bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4945: Inhibition of wild-type PI3Kα signaling is required for durable efficacy in PI3Kα mutant cancer cells due to robust re-activation of wild-type PI3Kα signaling
Authors: MacDougall John R. , Zhong Mengqi , Merritt Hanne , Cid Joselyn S. Del , Bradley John , Mak Raymond , Dhawan Neil , Chen Wei 
Published: April 2023

Abstract
PI3Kα is the most mutated oncogene with a high mutation rate in breast, lung, colorectal, gastric, bladder, and other tumor types. However, current inhibitors have had little efficacy in the clinic due to their inability to achieve maximal PI3Kα target engagement in a highly specific and durable manner. Contributing to this is that most PI3Kα mutant cancer cells are prone to robust pathway feedback and re-activation of remaining wild type PI3Kα signaling upon initial inhibition. We have analyzed pathway feedback in a variety of PI3Kα mutant cancer cell lines across multiple diverse indications and found this to be a common trait among PI3Kα mutant cancer cells. Additionally, when the mutant PI3Kα protein alone is targeted in these cells using mutant-specific inhibitors, we observed robust pathway re-activation and tumor cell proliferation. In contrast, TOS-358, a highly selective first-in-class covalent PI3Kα inhibitor, achieved complete inhibition of both PI3Kα mutant and wild type signaling and this correlated with the induction of cell cycle arrest and cell death across a wide variety of PI3Kα mutant tumor types. Furthermore, stimulation of PI3Kα signaling with serum rapidly re-activated the PI3K-AKT pathway in the presence of reversible and mutant specific inhibitors. Covalent molecules (namely TOS-358) achieved complete inhibition of pathway signaling in this format. Overall, this reveals the need to achieve sustained inhibition of both PI3Kα mutant and wild type signaling to achieve durable efficacy in PI3Kα mutant tumors.
Citation Format: John R. MacDougall, Mengqi Zhong, Hanne Merritt, Joselyn S. Del Cid, John Bradley, Raymond Mak, Neil Dhawan, Wei Chen. Inhibition of wild-type PI3Kα signaling is required for durable efficacy in PI3Kα mutant cancer cells due to robust re-activation of wild-type PI3Kα signaling. [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 4945.
Abstract 4951: Proteasome inhibitor carfilzomib induces apoptosis via downregulation of AKT pathway in HPV negative HNSCC
Authors: Jeong Woo-Jin , Kim Jiyeong , Lee Hye-Yeon , Wang Zhiyong , Amornphimoltham Walt , Gutkind Silvio 
Published: April 2023

Abstract
Background Head and neck squamous cell carcinoma (HNSCC) presents in heterogenous sites, varied etiology and risk factors, and has diverse genetic background which confer dissimilar response to treatments, including chemotherapy. Here we tested the hypothesis that investigation of HPV presence in a HNSCC cell line would identify pathway contributing to oncogenesis of other HNSCC. We sought to identify pathways that differentially affect HNSCC according to the genetic background, therefore identifying targets and suitable candidate for treatment. We used genetic and pharmacological approaches to inhibit AKT pathway in HNSCC cell lines.
Materials & methods Chemical genetic library screening against 6 HNSCC cell lines were performed. The high throughput combinatorial small molecule screening for cell viability and apoptosis was carried out. Candidate agents were validated in both CAL-27 (HPV-negative) and UM-SCC-47 (HPV-positive) cell lines. Identified pathways and representative targeted agents were validated in vitro. Expression of related protein were confirmed by western blot assay.
Results EGFR, PIK3CA, mTOR, CDK1, HSP90AB1, HDAC1, and PSMD1 pathways were identified to be susceptible pathways in HNSCC using high throughput chemical genetic library screening. In vitro validation of carfilzomib showed IC50 of 7.07nM in CAL-27 cells and IC50 of 26.3nM in UM-SCC-47 cells. Knockdown of PSMD1 transcripts by transfected siRNAs reduced CAL-27 cells viability. Carfilzomib regulates the AKT pathway by decreasing t-AKT, p-AKT, p-ERK, p-S6 proteins and increasing p21 in CAL-27.
Conclusion Inhibition of AKT pathway treatment with proteasome inhibitor carfilzomib is effective in HPV-negative HNSCC cells. Taken together, our findings reveal carfilzomib induced the apoptotic pathway and suggest that carfilzomib, the representative of a new class of chemotherapeutic drug, may be utilized for overcoming cisplatin-resistance in human SCC.
Citation Format: Woo-Jin Jeong, Jiyeong Kim, Hye-Yeon Lee, Zhiyong Wang, Walt Amornphimoltham, Silvio Gutkind. Proteasome inhibitor carfilzomib induces apoptosis via downregulation of AKT pathway in HPV negative HNSCC. [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 4951.
Abstract 4970: TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors
Authors: Briggs Kimberly J. , Tsai Alice , Zhang Minjie , Tonini Matthew R. , Haines Brian , Huang Alan , Cottrell Kevin M. 
Published: April 2023

Abstract
MTAP deletions occur in 10-15% of all human cancers, which provides one of the largest precision oncology patient populations. MTA-cooperative PRMT5 inhibitors leverage the well-characterized synthetic lethal relationship between PRMT5 inhibition and MTAP deletion. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors. TNG462 is an investigational stage MTA-cooperative PRMT5 inhibitor with significantly enhanced potency, selectivity, and extended target coverage designed to be a best-in-class treatment for patients with MTAP-deleted cancer. In vitro, TNG462 is 45X selective for MTAP-deleted cancer cell lines over isogenic MTAP WT cell lines and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. Oral administration of TNG462 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in cell line- and patient-derived xenograft models representative of clinically relevant histologies. Preclinical data suggest a low risk for drug-drug interactions, supporting clinical combination strategies. With enhanced potency and selectivity for MTAP-deleted cancer cells and improved pharmacokinetic properties to extend target coverage, TNG462 has the potential for broader and deeper clinical activity in MTAP-deleted solid tumors than the MTA-cooperative PRMT5 currently being evaluated in clinical trials.
Citation Format: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Matthew R. Tonini, Brian Haines, Alan Huang, Kevin M. Cottrell. TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors. [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 4970.
Abstract 5056: ABN401 demonstrates robust anti-tumor efficacy in orthotopic PDX models of MET-driven NSCLC brain metastases in a pre-clinical study
Authors: Rajasekaran Nirmal , Park Kyung Eui , Lee Saehyung , Kim Na Young , Chung Suk-Jae , Shin Young Kee , Choi Jun Young 
Published: April 2023

Abstract
Background Brain metastases (BM) are manifested in approximately 30-50% of patients with non-small cell lung cancer (NSCLC) and are associated with catastrophic implications on prognosis and survival. The development of blood-brain barrier-penetrant therapies for brain metastases of NSCLC is imperative and is a major clinical hurdle. ABN401, a highly potent and selective c-MET inhibitor, shows promising anti-tumor activity without significant safety concerns in patients with advanced NSCLC. Here, we report that ABN401 exhibits potent anti-tumor efficacy in pre-clinical orthotopic patient-derived xenografts (PDXs) derived from MET-driven NSCLC brain metastases.
Methods Anti-tumor efficacy of ABN401 was assessed in two lung cancer PDXs (LU5349 and LU5406) from BM models harboring high-level MET amplification grown in NOD/SCID mice. Subcutaneous PDXs (n=14/group) were treated with ABN401 (60 mg/kg QD, 125 mg/kg QD, and 165 mg/kg QD) or control groups. Established PDXs were orthotopically implanted into the brain (n=14/group) and were treated with ABN401 (125mg/kg QD), or control groups. The tumor volume of orthotopic model was monitored using magnetic resonance imaging (MRI). Brain, plasma, and tumor samples were collected for pharmacokinetics (PK) and pharmacodynamics (PD) correlation analysis.
Results The efficacy of ABN401(125 mg/kg QD) was confirmed in the subcutaneous PDX models (LU5349 and LU5406). Treatment with ABN401 showed up to 95% and 99% tumor growth inhibition in the LU5349 and LU5406 models, respectively. ABN401 (125 mg/kg QD) treatment induced complete or near-complete tumor growth regressions in the orthotopic tumor model. ABN401 also showed a desirable PK and safety profile with no significant changes in body weight.
Conclusions ABN401 treatment showed robust anti-tumor efficacy in PDX models of MET-driven NSCLC brain metastases. Our findings suggest that ABN401 has excellent potential for treating NSCLC patients with BM and supports its ongoing clinical development.
Citation Format: Nirmal Rajasekaran, Kyung Eui Park, Saehyung Lee, Na Young Kim, Suk-Jae Chung, Young Kee Shin, Jun Young Choi. ABN401 demonstrates robust anti-tumor efficacy in orthotopic PDX models of MET-driven NSCLC brain metastases in a pre-clinical study. [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 5056.
Abstract 5101: Inhibition of Notch reverses immunosuppression in basal-like breast cancer
Authors: Shen Qiang , Murakami Kiichi , Ohashi Pamela , Reedijk Michael 
Published: April 2023

Abstract
Aberrant Notch activation is a defining feature of basal-like breast cancer (BLBC), which has poor prognosis compared to other breast cancer molecular subtypes. Despite the clinical success of immune checkpoint blockade (ICB) in many malignancies including melanoma and small cell lung cancer, ICB has failed to demonstrate similar response in BLBCs, where most cases are highly infiltrated by tumor-associated macrophages (TAMs). There is increasing evidence that Notch is decisive in regulating intercellular communication in the tumor immune microenvironment (TIME). This includes the recruitment of TAMs which contribute to an immunosuppressive TIME, illuminating the potential of Notch-inhibition as adjuvant immunotherapy in BLBC. To examine the immune phenotype and therapeutic response of BLBC to combined Notch-inhibition and ICB, we employed an in vivo tumorgraft model using murine basal-like mammary tumor 4T1 cells. Briefly, tumor cells were orthotopically injected into the mammary fat pads of BALB/c mice. Using a crossover design, mice were randomly allocated to treatment with either Notch inhibitor (γ-secretase inhibitor, LY411575), anti-PD1 (RMP1-14), or control treatment for 12-days (stage-1), followed by randomization to a second 12-day period (stage 2) with the same, or one of the other treatments. Results: Despite the low response rate of BLBC to ICB alone, Notch inhibition reduced TAMs and induced responsiveness to sequential ICB. This response was characterized by increased cytotoxic T lymphocytes (GrB+, CTL) infiltration of the primary tumor. Similar results were observed when Notch-regulated cytokines (IL-1β and CCL2), crucial to TAM recruitment, were inhibited. Moreover, a more impressive therapeutic effect of sequential treatment was observed in lung metastasis, whereby TAM depletion and increased CTL infiltration were accompanied with near-complete abolition of metastases. Mechanistically, tumor cell Notch signaling upregulates a group of circulating cytokines including IL-1β and CCL2, which prime the lung for metastases. Additionally, compared to primary tumor cells, PD ligand 1 is up-regulated in lung metastases, rendering them profoundly sensitive to sequential ICB treatment. These findings highlight the potential of sequential Notch inhibition and ICB as a novel immunotherapeutic strategy in BLBC.
Citation Format: Qiang Shen, Kiichi Murakami, Pamela Ohashi, Michael Reedijk. Inhibition of Notch reverses immunosuppression in basal-like breast 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 5101.
Abstract 5106: The addition of radiation therapy to simultaneous targeting of PD-1 and IL2Rβγ enhances antigen-specific CD8 T cell anti-tumor immunity in pancreatic cancer models
Authors: Hoen Maureen , Piper Miles , Darragh Laurel B. , Nugyen Diemmy , Gadwa Jacob , Amann Maria , Durini Greta , Knitz Michael , Van Court Benjamin , Pham Tiffany , Kedl Ross , Umana Pablo , Codarri-Deak Laura , Klein Christian , D’Alessandro Angelo , Karam Sana D. 
Published: April 2023

Abstract
Although IL-2 has been shown to critically mediate NK and T cell effector functions, when used in clinical trials this cytokine has failed due to toxicity and severe side effects of the systemic treatment. Our lab has investigated the use of a next-generation IL-2 compound, murine PD1-IL2v, which consists of an anti-PD-1 antibody fused to a IL2-variant with abolished binding to IL2Rα. Previous work shows this molecule results in tumor-antigen specific T cell expansion and differentiation towards immune effectors. Here, we report for the first time that radiation therapy amplifies the anti-tumor effect observed with PD1-IL2v treatment of murine orthotopic models of local tumor growth and metastasis. This anti-tumor effect is correlated with increases in proliferative and polyfunctional CD8 T cells across tumor, lymph node, and blood compartments. Furthermore, using an OVA-antigen specific orthotopic model, we found that radiation in combination with PD1-IL2v treatment enhances infiltration and activation of antigen-specific CD8 T cells, which have been shown to be critical for immunotherapy clinical success. A portion of tumor-bearing mice treated with radiation and PD1-IL2v fully eradicated their primary tumors and tumor rechallenges, which we show correlates with increased markers of memory in CD8 T cells of these mice. To demonstrate the clinical relevance of these preclinical findings, we performed RNA sequencing on paired pancreatic adenocarcinoma (PDAC) patient tumor tissue samples prior to and following radiation. We observed enhanced IL2Rβ and IL2Rγ expression as well as IL2R signaling in PDAC-patient responders to radiation therapy compared to non-responders. In conclusion, the antigen-specific, lasting memory response to preclinical PDAC models demonstrated here provides rationale for the treatment of PDAC with a radiation and PD1-IL2v combination.
Citation Format: Maureen Hoen, Miles Piper, Laurel B. Darragh, Diemmy Nugyen, Jacob Gadwa, Maria Amann, Greta Durini, Michael Knitz, Benjamin Van Court, Tiffany Pham, Ross Kedl, Pablo Umana, Laura Codarri-Deak, Christian Klein, Angelo D’Alessandro, Sana D. Karam. The addition of radiation therapy to simultaneous targeting of PD-1 and IL2Rβγ enhances antigen-specific CD8 T cell anti-tumor immunity in pancreatic cancer models. [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 5106.
Abstract 5130: Multi-plex cytokine profiling for mice on Bleomycin induced systemic sclerosis model
Authors: Yuan Yanping , Qian Cheng , Yangmeng Chuanzhi , Fang Li , Yan Ruiqing 
Published: April 2023

Abstract
Systemic sclerosis (SSc) is recognized as an autoimmune disorder characterized by immune dysregulation, obliterative vasculopathy, excessive accumulation of extracellular matrix, and fibrosis of the skin and other organs. It also ranks on the highest position of disease-related mortality and morbidity with an impaired quality of life among the rheumatologic illnesses. However, the immunological mechanism related to SSc remains to be elucidated systemically, which may lay for the novel therapeutic methodology. In the present study, we combined the MSD methodology and flow cytometry to landscape the chemokine or cytokine network, immunology response and signaling axis in mice on Blomycin induced SSc model. Our results provide the reference and path for the future direction of novel therapeutic reagents discovery.
Citation Format: Yanping Yuan, Cheng Qian, Chuanzhi Yangmeng, Li Fang, Ruiqing Yan. Multi-plex cytokine profiling for mice on Bleomycin induced systemic sclerosis model. [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 5130.
Abstract 5161: Molecular mechanisms of early-stage lung adenocarcinoma initiation
Authors: Rodriguez-Fuguet Alice , Silva Luis , Asara John , Li Xiaoman , Kobayashi Susumu , Zhang Wen Cai 
Published: April 2023

Abstract
Lung cancer initiation and progression driven by epidermal growth factor receptor (EGFR) mutation has been extensively studied in the past decade. Though many leaps have been made in the field in terms of treatment, early diagnosis screening is not widely available or well established. Meanwhile, EGFR mutation is a significant driver of tumorigenesis and drug resistance. This receptor is related to many downstream pathways that influence cancer metabolism and the ability of tumor cells to adapt to changes in the tumor microenvironment. Our study finds that cancer metabolism plays a prominent role in the progression of tumorigenesis in early-stage lung cancer. Kynurenine, a metabolite from the tryptophan pathway, was highly upregulated in early-stage, EGFR-mutation driven lung cancer by metabolomic analysis. The connection between EGFR mutation and the upregulation of kynurenine remains largely unknown. We hypothesize that kynurenine, based on our preliminary data and as a ligand of the aryl hydrocarbon receptor, may have a dual role in early tumorigenesis. We propose that kynurenine may be used by tumor cells to modulate their response to stress by triggering anti-apoptotic pathways. Additionally, kynurenine may be used as a signaling molecule in the tumor microenvironment to allow the early tumor cells to evade immune detection through the transformation of macrophages from M1 to M2. Currently, our data show that indoleamine 2,3- dioxygenase 1 (IDO1), the rate-limiting enzyme of the tryptophan-kynurenine pathway, is significantly upregulated in early-stage, EGFR-driven lung cancer murine models by RNA-seq analysis. This supports our idea that IDO1 could help to modulate the response to cellular stress and to regulate the immune response to favor tumor development. We hope that IDO1 could be a potential clinical target and a potential biomarker for the dysregulation of this pathway.
Citation Format: Alice Rodriguez-Fuguet, Luis Silva, John Asara, Xiaoman Li, Susumu Kobayashi, Wen Cai Zhang. Molecular mechanisms of early-stage lung adenocarcinoma initiation. [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 5161.
Abstract 5165: In vivo therapeutic validation of NRT-YHD_001, a novel macrophage checkpoint inhibitor, in liver cancer
Authors: Nam Suk Woo , Kim Sangyean , Na Min Jeong , Shin Eunbi , Ha Jin Woong , Jeon Soyoung , Yoon Jeong Hwan 
Published: April 2023

Abstract
Previously, we demonstrated that recovery of Histone deacetylase 6 (HDAC6) elicited let-7i-5p suppression to de-repress the thrombospondin-1 (TSP1) expression, and thereby it occupied CD47 receptor to block CD47-SIRPα mediated anti-phagocytosis of macrophage in liver cancer. NRT-YHD_001 is a modified antisense miRNA of let-7i-5p for liver cancer treatment. NRT-YHD_001 was substituted with O-methoxyethyl and phosphothioate for stability, and N-acetylgalactosamine was attached for specific delivery to the liver. In in vitro phagocytosis assay, NRT-YHD_001 showed macrophage phagocytosis activity with similar or better results compared to non-modified antisense let-7i-5p (AS_let-7i-5p). In addition, it was confirmed that NRT-YHD_001 inhibited endogenous let-7i-5p of liver cancer cells and activated macrophage phagocytosis at 4°C or 25°C for up to 2 weeks. When NRT-YHD_001 activity was investigated in vivo after 1 week, 2 weeks, and 4 weeks after administration of single dose NRT-YHD_001 to the tail vein of a mouse, NRT-YHD_001 was not degraded, and let-7i-5p was inhibited while maintaining activity in liver tissue for 2 weeks after injection. To investigate the in vivo therapeutic effect, a mouse spontaneous (Ras-transgenic) liver cancer model was used and compared with the sorafenib-administered group. After administration of NRT-YHD_001 and sorafenib each week at the time when liver mass was detected, the tumor size and growth rate were compared. As a result, the NRT-YHD_001 administration group showed significant therapeutic effect compared to sorafenib. These results showed that NRT-YHD_001 had a strong anticancer effect by converting the macrophage of don't eat me into eat me signal in the tumor microenvironment of liver cancer, thereby removing or inhibiting liver cancer cells.
Keywords: let-7i-5p, macrophage, phagocytosis, liver cancer, NRT-YHD_001
Citation Format: Suk Woo Nam, Sangyean Kim, Min Jeong Na, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, Jeong Hwan Yoon. In vivo therapeutic validation of NRT-YHD_001, a novel macrophage checkpoint inhibitor, in liver 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 5165.