 was critical for mutant RAS (G12V) activation and SOS1 inhibition augmented the efficacy of mutant RAS inhibitors. RTK−SOS2−PI3K signaling protected cells from anoikis and mediated mutant KRAS-driven transformation. These results should inform the design of clinical trials for patients with RAS-mutated cancers.
Citation Format: Nancy E. Sealover, Robert L. Kortum. WT RAS signaling is an essential therapeutic target in RAS mutated cancers [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 413.
Abstract 4134: Stromal FAP expression is associated with MRI visibility and patient survival in prostate cancer
Authors: Pellinen Teijo , Smith Kevin , Blom Sami , Turkki Riku , Hemmes Annabrita , Välimäki Katja , Eineluoto Juho , Kenttämies Anu , Nordling Stig , Kallioniemi Olli , Rannikko Antti , Mirtti Tuomas 
Published: June 2022

Abstract
Some clinically significant prostate cancers (PCa) are missed by magnetic resonance imaging (MRI). We asked if the tumor stroma in surgically treated primary PCa lesions positive or negative with MRI are different in their cellular and molecular properties, and whether the differences are reflected to the clinical course of the disease.
We profiled the stromal and immune cell composition of MRI-classified tumor lesions by applying multiplexed fluorescence immunohistochemistry (mfIHC) and automated image analysis in a clinical cohort of 343 patients (Cohort I). We compared stromal variables between MRI-visible, invisible lesions, and benign tissue and assessed the predictive significance for biochemical recurrence (BCR) and disease-specific survival (DSS) using Cox regression and Log rank analysis. Subsequently, we carried out a prognostic validation of the identified biomarkers in a population-based cohort of 319 patients (Cohort II).
MRI true-positive lesions are different from benign tissue and MRI false-negative lesions in their stromal composition. CD163-positive cells and fibroblast activation protein (FAP)-positive cells were more abundant in MRI true-positive than in MRI false-negative lesions or benign areas. In MRI true-visible lesions, a high proportion of stromal FAP-positive cells was associated with PTEN status and increased immune infiltration (CD8+, CD163+), and predicted elevated risk for BCR. High FAP phenotype was confirmed to be a strong indicator of poor prognosis in two independent patient cohorts using also conventional IHC.
The molecular composition of the tumor stroma may determine whether early prostate lesions are detectable by MRI and associates with survival after surgical treatment.
Citation Format: Teijo Pellinen, Kevin Smith, Sami Blom, Riku Turkki, Annabrita Hemmes, Katja Välimäki, Juho Eineluoto, Anu Kenttämies, Stig Nordling, Olli Kallioniemi, Antti Rannikko, Tuomas Mirtti. Stromal FAP expression is associated with MRI visibility and patient survival in prostate 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 4134.
Abstract 4156: BI-1808 - a first in class ligand-blocking αTNFR2 antibody for cancer immunotherapy
Authors: Mårtensson Linda , Cleary Kirsty , Holmkvist Petra , Kovacek Mathilda , Svensson Carolin , Semmrich Monika , Blidberg Therese , Demiri Mimoza , Dadas Osman , Borggren Marie , Pitic Vici , Lim Sean H. , Beers Stephen A. , Gertsson Susanne , Rohrberg Kristoffer S. , Karlsson Ingrid , McAllister Andres , Cragg Mark S. , Frendeus Björn , Teige Ingrid 
Published: June 2022

Abstract
The pleiotropic TNF-α:TNFR axis plays a central role in immune regulation. While the cellular expression of TNFR1 is broad, TNFR2 expression is mainly restricted to immune cells. The therapeutic potential of targeting TNFR2 for cancer treatment has been previously indicated and to gain further insight, we generated a wide panel of TNFR2-specific antibodies using the n-CoDeR F.I.R.S.T™ target and antibody discovery platforms. We identified antibodies against mouse or human TNFR2 that could block TNF-α binding and showed potent anti-tumor activity in several immune-competent models, both as single agent and in combination with anti-PD1. The mechanism-of-action was shown to be FcγR dependent and likely mediated through a combination of intra-tumor T reg depletion, CD8+ T cell expansion and modulation of innate immune cells e.g. neutrophils and myeloid cells. Toxicological studies of the human lead-candidate BI-1808 in non-human primates (NHP) demonstrated very good tolerability at doses up to 200 mg/kg, and in vitro studies with human cells showed no signs of harmful cytokine release. Furthermore, in vivo studies using immune competent mouse cancer experimental models showed a clear relationship between dose, receptor occupancy (RO) and efficacy. In both murine models and in the NHPs, soluble TNFR2 was clearly modulated by the treatment and closely correlated with RO. In addition, several changes in the immune cells (e.g. T cells and neutrophils) in the blood compartment were observed. Since January 2021, BI-1808 is evaluated in an ongoing Phase I/IIa trial. Similar to the preclinical studies, correlations between dose, RO and soluble TNFR2 has been clearly observed in the patients. In addition, and consistent with TNF-α:TNFR biology being conserved across the species, modulations of T cell and neutrophil numbers are also paralleled between the patients, NHPs and mice, increasing the likelihood of successful clinical translation of our findings.
Citation Format: Linda Mårtensson, Kirsty Cleary, Petra Holmkvist, Mathilda Kovacek, Carolin Svensson, Monika Semmrich, Therese Blidberg, Mimoza Demiri, Osman Dadas, Marie Borggren, Vici Pitic, Sean H. Lim, Stephen A. Beers, Susanne Gertsson, Kristoffer S. Rohrberg, Ingrid Karlsson, Andres McAllister, Mark S. Cragg, Björn Frendeus, Ingrid Teige. BI-1808 - a first in class ligand-blocking αTNFR2 antibody for cancer immunotherapy [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 4156.
Abstract 5134: Biomarker concordance between matched primary and metastatic colorectal tumors
Authors: Yang Yun , Xin Ying , Song Jianning , Jing Chao , Zhao Baoyi , Huang Depei , Deng Wei 
Published: June 2022

Abstract
Background: Distant metastasis accounts for ~90% of deaths from colorectal cancer (CRC). The use of biomarkers for targeted therapy in metastatic CRC is well-established, requiring genetic testing of primary or metastatic biopsies. Here we aimed to assess the concordance of actionable alterations in matched primary and metastatic colorectal tumors.
Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in a CAP/CLIA-approved laboratory (3DMed). NGS testing for SNV, InDel, CNV, MSI and TMB were performed on 19 primary tumors and 23 matched metastatic biopsies.
Results: 42 matched primary and metastatic tumor samples from 19 CRC patients were analyzed. 68.4% of the patients had only liver metastases, 5.3% ovarian metastases, 5.3% peritoneal metastases and 10.5% of the patients had more than one metastatic site. Mutational landscape showed that the primary samples and the metastases shared 80% of top 20 mutations. Biomarker concordance for KRAS was 89.5% (17/19), NRAS was 89.5% (17/19), BRAF was 94.7% (18/19), EGFR was 89.5% (17/19), BRCA2 was 94.7% (18/19) and MS status was 100% (19/19). Inconsistent RAS/BRAF status was found in two liver metastases and one ovarian metastasis. The frequencies of SRC amplification (P = 0.08) and ACVR2A mutation (P = 0.31) seem to be higher in the primary tumors, although these were not statistically significant. Conversely, mutations of NRAS, EGFR and MAP2K4 were detected only in the metastases. One patient harbored EGFR amplification in the ovarian metastasis, while this variant was not present in liver and primary sites. Copy number loss of MAP2K4 was found in the metastatic biopsies of two patients. Tumor mutation burden was comparable between the primary tumors and metastases (3.12 vs 2.17muts/Mb, P=0.29).
Conclusions: Our results demonstrates high concordance across multiple biomarkers between the primary and paired metastatic colorectal tumors. Molecular features of ovarian metastasis is more prone to inconsistent with primary sites than liver metastasis, which remains to be further verified in a large population.
Citation Format: Yun Yang, Ying Xin, Jianning Song, Chao Jing, Baoyi Zhao, Depei Huang, Wei Deng. Biomarker concordance between matched primary and metastatic colorectal tumors [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 5134.
Abstract 5177: Lymph node ratio is superior to AJCC N stage for predicting recurrence in papillary thyroid carcinoma
Authors: Parvathareddy Sandeep K. , Siraj Abdul K. , Qadri Zeeshan , Ahmed Saeeda O. , Siraj Nabil , DeVera Felisa , Annaiyappanaidu Padmanaban , Sabido Maria A. , Haqawi Wael , Aldossari Hassan , Al-Kuraya Khawla S. 
Published: June 2022

Abstract
Objective: Recently, lymph node ratio (LNR) has emerged as an alternative to American Joint Committee on Cancer (AJCC) N stage, with superior prognostic value. The utility of LNR in Middle Eastern Papillary thyroid carcinoma (PTC) remains unknown. Therefore, we retrospectively analyzed a large cohort of 1407 PTC patients for clinico-pathological associations of LNR.
Methods: Receiver operating characteristics (ROC) curve was used to determine the cut-off for LNR. We also performed multivariate logistic regression analysis to determine whether LNR or AJCC N stage was superior in predicting recurrence in PTC.
Results: Based on ROC curve analysis, a cut-off of 0.15 was chosen for LNR. High LNR was significantly associated with adverse clinico-pathological characteristics such as male sex, extrathyroidal extension, lymphovascular invasion, multifocality, bilateral tumors, T4 tumors, lateral lymph node (N1b) involvement, distant metastasis, advanced tumor stage, ATA high risk category and tumor recurrence. On multivariate analysis, we found that LNR was a better predictor of tumor recurrence than AJCC N stage (Odds ratio: 1.96 vs. 1.30; p value: 0.0184 vs. 0.3831). We also found that LNR combined with TNM stage and ATA risk category improved the prediction of recurrence-free survival, compared to TNM stage or ATA risk category alone.
Conclusions: The present study suggests LNR is an independent predictor of recurrence in Middle Eastern PTC. Integration of LNR with 8th edition AJCC TNM staging system and ATA risk stratification will improve the accuracy to predict recurrence in Middle Eastern PTC and help in tailoring treatment and surveillance strategies in these patients.
Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Zeeshan Qadri, Saeeda O. Ahmed, Nabil Siraj, Felisa DeVera, Padmanaban Annaiyappanaidu, Maria A. Sabido, Wael Haqawi, Hassan Aldossari, Khawla S. Al-Kuraya. Lymph node ratio is superior to AJCC N stage for predicting recurrence in papillary thyroid 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 5177.
Abstract 5230: Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable esophageal squamous carcinoma: an open-label, single-arm study
Authors: Jiang Bo , Yang Xin , Zhang Junling , Huang Mengli 
Published: June 2022

Abstract
Objective: Although neoadjuvant chemotherapy has been recommended for resectable ESCC patients, the 5-year overall survival rate was less than 50%. Immune checkpoint inhibitors have been shown to be efficient for advanced ESCC, while few studies focus on the neoadjuvant immunotherapy combined with chemotherapy. Herein, we designed a trial to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy for resectable ESCC.
Methods: All patients had treatment-naïve resectable ESCC (stage III) that were confirmed by histopathology. All patients were scheduled to receive surgery within 4-6 weeks after neoadjuvant treatment (2 cycles) consisting of PD-1 inhibitors (Camrelizumab 200mg or Sintilimab 200 mg or Tislelizumab 200 mg) combined with two conventional chemotherapy regimens (Cisplatin + paclitaxel). The primary endpoint was the major pathologic response (MPR). Secondary endpoints were disease-free survival (DFS), R0 resection rate and safety profile. Immune signature of immune cells were evaluated in surgical specimens using immunofluorescence.
Results: Between Aug. 1, 2020, and Oct. 1, 2021, we assessed 10 patients for screening, of whom 10 patients were enrolled. Neoadjuvant therapy was not associated with delays in surgery or increased surgical complications/mortality. The median follow-up was 5.0 months (range 2.0∼31.0 months). Ten (100.0%) successfully underwent R0 resection. Of the 10 evaluable patients, 6 (60.0%) were MPR, 4 (40.0%) were pathologic complete response (pCR). Imaging evaluation was feasible in all patients. Partial response (PR) was achieved in 1 (10.0%) and stable disease (SD) was observed in 8 (80.0%). The most common treatment-related grade 1-2 adverse events were anemia (5, 50.0%), nausea (3, 30.0%), vomiting (3, 30.0%), constipation (2, 20.0%) and myelosuppression (2, 20.0%). There was no grade 3-4 events and treatment-related deaths. The presence of CD3+ T cells, B cell, and CD56 bright were statistically comparable patient groups of MPR and pCR, with an increased tendency in pCR patients. In addition, macrophages, CD8+ T cells, PD-1+CD8+ T cell, Treg cells, and PD-L1+CD68+ cells in pCR patients showed a downward trend.
Conclusions: Neoadjuvant PD-1 inhibitors plus chemotherapies had manageable treatment-related toxic effects. This regimen induced pCR or MPR in 100.0% of resected tumor, demonstrating its antitumor efficacy in resectable ESCC.
Citation Format: Bo Jiang, Xin Yang, Junling Zhang, Mengli Huang. Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable esophageal squamous carcinoma: an open-label, single-arm 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 5230.
Abstract 5284: M1231 is a bispecific anti-MUC1xEGFR antibody-drug conjugate designed to treat solid tumors with MUC1 and EGFR co-expression
Authors: Knuehl Christine , Toleikis Lars , Dotterweich Julia , Ma Jianguo , Kumar Seema , Ross Edith , Wilm Claudia , Schmitt Martina , Grote Hans Juergen , Amendt Christiane 
Published: June 2022

Abstract
Mucin 1 (MUC1) and epidermal growth factor receptor (EGFR) are co-expressed at high prevalence in multiple cancer indications such as non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma, triple negative breast cancer and ovarian cancer. Tumor-associated MUC1 is hypoglycosylated and exposes peptide epitopes within its extracellular domain, which are not accessible to antibodies in normal epithelial tissue. MUC1 co-localizes with EGFR as a result of loss of cell polarity in tumor cells. M1231 is a bispecific antibody-drug conjugate (ADC) based on a SEED (strand-exchange engineered domain)-antibody scaffold targeting tumor-associated MUC1 and EGFR. Sutro Biopharma’s cell free expression system Xpress CF+™ enables incorporation of non-natural amino acids at precise positions in the SEED-antibody for site-specific linker-payload conjugation. The cytotoxic payload of M1231 (SC209) is a hemiasterlin-related microtubule inhibitor. The cleavable linker (ValCit-PABA) maintained ADC stability in human plasma in vitro, ensuring low systemic payload release. Pre-clinical activity of M1231 was assessed in vitro in cancer cell lines and in vivo in NSCLC and ESCC patient-derived xenograft (PDX) models. M1231 inhibited tumor cell viability in vitro at sub-nanomolar IC50 values. The bispecific MUC1xEGFR antibody has demonstrated superior internalization and lysosomal trafficking compared to monospecific bivalent antibodies. Efficient ADC uptake resulted in superior antitumor activity of M1231 in PDX models compared to monospecific bivalent ADCs. M1231 demonstrated durable and dose-dependent antitumor activity in PDX models. Strong antitumor activity with complete regression was observed in NSCLC and ESCC PDX models following a single treatment of M1231. M1231 antitumor activity was associated with high target expression in NSCLC PDX models and was observed across a range of target expression levels in ESCC models. In summary, efficient payload delivery to tumor cells and strong antitumor activity of M1231 indicate that M1231 may have the potential to deliver an efficacy benefit to patients with tumors co-expressing MUC1 and EGFR.
Citation Format: Christine Knuehl, Lars Toleikis, Julia Dotterweich, Jianguo Ma, Seema Kumar, Edith Ross, Claudia Wilm, Martina Schmitt, Hans Juergen Grote, Christiane Amendt. M1231 is a bispecific anti-MUC1xEGFR antibody-drug conjugate designed to treat solid tumors with MUC1 and EGFR co-expression [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 5284.
Abstract 5426: Down-regulation of cancer metabolism enhances radiosensitivity by impairing the heat shock response
Authors: Schwab Melissa , Thunborg Katharina , Azimzadeh Omid , von Toerne Christine , Shevtsov Maxim , Zdralevic Masa , Pouyssegur Jacques , Renner Kathrin , Kreutz Marina , Vaupel Peter , Multhoff Gabriele 
Published: June 2022

Abstract
Therapy (radiation) resistance can, inter alia, be caused by an increased lactate dehydrogenase (LDH) activity, elevated concentrations of the oncometabolite lactate and an overexpression of anti-apoptotic heat shock proteins (HSPs). In this study we aimed to break radioresistance by targeting the cancer metabolism. We could show, for the first time, that the lactate metabolism and heat shock response are co-regulated in two cancer cell systems (murine B16F10 melanoma cells, human LS174T colorectal adenocarcinoma cells). A CRISPR/Cas9 induced double knockout of LDHA/B (LDH−/−) as well as a pharmacological inhibition of LDH by Oxamate or GNE-140 reduces tumor growth, ROS production and synthesis of different HSPs, including Hsp90, Hsp70 and Hsp27. Moreover, the membrane Hsp70 density was significantly reduced on tumor cells after inhibition of the LDH activity as a consequence of a down-regulated lipid metabolism affecting the Hsp70-anchoring, tumor-specific glycosphingolipid Gb3. Our results demonstrate that influencing cancer metabolism increases radiation sensitivity by an impairment of the stress response. Since presently available LDH inhibitors have a low stability and high toxicity in vivo, we are currently investigating more potent LDH inhibitors with a beneficial safety profile. In summary, targeting the lactate metabolism provides a promising strategy to improve radiosensitivity by impairing the stress response.
Citation Format: Melissa Schwab, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Maxim Shevtsov, Masa Zdralevic, Jacques Pouyssegur, Kathrin Renner, Marina Kreutz, Peter Vaupel, Gabriele Multhoff. Down-regulation of cancer metabolism enhances radiosensitivity by impairing the heat shock response [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 5426.