bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A07: Role of the class IA PI3K p110β subunit in pancreatic cancer
Authors: Arcucci Silvia , Therville Nicole , Basset Céline , Vertut Aurélie , Guillermet-Guibert Julie 
Published: December 2020

Abstract
Introduction: Class I PI3K signaling is constitutively active and correlated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). The modest effect of pan-PI3Ks inhibitors (targeting all p110 isoforms) clinically tested on different types of cancer highlighted the need to understand the roles of each PI3K isoform in cancer cell, with isoform-specific inhibitors of PI3K and murine models that conditionally target their activity. My team has developed unique mouse models that recapitulate the carcinogenesis of PDAC and that conditionally target the activity of p110α or p110β specifically in pancreatic epithelial cells.
Methods: We analyzed the biologic impact of pancreas-restricted genetic inactivation of p110β during pancreatic cancer progression induced by oncogenic Kras with or without mutated p53 combined with experimentally induced risk factor conditions such as inflammation. In particular, we searched the mechanisms of action of p110β in pancreatic cancerogenesis and in lesion-driven stroma formation.
Results: Inhibition of p110β prevented tumor progression towards metastatic cancer and led to the formation of low-grade neoplastic lesions, demonstrating the role of this isoform in pancreatic carcinogenesis. We found that upon genetic inactivation of the p110β isoform, the only present lesions are duct-like preneoplastic structures. Besides, mice harboring genetic inactivation of p110β in their pancreas are protected from mutated Kras and p53-induced lethality. Interestingly, p110β inactivation in pancreatic epithelial cells is responsible for changing the immune cell recruitment and the stromal response to epithelial oncogenic Kras signal or to inflammation.
Conclusion: Our data suggest that p110β in pancreatic lineage plays an important role in murine pancreatic cancer initiation induced by genetic alterations commonly found in pancreatic cancer, by impacting cell dedifferentiation and reprogramming tumor microenvironment.
Citation Format: Silvia Arcucci, Nicole Therville, Céline Basset, Aurélie Vertut, Julie Guillermet-Guibert. Role of the class IA PI3K p110β subunit in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A07.
Abstract A23: Dissecting the SMAD4 metastasis suppressor complex to identify novel prognostic biomarkers and therapeutic targets for colon cancer
Authors: Wong Chen Khuan , Thiagalingam Sam 
Published: December 2020

Abstract
Colon cancer is the second most lethal cancer in men and women in the United States and metastasis is the primary cause of mortality. Hence, there is an urgent need to elucidate the molecular mechanisms underlying metastasis to identify new prognostic biomarkers and therapeutic targets. Previous studies reported that SMAD4 is either mutated frequently (10-20%) or exhibits low expression, which is associated with poor prognosis, presence of metastases, and resistance to 5-fluorouracil (5-FU), the common chemotherapeutic agent for colon cancer. Our analyses confirmed that the probability of overall survival (OS) and relapse-free survival (RFS) is worse in patients with low levels of SMAD4 expression and found that it is associated with resistance to both 5-FU and irinotecan, two of the most widely used chemotherapeutic agents for treating colon cancer. Since our previous studies found that SMAD4 interacts with and inhibits HIF1α, leading to reduced expression of HIF1α target genes such as VEGF (angiogenesis) and GLUT1 (glucose uptake), we hypothesized that SMAD4 forms a metastasis suppressor complex to inhibit colon cancer progression. Here, we report the identification of the components in the SMAD4 metastasis suppressor complex using co-immunoprecipitation and mass spectrometry, with potential roles in regulating metastasis and for conferring resistance to chemotherapy. We will discuss the characterization of candidate genes, which include PI3K/mTOR pathway genes that might serve as biomarkers in predicting disease progression/prognosis and as therapeutic targets to treat metastatic colon cancer.
Citation Format: Chen Khuan Wong, Sam Thiagalingam. Dissecting the SMAD4 metastasis suppressor complex to identify novel prognostic biomarkers and therapeutic targets for colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A23.
Abstract A24: CD146-Rictor interaction reveals a pathway linking mTORC2 activation with extracellular stimuli
Authors: Xu Wenyi , Luo Yongting , Cui Wei 
Published: December 2020

Abstract
In all eukaryotes, the mechanistic target of rapamycin (mTOR) signaling emerges as a master regulator of homeostasis, which integrates environmental inputs to regulate many fundamental cellular processes such as cell growth and metabolism. The mTOR signaling functions through two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which correspond to two major branches of signal output. However, it remains enigmatic how extracellular stimuli regulates mTOR signaling, particularly for mTORC2. Here, we demonstrate that in human umbilical vein endothelial cells (HUVEC), vascular endothelial growth factor (VEGF) promotes the activation of mTORC2 signaling, exhibited as phosphorylation of Akt /PKCα/SGK1. Cell adhesion molecule CD146, as VEGFR2 co-receptor, plays the pivotal role in mediating mTORC2 activation in response to VEGF. Deletion of CD146 resulted in dramatic reduction in mTORC2 activity, without affecting other PI3K/Akt/mTOR signaling pathways, such as mTORC1 and PI3K/PDK1, indicating that CD146 specifically regulates mTORC2 activity. By means of co-immunoprecipitation (co-IP) assay, CD146 is bestowed to interact with Rictor via its juxta-membrane KKGK motif upon VEGF stimulation, CD146-Rictor (mTORC2) interaction not only stabilizes Rictor from ubiquitin-proteasome-mediated degradation but also activates mTORC2 signaling, thus promoting VEGF-induced endothelial cell proliferation and survival. Collectively, our findings have identified a previously unanticipated mechanism by which mTORC2 signaling pathway is directly under the control of extracellular stimuli, linking environmental cues with mTORC2 activity, and implicate that targeting CD146-mTORC2 axis might be a novel strategy for diseases driven by uncontrolled cell proliferation.
Citation Format: Wenyi Xu, Yongting Luo, Wei Cui. CD146-Rictor interaction reveals a pathway linking mTORC2 activation with extracellular stimuli [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A24.
Abstract B06: Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses Kras-mutated non-small cell lung cancer
Authors: Wang Yu-xiang , Li Xian , Liu Xue-ling , Wang Bo-bo , Chen Yi , Yang Chun-hao , Ding Jian , Meng Ling-hua 
Published: December 2020

Abstract
Activating KRAS mutation is the most common driver mutation in the initiation and promotion of non-small cell lung cancer (NSCLC). Direct inhibition of the enzymatic activity of mutated Kras has been proved unsuccessful. Deregulation of PI3K-Akt-mTOR signaling, one of the most important downstream effectors of Kras, plays important roles in tumorigenesis and drug resistance in NSCLC. In this study, we found that a novel PI3Kα-specific inhibitor, CYH33, possessed variable activity against a panel of Kras-mutated NSCLC cell lines. Though CYH33 blocked Akt phosphorylation in all tested cells, phosphorylated Rb decreased in CYH33-sensitive but not resistant cells, which was consistent with G1 phase arrest in CYH33-sensitive cells. Consequently, combination of a CDK4/6 inhibitor PD0332991 with CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and -resistant cells, which was accompanied with enhanced cell population in G1 phase compared to single-agent treatment. Moreover, downregulation of cyclin D1 with siRNA sensitized A549 and H23 cells to CYH33. Reciprocally, CYH33 abrogated PD0332991-induced upregulation of phosphorylated Akt and cyclin D1 in A549 cells. Cotreatment of these two drugs demonstrated synergistic activity against A549 and H23 xenografts with enhanced inhibition on the phosphorylation of Akt and Rb compared to administration of CYH33 or PD03332991 alone. Thus, simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against Kras-mutated NSCLC and provided a mechanistic rationale for a combination approach using PI3Kα inhibitor and CDK4/6 inhibitor CYH33 for the therapy of Kras-mutated NSCLC.
Citation Format: Yu-xiang Wang, Xian Li, Xue-ling Liu, Bo-bo Wang, Yi Chen, Chun-hao Yang, Jian Ding, Ling-hua Meng. Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses Kras-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B06.
Abstract B09: Structural biology of the PI3K pathway: On with phosphorylation, down with ubiquitination
Authors: Gabelli Sandra 
Published: December 2020

Abstract
The regulation of the PI3K pathway is central to cell growth and is deregulated in diseases such as cancer and cardiovascular disease. We are using biochemistry, structural biology, and chemical biology to probe the activation and inhibition mechanisms of the nodes of the pathway PI3Ka, AKT and PTEN. We have determined the roles of Lys776, His 936 and His 917 in the lipid and protein activity of PI3Ka. While H936A inactivates the lipid kinase activity without affecting auto-phosphorylation, H197 abolishes both the lipid and protein kinase activities of PI3Ka. The signature aspect of the Ser/Thr protein kinase Akt's regulation involves its C-terminal phosphorylation, classically understood to be the mTORC2-mediated phosphorylation of Ser473, which converts the Akt kinase into its active conformation. Using a multi-technique approach we determined that pS473-Akt activation is driven by an intramolecular interaction between the C-tail and the PH-domain linker to relieve autoinhibition. In contrast, the activating pSer477/pThr479 modifications of Akt have a different mechanism in which the relief from autoinhibition is by binding to the activation loop. All three nodes are regulated by NEDD4-family of ligases.
Note: This abstract was not presented at the conference.
Citation Format: Sandra Gabelli. Structural biology of the PI3K pathway: On with phosphorylation, down with ubiquitination [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B09.
Abstract B11: mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB
Authors: Biondini Marco , Rose April , Annis Matthew , Ferrario Cristiano , Puertollano Rosa , Basik Mark , Siegel Peter 
Published: December 2020

Abstract
The biggest challenge in the effective management of breast cancer is the limited duration of therapeutic benefit that is achieved with the current treatment options. Patients diagnosed with triple-negative breast cancer (TNBC), a type of breast tumor with worst prognoses, are currently treated with surgery, radiation and chemotherapy. Unfortunately, despite initial responses cancer cells become resistant to drugs and tumors relapse. We previously identified the cell surface protein GPNMB as a key mediator of breast cancer metastasis. Recently, an antibody-drug conjugate targeting GPNMB (Cdx-011) was developed that has been tested as single agent for the treatment of metastatic TNBC in a clinical trial. We have recently uncovered a novel response of TNBCs to therapeutic treatments: GPNMB expression is greatly elevated following treatment with mTOR pathway inhibitors (i.e., rapamycin, INK-128, AZD2014 and Torin-1) as well as conventional chemotherapy agents (doxorubicin, paclitaxel or cisplatin) and experimental treatments, i.e., MEK pathway inhibitors. Pharmacologically induced enhancement of GPNMB was also observed in ER+ cancers treated with antiestrogens (i.e., Fulvestrant). Interestingly, tumor cells that developed resistance to chemotherapy or antiestrogens exhibit higher levels of GPNMB. We found that therapy-induced GPNMB upregulation is mediated by the mobilization of the stress-induced MiTF/TFE family of transcription factors. In TNBC cells, mTOR inhibition promotes TFE3 nuclear translocation and GPNMB transcription. In ER+ cells, antiestrogens inactivate mTOR pathway causing TFE3 nucleus localization and GPNMB expression. We are currently conducting preclinical studies to investigate whether the upregulation of GPNMB caused by treatment with mTOR inhibitors could sensitize breast cancer cells to the activity of an antibody-drug conjugate targeting GPNMB (Cdx-011).
Citation Format: Marco Biondini, April Rose, Matthew Annis, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter Siegel. mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B11.
Abstract B12: Examining EGFR-mediated PI3K/Akt pathway in combination therapy of cetuximab and dynamin inhibition
Authors: Chew Hui Yi , Panizza Benedict , Cooper Caroline , Dolcetti Riccardo , Coward Jim , McCluskey Adam , Robinson Phillip J. , Wells James W. , Simpson Fiona 
Published: December 2020

Abstract
Adenoid cystic carcinoma (ACC) is a rare and highly aggressive malignant tumor that affects the salivary glands, lacrimal and ceruminous glands of the head and neck region. ACC tends to spread to neighboring regions via perineural methods and metastasize from the primary region to the lung, liver and bones. Current treatment includes surgical resection of the primary lesion followed by radiotherapy. However, about 80% of the patients develop metastatic disease with poor prognosis; hence, new treatment is necessary for ACC patients. EGFR is known to be overexpressed in most of salivary gland carcinomas, particularly ACC. Numerous targeted therapies, including anti-EGFR monoclonal antibody, have been trialed in ACC patients, with disease stabilization reported in approximately half of the trial patients. Our laboratory is examining a combination therapy in which we combined the use of a dynamin inhibitor with monoclonal antibody to enhance antibody-dependent cellular cytotoxicity (ADCC) response in murine models and now in clinical trial. As preclinical data, we examined the signaling profile of the tumor cells in the combination therapy with different dynamin inhibitors.
Citation Format: Hui Yi Chew, Benedict Panizza, Caroline Cooper, Riccardo Dolcetti, Jim Coward, Adam McCluskey, Phillip J. Robinson, James W. Wells, Fiona Simpson. Examining EGFR-mediated PI3K/Akt pathway in combination therapy of cetuximab and dynamin inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B12.
Abstract IA14: mTOR as a central regulator of T-cell activation, differentiation, and function
Authors: Powell Jonathan , Patel Chirag , Sun Hong , Claiborne Michael 
Published: December 2020

Abstract
While the exquisite specificity of the T-cell receptor (TCR) MHC + peptide interaction heralds recognition, it is ultimately the cues from the immune microenvironment that dictate the outcome of this recognition. Our lab has proposed that mTOR plays a critical role in integrating signals and thus determining the outcome of antigen recognition. Indeed, we have demonstrated that mTORC1 and mTORC2 signaling can selectively guide CD4+ effector and regulatory T-cell differentiation and function as well as CD8+ effector and memory T-cell differentiation and function. Recent studies have revealed that mTOR performs this function in part by coordinating T-cell activation and function with metabolic reprogramming. Consequently, targeting downstream mTOR signaling and metabolism can promote T-cell effector function and persistence in order to enhance cancer immunotherapy. Likewise, targeting mTOR can inhibit T-effector function and promote the generation of regulatory T cells to treat autoimmune disease and prevent transplantation rejection.
Citation Format: Jonathan Powell, Chirag Patel, Hong Sun, Michael Claiborne. mTOR as a central regulator of T-cell activation, differentiation, and function [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA14.
Abstract IA19: PI3Kgamma control of antitumor immunity
Authors: Varner Judith A. 
Published: December 2020

Abstract
Macrophages play key roles in promoting immune suppression, tumor growth and resistance to therapy. Our recent studies show that tissue-resident macrophages (TRM) as well as bone marrow-derived macrophages (BMDM) play critical but unique roles in promoting tumor growth. While BMDM are recruited to tumors in a PI3K, integrin α4, and CCR2-dependent manner, TRMs accumulate in tumors independently of integrin α4, PI3Kγ, or the trafficking receptor CCR2. Gene expression and functional studies indicate that tumor-derived TRM are highly proliferative, immune suppressive, and distinct from BMDM. We show that TRM develop from macrophage progenitors that are abundant in tumors but not in normal tissues; purified progenitors differentiate into macrophages that potently stimulate tumor growth when adoptively transferred into mice. Notably, we found that the lipid kinase PI3Kγ promotes immune-suppressive polarization of TRM and BMDM. Inhibition of PI3Kγ repolarizes macrophages, induces dendritic cell maturation, and stimulates CD8+ T-cell recruitment to tumors and activation. Inhibition of PI3Kγ also synergizes with checkpoint inhibitors and chemotherapeutics to promote tumor regression and immunologic memory, leading to sustained tumor suppression. Our studies identify PI3Kγ as a valuable target for immune therapy of solid tumors.
Citation Format: Judith A. Varner. PI3Kgamma control of antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA19.
Abstract IA23: PI3K inhibitors as a backbone for combination treatments for breast and ovarian cancer
Authors: Wulf Gerburg , Konstantinopoulos Panos , Barry William , Sonzongi Olmo , Eismann Julia , Kucherlapati Bose , Matulonis Ursula 
Published: December 2020

Abstract
PI3K inhibitors reduce glucose uptake and utilization by tumors. Yet in solid tumor clinical trials the efficacy of PI3K -inhibitors as single agents has been limited. Therefore, we have focused on harnessing the antimetabolic efficacy of PI3K inhibitors to augment the efficacy of antineoplastic treatments. A recently completed clinical trial (NCT01623349) examined the combination of PI3Ki BYL719 and the PARPi olaparib in ovarian cancer (EOC). Of the 28 EOC patients, 10 (35.7%) had partial response (PR), 14 (50%) had stable disease (SD), 3 (10.7%) had progressive disease (PD), and 1 (3.6%) patient was unevaluable. ORR was 33.3% and 31.3% in platinum resistant/refractory gBRCAmut and gBRCAwt patients, respectively. These data show that combining BYL719 and olaparib is feasible with no unexpected toxicities and that the activity of olaparib/BYL719 in gBRCAwt platinum-resistant EOC appears significantly higher than expected compared to either olaparib or BYL719 monotherapies. Next-generation sequencing did not identify markers of responsiveness to this combination. To assess responsiveness to this combination functionally, we have developed novel methods to monitor the antimetabolic activity of PI3K inhibitors in vivo using functional MRI of tumors based on the interconversion of 13C-pyruvate to 13C-lactate as well as NMR spectroscopy of tumoral ATP stores.
Citation Format: Gerburg Wulf, Panos Konstantinopoulos, William Barry, Olmo Sonzongi, Julia Eismann, Bose Kucherlapati, Ursula Matulonis. PI3K inhibitors as a backbone for combination treatments for breast and ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA23.
Abstract IA25: Development of PI3K inhibitors in breast cancer
Authors: Ma Cynthia X. 
Published: December 2020

Abstract
The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is crucial to many aspects of cell growth and survival. PI3K pathway is frequently deregulated in breast cancer due to genetic or epigenetic alterations in components of this pathway and contributes to treatment resistance. Notably, PIK3CA mutation is the most frequent genetic event in estrogen receptor-positive (ER+) breast cancer, while loss of PTEN expression is commonly observed in triple-negative disease (TNBC). There has been significant interest in developing PI3K inhibitors in breast cancer. Several randomized clinical trials assessing the benefit of adding PI3K inhibitors to fulvestrant in patients with advanced ER+ breast cancer, including BELLE-2, BELLE-3, FERGI, and SANDPIPER, have been reported. Significant improvement in progression-free survival (PFS) has been observed in these trials. However, dose-limiting toxicities of pan-PI3K inhibitors are common, which limit their clinical application. Isoform selective inhibitors, such as alpha selective PI3K inhibitor, are in clinical trials with the hope to reduce toxicity. There is ongoing effect in the investigation of predictors of response and mechanisms of treatment resistance. This presentation will summarize clinical trial data in breast cancer and challenges in the development of PI3K inhibitors in breast cancer.
Citation Format: Cynthia X. Ma. Development of PI3K inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA25.