bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3316: Intra-tumor heterogeneity assessment of liver lesions for colorectal cancer patients on CT-scans
Authors: Ghermi Ridouane , Ammari Samy , Garcia Gabriel , Harguem-zayani Sana , Lassau Nathalie , Schutte Kathryn 
Published: April 2023

Abstract
The objective is to find a consensus definition of intra-tumor heterogeneity of liver lesions for colorectal cancer patients on computed tomography (CT) scans and to evaluate the prognostic value of the newly defined criteria.
89 patients with colorectal cancer treated by antiangiogenics having standard pretreatment CT-scans were included. Lesions were manually segmented in a previous study. We reached a consensus definition by bringing three radiologists together to determine which criteria make a tumor heterogeneous. We asked two of the three radiologists to score lesions from one to three based on the consensus definition. A subset of 50 lesions was shared between annotators in order to check their agreement. 898 lesions were scored, which corresponds to a median of 6 lesions per patient. We associate a unique heterogeneity score to each patient defined as the difference between the number of very heterogeneous tumors and the number of heterogeneous tumors. The prognostic value of this heterogeneity score was assessed using a Cox regression.
Intra-tumor heterogeneity of a single lesion is defined on a scale of one to three: homogeneous (pixels are of similar intensities), heterogeneous (pixels are of different intensities but organized as a ring), very heterogeneous (pixels are of different intensities and randomly organized). We note that the shape of the tumor is not taken into account in the heterogeneity assessment. The two radiologists agreed on the lesion heterogeneity score in 53% of cases. The patient heterogeneity score is significantly prognostic in both the univariate analysis (Kaplan-Meier estimator with median cut-off; p-value = 0.016) and the multivariate analysis (Cox model with control variables including gender, age, weight, treatment and tumor burden; p-value = 0.024).
Three radiologists have reached a consensus to define intra-tumor heterogeneity of liver lesions for colorectal patients. According to this definition, intra-tumor heterogeneity was shown to be a prognostic factor.
Citation Format: Ridouane Ghermi, Samy Ammari, Gabriel Garcia, Sana Harguem-zayani, Nathalie Lassau, Kathryn Schutte. Intra-tumor heterogeneity assessment of liver lesions for colorectal cancer patients on CT-scans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3316.
Abstract 3401: Discovery of GH658, a novel tead allosteric inhibitor as a cancer therapy
Authors: Li Jie Jack , Zhang Guiping , Li Jiapeng 
Published: April 2023

Abstract
The Hippo pathway is an evolutionarily conserved signaling cascade. Its dysregulation may lead to cancer progression, metastasis, cancer therapy resistance, and immune evasion. Diverse genetic aberrations leading to YAP/TAZ hyperactivation have been elucidated over the last 20 years. Almost all the pro-tumor mutations lead to constitutive TEAD transcription factor activation, suggesting that targeting TEAD transcription factors could offer an important therapeutic opportunity. Employing structure-based drug design, we have discovered GH658, a novel allosteric TEAD inhibitor that selectively targets the auto-palmitoylation pocket of TEAD proteins. In vitro, GH658 displayed a low nM potency in TEAD-based reporter assays, which translated to specific low nM inhibition of NF2 deficient mesothelioma proliferation. In vivo, GH658 demonstrated favorable pharmacokinetic properties in different species and showed acceptable safety profile. Furthermore, daily oral dosing of GH658 led to complete growth inhibition of NF2 mutant xenograft tumors without adverse effect on body weight. More importantly, GH658 displayed significant in vivo effect on drug tolerant persistent cancer cells and drug resistance against inhibitors targeting EGFR‒RAS signaling pathways in combination studies. In summary, with potent in vitro and in vivo efficacy of targeting YAP/TAZ‒TEAD transcriptional complex, GH658 not only showed consistent monotherapy activity in selected cancer models, but also demonstrated significant synergistic effects in diverse drug combination studies.
Citation Format: Jie Jack Li, Guiping Zhang, Jiapeng Li. Discovery of GH658, a novel tead allosteric inhibitor as a cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3401.
Abstract 3441: A multivalent peptoid conjugate that inhibits therapy-resistant prostate cancer cell proliferation by modulating androgen receptor transcriptional activity
Authors: Habault Justine , Schneider Jeffrey A. , Ha Susan , Ruoff Rachel , Puccini Joseph , Bar-Sagi Dafna , Wong Kwok-Kin , Zoubeidi Amina , Claessens Frank , Wise David R. , Logan Susan K. , Kirshenbaum Kent , Garabedian Michael J. 
Published: April 2023

Abstract
Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance despite the continued expression and function of the AR. We developed a new approach to antagonize the proliferative activity of AR and inhibit castration-resistant prostate cancer (CRPC) growth using multivalent peptoid conjugates (MPCs). Our strategy is to display multiple copies of the AR antagonist, ethisterone, on a peptoid scaffold. Such a multivalent display increases the ligand’s effective local concentration, thus targeting AR with high affinity and affecting AR interactions with coregulators. Here, we report a new potent MPC called MPC309, which displays three ethisterone groups and binds to AR with nanomolar affinity. MPC309 reduces the proliferation of enzalutamide-resistant prostate cancer cells, including those harboring AR splice variants, AR ligand binding mutations, and non-canonical AR gene expression programs. We provide evidence that MPC309 enters cells via macropinocytosis, which facilitates the fluid-phase uptake of extracellular macromolecules. Macropinocytotic uptake of MPC309 enhances cancer cell-specific delivery, thus limiting systemic toxicities. MPC309 displays favorable pharmacological properties and produced significantly greater tumor suppression in xenograft studies than enzalutamide, the standard of care anti-androgen in clinical use. Mechanistically, MPC309 inhibits prostate cancer growth by eliciting a unique gene expression program through alterations in AR chromatin occupancy compared to dihydrotestosterone (DHT) or enzalutamide. Thus, MPC309 represents a novel AR antagonist that activates an AR anti-proliferative program to repress the growth of CRPC and supports further investigation of the MPC compound class for treating CRPC.
Citation Format: Justine Habault, Jeffrey A. Schneider, Susan Ha, Rachel Ruoff, Joseph Puccini, Dafna Bar-Sagi, Kwok-Kin Wong, Amina Zoubeidi, Frank Claessens, David R. Wise, Susan K. Logan, Kent Kirshenbaum, Michael J. Garabedian. A multivalent peptoid conjugate that inhibits therapy-resistant prostate cancer cell proliferation by modulating androgen receptor transcriptional activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3441.
Abstract 3460: Targeting the MIF-CD74 axis to overcome resistance to tyrosine kinase inhibitors in non-small cell lung cancer
Authors: Izumi Motohiro , Lee Meghan , Shibahara Daisuke , Kobayashi Ikei S. , Plotnick David , Kobayashi Susumu S. 
Published: April 2023

Abstract
Development of tyrosine kinase inhibitors (TKIs) against oncogenic drivers has significantly improved survival of patients with oncogene-mutated non-small cell lung cancer (NSCLC). However, acquired resistance to TKIs emerges over time in essentially all patients who initially respond. Recent evidence suggests that drug-tolerant persister (DTP) cells, which survive and adapt to targeted therapies during an early phase of treatment, play an important role in the emergence of drug resistance. We previously reported that CD74 expression is upregulated in EGFR-mutated lung cancer after treatment with EGFR-TKIs and that CD74 can be one of the DTP cell markers. However, the mechanism underlying CD74 expression and the role of CD74 in DTP cells remain unclear. Here, we sought to identify the mechanism using cell culture systems and transgenic mouse models. We confirmed that CD74 upregulation at the mRNA level after TKIs treatments in various oncogene-mutated cell lines, including those with EGFR mutations, ROS1 fusions, and ALK fusions. We found that CIITA, upstream of CD74, and TNF-α expression were induced by TKIs treatments in tumor cells, leading to an increase in CD74 expression. In addition, we found that TKIs treatments enhanced the autocrine secretion of macrophage migration inhibitory factor (MIF), a ligand of CD74, from tumor cells, suggesting that autocrine stimulation of the CD74 signaling results in block of apoptosis and emergence of DTP cells. To examine whether CD74 plays an important role in the emergence of resistance to TKIs in vivo, we crossed lung-specific EGFR-L858R-T790M transgenic mice with Cd74 knockout mice. Complete deletion of CD74 overcame or delayed resistance to TKIs. Taken together, the MIF-CD74 axis can be a novel target to overcome resistance in driver-mutated NSCLC.
Citation Format: Motohiro Izumi, Meghan Lee, Daisuke Shibahara, Ikei S. Kobayashi, David Plotnick, Susumu S. Kobayashi. Targeting the MIF-CD74 axis to overcome resistance to tyrosine kinase inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3460.
Abstract 347: Revealing the intracellular cytomatrix, immobilized biocatalysis, and concept of the operating cell
Authors: Shaiken Tattym E. 
Published: April 2023

Abstract
The central problem of cell biology is the arrangement of biochemical reactions in the cytoplasm responsible for sustaining cellular life where, paradoxically, a myriad of metabolic reactions that could exclude each other coincide. Despite this well understood fact, the structural organization of the cytoplasm remains unclear, so far. Recent models indicate that cytoplasm contains viscous fluid and elastic solid phases. We separated the viscous fluid and elastic solid compartments, identifying them as the cytosol and cytomatrix, respectively. The distinctive composition of the cytomatrix included structural proteins, ribosomes, and metabolome enzymes. High-throughput analysis revealed unique biosynthetic pathways within the cytomatrix. The enrichment of biosynthetic pathways in the cytomatrix indicated the presence of immobilized biocatalysis. Enzymatic immobilization and segregation can surmount spatial impediments, and the local pathway segregation may form cytoplasmic organelles. Protein translation was reprogrammed within the cytomatrix under the restriction of protein synthesis by drug treatment. Thus, cytosol and cytomatrix are an elaborately interconnected network that promotes operational flexibility in healthy cells and the survival of malignant cells. Immobilized biocatalysis integrates the intracellular and extracellular matrices and receptors with the nuclear processes, thus removing the spatial hindrances for biochemical processes, which elucidates human cell operation.
Citation Format: Tattym E. Shaiken. Revealing the intracellular cytomatrix, immobilized biocatalysis, and concept of the operating cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 347.
Abstract 3491: Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates
Authors: Zhang Jason Z. , Nguyen William H. , Rose John C. , Ong Shao-En , Maly Dustin J. , Baker David 
Published: April 2023

Abstract
While Ras is known to dynamically shuttle around the cell, the activity, mechanism of activation, and function of non-plasma membrane-localized Ras is unclear due to lack of suitable tools. To address these questions, we used the Latching Orthogonal Cage-Key pRotein (LOCKR) switch platform to generate first-in-class intracellular sensors for endogenous Ras activity (Ras-LOCKR-S) and signaling-dependent proximity labelers (Ras-LOCKR-PL). We find that: 1) Receptor activation leads to endogenous Ras signaling at endomembranes, which is enhanced by golgi-localized guanine exchange factors. 2) Recruitment of SAM68 and MARCKS to oncogenic condensates fuels local Ras signaling and cell growth. 3) Major Vault Protein drives RasG12C inhibitor resistance by enhancing signaling at the golgi and altering mitochondrial metabolism. Together, these results highlight the importance of non-plasma membrane Ras signaling (endomembranes and condensates), and our new sensors should accelerate the discovery of new therapeutic targets.
Citation Format: Jason Z. Zhang, William H. Nguyen, John C. Rose, Shao-En Ong, Dustin J. Maly, David Baker. Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3491.
Abstract 3492: The small GTPase ARF6 augments BRAFV600E-MAPK signaling in melanomagenesis
Authors: Wang Junhua , Rogers Aaron , Rich Coulson , Sorensen Lise , Holmen Sheri , Wolff Roger , Grossmann Allie 
Published: April 2023

Abstract
ARF6 is a member of the Ras superfamily of small GTPases and has critical functions in endo-membrane trafficking pathways. We previously reported that ARF6 is aberrantly activated in metastatic melanoma and that activation of ARF6 stimulates WNT5A/beta-catenin and PI3K/AKT signaling to promote invasion and accelerate metastasis. Herein, we discovered an ARF6 activation signature in primary melanomas that is associated with inferior overall survival, supporting a novel role for ARF6 in early-stage progression. Conversely, melanocyte-specific deletion of Arf6 in Dct;TVA::BrafV600E;Cdkn2aNull murine melanoma significantly reduced tumorigenesis and progression, and improved survival. Importantly, bulk tumor transcriptome analysis showed reduced expression of ERK-induced genes in these BRAFV600E tumors. Likewise, immunofluorescent staining of tumor sections showed a significant reduction of cytoplasmic and nuclear p-ERK levels. Together these data demonstrate that loss of ARF6 reduces BRAFV600E-MAPK signaling output in vivo. This is a provocative finding because it implies that endomembrane trafficking has a major role in promoting BRAFV600E-driven tumorigenesis. More specifically, ARF6 may be critical for augmenting BRAFV600E signaling. Consistent with this hypothesis, expression of activated ARF6(ARF6Q67L) in our murine BRAFV600E melanoma cells was associated with upregulation of BRAFV600E, p-MEK, and p-ERK levels, detected by Reverse Phase Protein Array analysis. In addition, ARF6Q67L tumor cells showed an increase in anti-apoptotic proteins with a reciprocal decrease in pro-apoptotic proteins. Knockdown of Arf6 in BRAFV600E human melanoma cells significantly reduced proliferation and sensitized cells to vemurafenib-induced apoptosis. Overall, our data reveal that ARF6 augments MAPK signaling in BRAFV600E-driven tumorigenesis. Further work is needed to understand if ARF6 mediates endomembrane-dependent signaling of the BRAFV600E-MAPK pathway.
Citation Format: Junhua Wang, Aaron Rogers, Coulson Rich, Lise Sorensen, Sheri Holmen, Roger Wolff, Allie Grossmann. The small GTPase ARF6 augments BRAFV600E-MAPK signaling in melanomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3492.
Abstract 3513: Developing a 3D biomimetic liver metastatic niche model for pancreatic cancer
Authors: Pahlavanneshan Mahsa , Xiao Weikun , Eun Chae Young , Hwang Chang-Il , Hill Reginald 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the Unites States with a 5-year survival rate of only 11%. Early diagnosis is very difficult and thus 53% of patients are diagnosed after metastasis has already occurred, with the liver being the most frequently affected site. Both primary tumors and metastases have highly fibrotic stroma. Thus, stromal targeting agents have the potential to benefit patients, even those with metastatic disease. However, in addition to different resident fibroblasts, a study based on a rapid autopsy program of metastatic PDAC patients showed that tumor ECM density is actually lower at sites of liver metastasis compared to the primary tumor. These results highlight some of the differences between the microenvironment of the liver metastatic niche (LMN) compared to that of the primary tumor. Thus, to best help patients, models which recapitulate the LMN are needed. We developed a 3D biomimetic model to co-culture PDAC organoids and host matching primary CAFs to recapitulate the desmoplastic environment of primary PDAC. Our preliminary results show that primary site derived CAFs induce organoid growth, chemoresistance, and ECM remodeling when co-cultured with PDAC organoids. Utilizing paired organoids which metastasized to the liver (LM organoids), we tested if primary site derived CAFs would have the same effect on LMs. Interestingly, we observed that while LM organoids were intrinsically more drug resistant, co-culture with primary site derived CAFs had no effect on chemoresistance or ECM remodeling. Next, we utilized a metastasis associated fibroblast (MAF) liver cell line to investigate the role of MAFs in tumor growth, chemoresistance, and ECM remodeling. Our results show that primary and metastatic organoids use different mechanism to induce ECM stiffness triggered by fibroblast activation and remodeling in their resident fibroblasts.
Citation Format: Mahsa Pahlavanneshan, Weikun Xiao, Chae Young Eun, Chang-Il Hwang, Reginald Hill. Developing a 3D biomimetic liver metastatic niche model for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3513.
Abstract 3617: Investigating a role for PIKfyve in cell migration and invasion of clear cell renal cell carcinoma
Authors: Cormier Jolène , Turcotte Sandra 
Published: April 2023

Abstract
Introduction. Clear cell renal cell carcinoma (ccRCC) is the most frequent type of kidney cancer. These highly vascularized tumors are characterized by mutations that inactivate the von Hippel-Lindau (VHL) tumor suppressor gene. About 30 % of patients present metastasis at diagnosis and 30-40% of patients with localized tumors relapse after surgery. Unfortunately, metastatic ccRCC remains incurable and are resistant to standard therapies. Our studies demonstrated that ccRCC with a loss of VHL can be targeted using a small molecule named STF-62247. This molecule blocks the autophagic flux causing enlargement of endolysosomes leading to cell death. More recently, we identified the lipid kinase PIKfyve as a target of STF-62247. A central complex assuring the functionality of the lysosome is formed by the lipid kinase PIKfyve, the scaffold protein ArPIKfyve (Vac14), and the phosphatase Sac3 (Fig4). Interestingly, PIKfyve has shown to play a role in cell migration but the mechanisms are not well understood.
Objectives. Our project aims to i) assess a role for PIKfyve in ccRCC migration/invasion, ii) evaluate the potential of PIKfyve inhibitors on angiogenesis, and iii) assess the effect of PIKfyve inhibitors or genetic knockdown of PIKfyve, Vac14 or Fig4 on tumor growth in vivo.
Methods and Results. PIKfyve, Vac14 and Fig4 gene expression were modified using CRISPR/Cas9 (Cr) or the SMARTvectorTM Inducible Lentiviral shRNA system. qRT-PCR and western blot validated our models. Results obtained in Cr.PIKfyve and Cr.Vac14 indicated that loss of Vac14 decreased survival of VHL-deficient ccRCC. Moreover, our recent results show that migration measured by wound healing assay is reduced in CRISPR cells compared to control. To investigate a role for PIKfyve in angiogenesis, tube formation assay was performed in treated cells with PIKfyve inhibitors. Our results indicated a reduction in tube formation in STF-62247 and apilimod treated cells. Furthermore, we will use the proteome profiler human angiogenesis array to identify angiogenic proteins linked to PIKfyve activity.
Conclusion. Understanding how PIKfyve is involved in the process of angiogenesis would play a major role in the knowledge for new targeted therapies inkidney cancer.
Citation Format: Jolène Cormier, Sandra Turcotte. Investigating a role for PIKfyve in cell migration and invasion of clear cell renal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3617.