bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4053: NGY-B is a novel inhibitor of MCT transporters blocking lactate and glucose metabolisms
Authors: Sharma Sambad , Goreczny Gregory , Bowman Nicole , Duffy Jennifer , Banerjee Daliya , Wijerathna Sanath , Dzuris John , Escobedo Jaime , Sandanayaka Vincent 
Published: June 2022

Abstract
Aberrant glycolytic flux and mitochondrial respiration are known to drive tumor progression and metastasis. Therefore, targeting metabolic alterations in cancer is critical for developing novel cancer therapeutics. We have developed NGY-B as a first-in-Class small molecule inhibitor of the lactate transporters, MCT1 and MCT4, that also decreases mitochondrial respiration. These transporters play a crucial role in regulating both glycolysis and oxidative phosphorylation in cancer cells. NGY-B treatment exhibited potent in vitro cytotoxicity in cancer cells with various levels of MCT1 and MCT4 expression. The on-target activity of NGY-B was validated by measuring intracellular and extracellular lactate levels. NGY-B blocks lactate import through MCT1 under high lactate conditions and lactate export through MCT4 in high glucose conditions. Seahorse and U-13C-glucose tracing analysis demonstrated NGY-B treatment modulates glycolysis and oxidative phosphorylation consistent with the lactate measurement data. Therefore, NGY-B is a novel inhibitor of MCT1/4 while also exhibiting inhibition of mitochondrial respiration.
Citation Format: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Jaime Escobedo, Vincent Sandanayaka. NGY-B is a novel inhibitor of MCT transporters blocking lactate and glucose metabolisms [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 4053.
Abstract 4062: Activity of 3 Bromopyruvate in human tumor primary culture 3-dimensional explants using ex vivo analysis of programmed cell death
Authors: Nagourney Adam Jeremiah , D'Amora Paulo , Evans Steven Scott , Bernard Paula , Francisco Federico , Ko Young , Stockwell Thomas , Johnson Maxine , Nagourney Robert Alan 
Published: June 2022

Abstract
Altered metabolism is a hallmark of human malignancy. The “Warburg Effect “reflecting increased glycolytic activity in the presence of oxygen represents an opportunity to target specific features of cancer to induce selective toxicity to malignantly transformed cells. 3-bromopyruvate (3-BP) is a pyruvate analogue that inhibits hexokinase II at the mitochondrial level resulting in cancer cell death. Numerous studies have confirmed activity for 3-BP in human SW480 and HT 29 colon carcinoma, glioblastoma (U373MG), HTP-1 leukemic and other cell lines. Our interest in exploring the activity of 3-BP in human tumor primary culture explants led to the application of the ex vivo analysis of programmed cell death in 19 patient tumors. The intent was to develop concertation ranges for future studies and explore disease-specific activity.
Methods: Fresh Sterile tumor samples were mechanically and enzymatically disaggregated and 3-dimensional organoids of desired size isolated by density centrifugation. Blood samples were isolated by density centrifugation. Cell suspensions in modified RPMI media were exposed to serial dilutions of 3-BP for 72 hours and then assessed for cell death by morphology, staining characteristics and ATP content by luciferase. Viability was scored against saline-exposed controls, normalized to 100%.
Results: 3BP reveals activity in human tumor explants. Activity varied by cancer type. Hematologic tumors including NHL, CLL and AML were found sensitive as were several solid tumors including GI and lung cancers. Of interest lower degrees of activity were observed in breast and ovarian cancers that are generally considered chemo-sensitive . Activity in 2 fibrolamellar cancers could suggest a novel therapy for this drug refractory neoplasm. Studies are underway examining 3-BP correlations with other classes of drugs and metabolic inhibitors as well as 3-BP combinatorial potential. Supported by the Fibro fighters Foundation
Citation Format: Adam Jeremiah Nagourney, Paulo D'Amora, Steven Scott Evans, Paula Bernard, Federico Francisco, Young Ko, Thomas Stockwell, Maxine Johnson, Robert Alan Nagourney. Activity of 3 Bromopyruvate in human tumor primary culture 3-dimensional explants using ex vivo analysis of programmed cell death [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 4062.
Abstract 4065: Efficacy of the Rac/Cdc42 inhibitor MBQ-167 in combination therapy with Paclitaxel
Authors: Cruz-Collazo Ailed M. , Katsara Olga , Salvo Elizabeth , Ruiz Jean , Schneider Robert , Dharmawardhane Suranganie 
Published: June 2022

Abstract
Triple negative breast cancer (TNBC) represents a challenge because of its aggressiveness and resistance to standard chemotherapy. Since TNBC lacks targeted therapy options, the frontline therapy is Paclitaxel, which targets actively dividing cells inducing subsequent apoptosis. Since dormant cells or metastatic cancer cells are not targeted by Paclitaxel, more targeted treatment options are needed. MBQ-167, a small molecule developed by us to target the metastasis drivers Rac and Cdc42, is highly effective in reducing tumor growth and metastasis in mouse models of TNBC (Cruz-Collazo et al., 2021, Molecular Cancer Therapeutics). The purpose of this study is to test the hypothesis that MBQ-167 is a viable candidate for combined therapy with Paclitaxel in TNBC. Therefore, we tested the efficacy of MBQ-167 in combination with Paclitaxel in MDA-MB-231 human TNBC cells via MTT viability assays and caspase 3/7 apoptosis, using effective concentrations of MBQ-167 and/or Paclitaxel for 24, 48, 96 & 120 hrs. We found that individual MBQ-167 or the combination therapy was more effective at 48-120 hrs at reducing cell viability by ~80% compared to ~60% by Paclitaxel treatment alone and significatively increasing apoptosis. Next, we tested individual or combined MBQ-167 (5 mg/kg 5X a week) and Paclitaxel (10 mg/kg 1X a week) on SCID mice bearing MDA-MB-231 tumors, via intraperitoneal administration. We report a significant reduction in tumor growth and lung metastasis in response to combined MBQ-167 and Paclitaxel compared to either treatment alone. A more aggressive syngeneic model of 4T-1 mouse breast cancer cells in BALB/c immunocompetent model was used to determine the direct effect of MBQ-167 and Paclitaxel on metastasis. When 4T-1 tumors were surgically removed and MBQ-167, Paclitaxel, or the combination administered for 17 days, the combination treatment, but not individual compounds, significantly reduced lung metastases by ~80%. In conclusion, this study validates the clinical testing of MBQ-167 in combination with Paclitaxel as a potential therapeutic for TNBC.
Citation Format: Ailed M. Cruz-Collazo, Olga Katsara, Elizabeth Salvo, Jean Ruiz, Robert Schneider, Suranganie Dharmawardhane. Efficacy of the Rac/Cdc42 inhibitor MBQ-167 in combination therapy with Paclitaxel [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 4065.
Abstract 407: OTS964, a TOPK inhibitor, is susceptible to ABCG2-mediated drug resistance
Authors: Yang Yuqi , Wu Zhuo-Xun , Wang Jing-Quan , Teng Qiu-Xu , Lei Zi-Ning , Lusvarghi Sabrina , Ambudkar Suresh V. , Ji Ning , Chen Zhe-Sheng 
Published: June 2022

Abstract
The overexpression of ATP-binding cassette (ABC) transporters has known to be one of the most important mechanisms responsible for the development of multidrug resistance (MDR). OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and MDR-associated ATP-binding cassette sub-family G member 2 (ABCG2, breast cancer resistance protein/BCRP). The cell viability assay indicated that the effectiveness of OTS964 is limited in drug-resistant and gene-transfected cells overexpressing ABCG2. We found that the known ABCG2 inhibitor is able to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein and mRNA expression levels, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner, and that this stimulation can be antagonized by a verified ABCG2 ATPase inhibitor. Additionally, the computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 protein and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells.
Citation Format: Yuqi Yang, Zhuo-Xun Wu, Jing-Quan Wang, Qiu-Xu Teng, Zi-Ning Lei, Sabrina Lusvarghi, Suresh V. Ambudkar, Ning Ji, Zhe-Sheng Chen. OTS964, a TOPK inhibitor, is susceptible to ABCG2-mediated drug resistance [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 407.
Abstract 4076: Single cell RNA analysis reveals heterogeneous sub populations in aggressive variants of prostate cancer
Authors: Urban Rosalia Quezada , Keerthikumar Shivakumar , Clark Ashlee K. , Porter Laura H. , Lawrence Mitchell G. , Taylor Renea A. , Risbridger Gail P. , Toivanen Roxanne , Goode David L. 
Published: June 2022

Abstract
Neuroendocrine prostate cancer (NEPC) represent an aggressive malignancy that results in poor patients outcomes. At a histological level, NEPC exhibits heterogeneous pathologies; nevertheless, the molecular features, drivers and therapeutic implications of this heterogeneity are poorly understood. Single cell technology enables the resolution needed to unveil the complex heterogeneity of NEPC that bulk RNA analysis could not previously detect. Therefore, we aim to characterize the molecular heterogeneity of NEPC at a single cell level to detect common phenotypes across patients and identify new therapeutic targets. We performed single cell RNA sequencing on a novel cohort of nine patient derived xenograft (PDX) models that recapitulate the pathological and clinical heterogeneity of NEPC. Downstream analysis of single cell data was first completed on individual samples to identify distinct subpopulations of cells within each tumor. Then, integration analysis was performed to identify common and unique neuroendocrine populations across the different tumors. We profiled the transcriptome of 19,361 cells captured from the eight NEPCs. On an individual sample analysis, we detected 3 to 8 different subpopulations in each tumor, where every subpopulation displayed distinct biological properties such as epithelial mesenchymal transition, quiescence and stemness. Data integration of all samples revealed 16 subpopulations of tumor cells across all patients, of which 10 populations were primarily unique to one patient. Enriched pathway analyses revealed heterogeneous expression of most cancer hallmarks and oncogenic pathways across subpopulations, although some pathways were common to several neuroendocrine subpopulations such as EMT, P53 and KRAS. The detection of heterogeneous subpopulations in NEPC provides novel insight into why finding effective treatments for these aggressive tumors is challenging. Future work should focus on further evaluation of common druggable pathways that are shared across NEPC subpopulations. Alternatively, efforts could look at combination therapies that could effectively target these heterogeneous tumors.
Citation Format: Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee K. Clark, Laura H. Porter, Mitchell G. Lawrence, Renea A. Taylor, Gail P. Risbridger, Roxanne Toivanen, David L. Goode. Single cell RNA analysis reveals heterogeneous sub populations in aggressive variants of 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 4076.
Abstract 4107: Discovery and preclinical evaluation of VRTX126, a novel, highly selective and potent KRASG12Cinhibitor
Authors: Bhavar Prashant Kashinath , Surampudi Uday Kumar , Sarma Partha Pratim , Shidore Mahesh Mohan , Kshirsagar Anuj Ramesh 
Published: June 2022

Abstract
KRASG12C is an important oncogenic driver mutation and occurs in about 13% of NSCLC and 1-3% of colorectal and other solid tumors. Lumakras࣪ (sotorasib), a KRASG12C inhibitor was recently approved for treatment of NSCLC, and others, such as, Adagrasib have shown relatively modest activity for KRASG12C.This modest activity may be partly due to incomplete target occupancy or due to unavailability of the drug at the target site, to elicit maximum clinical response. Clearly, this gives path for development of inhibitors which are potent, but also have desired drug like properties to achieve maximal clinical benefit in patients harboring KRASG12C mutation. Here, we report the identification of VRTX126, a novel, highly selective and potent inhibitor of the KRASG12C, discovered using fragment-based drug design. VRTX126 exhibited an IC50 of 10 nM in H358. VRTX126 also inhibited phospho-ERK with an IC50 of &lt;20 nM and &lt;10 nM in H358 and Mia-Paca-2 cell lines respectively, while demonstrating multi fold selectivity over KRAS wild-type or nonG12C mutant cells lines. In xenograft model harboring KRASG12C mutation, VRTX126 exhibited tumor growth inhibition at therapeutically relevant doses. Combination strategies with other targeted therapies such as, our proprietary SOS1 inhibitor, and other marketed or available MEK1/2, SHP2 inhibitors targeting Ras/Raf/MEK pathway is being explored. VRTX126 showed favourable oral properties with dose proportional pharmacokinetics. VRTX126 was found to have no adverse effect on hERG (10 uM). Additionally, early evaluation in acute (&gt;1 g/kg (p.o.) and &gt;0.2 g/kg (i.v.) was well tolerated, with no elevation in liver enzymes and repeat does studies indicated good safety margins, thus supporting further evaluation of VRTX126 in IND enabling studies. A first-in-human Phase 1 clinical study in KRASG12C mutated patients of NSCLC and mCRC will be planned upon completion of through safety evaluations.
Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Mahesh Mohan Shidore, Anuj Ramesh Kshirsagar. Discovery and preclinical evaluation of VRTX126, a novel, highly selective and potent KRASG12Cinhibitor [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 4107.
Abstract 4121: Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous cell carcinoma
Authors: Choi Horyun , Kim Jinah , Lee Yeun Ho , Kim Leeseul , Chae Young Kwang 
Published: June 2022

Abstract
Background: Recurrent respiratory papillomatosis (RRP) is a human papilloma virus (HPV) associated benign disease, which, in rare cases, can develop into lung squamous cell carcinoma. Treatment options are limited with no approved systemic adjuvant therapy and the disease requires frequent surgical resection to prevent airway obstruction. Therefore, expanding available treatment options remains a highly important, but unmet need in RRP. Herein, we present a case of RRP with squamous cell carcinoma of lung that demonstrated durable stable disease with nivolumab and subsequent bevacizumab.
Case presentation: A 48-year-old woman with long standing RRP since teenager, who underwent multiple microsuspension laryngoscopies, debridements including laryngeal lesions, and ultimately, 5 years ago, video assisted thoracic surgery (VATS) resection of right upper lobe mass, confirming squamous cell carcinoma, has been managed with debulking surgery on tracheal lesions by ENT on regular basis. Nivolumab, a programmed death-1 blockade, 3 mg/kg every 2 weeks was started given squamous cell carcinoma of lung. Stable disease (SD) in lung lesions was achieved on nivolumab for one year but she required more frequent debulking of tracheal lesions. After multidisciplinary discussion with Otorhinolaryngology, she was started on bevacizumab, vascular endothelial growth factor inhibitor, 10 mg/kg every 6 weeks. Follow-up CT scans in 10 weeks showed a decrease in size of a left lower lobe mass to 27 mm from 32 mm in the previous image. After one year, administration of bevacizumab was spaced out to every 12 weeks. She requires less debulking surgery and the last debulking surgery was approximately 3 years ago. She maintains SD for over 4 years since starting bevacizumab.
Discussion: Our patient with RRP and squamous cell carcinoma of lung demonstrated SD on nivolumab before she was switched to bevacizumab. In addition, her SD on bevacizumab of more than 4 years with 12 weeks of maintenance interval is encouraging as there is no current standard of care treatment for RRP. Despite difficulty in running clinical trials in RRP due to its rareness, additional studies evaluating the efficacy of PD-1 inhibitor or anti-VEGF monoclonal antibody on RRP are warranted.
Citation Format: Horyun Choi, Jinah Kim, Yeun Ho Lee, Leeseul Kim, Young Kwang Chae. Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous 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 4121.
Abstract 4131: Antitumor effects of ensartinib in non-small cell lung cancer harboring MET exon 14-skipping mutations
Authors: Xia Yang , Lan Fen , Zhao Jing , Shen Hua-Hao , Selvaggi Giovanni , Li Wen 
Published: June 2022

Abstract
Background: Met proto-oncogene (MET) exon 14 skipping mutations are tumor drivers in approximately 3% of lung cancer patients. The antitumor efficacy of ensartinib, a novel multi-kinase inhibitor, against non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations was investigated in this study.
Methods: The MET-mutant binding affinity and antitumor activity of ensartinib were assessed in vitro and in vivo. Preliminary therapeutic activity of ensartinib in patient-derived organoids was observed. To explore clinical activity, 17 NSCLC patients with MET exon 14 skipping mutations were treated with ensartinib at 225 mg qd.
Results: Molecular dynamic simulations revealed that ensartinib exhibited favorable binding to c-MET. Ensartinib was highly effective in inhibiting the kinase activity of the MET exon 14 deletion protein (IC50 = 7.9 nM). Furthermore, ensartinib potently suppressed the MET pathway and the growth of Hs746T cells that were subcutaneously implanted into mice. Most importantly, of 17 patients with 14 different types of MET exon 14 skipping mutations undergoing ensartinib treatment, 1 (6%) showed a complete response, 11 (65%) achieved a partial response, and 4 (24%) exhibited stable disease. Thus, the objective response rate (ORR) was 71% and the disease control rate (DCR) was 94%, and the ORR in MET-TKI naive patients was even higher (12/15, 80%). In 2 patients with brain metastasis without prior brain radiation, we observed one partial response in the brain, while in the other patient the brain lesions were stable for 6 months. The most frequently reported adverse events were rash, peripheral edema, and nausea; however, no fatal adverse events occurred.
Conclusions: These results provide the first evidence that ensartinib exhibits both preclinical and clinical antitumor activity against MET exon 14 skipping mutations with the potential of strong intracranial efficacy and warrant further evaluation in a planned phase II study thus providing more options to patients with MET exon 14 skipping mutations. Updated data including duration of response, PFS and and OS will be provided at the time of the presentation with additional few months of follow up.
Citation Format: Yang Xia, Fen Lan, Jing Zhao, Hua-Hao Shen, Giovanni Selvaggi, Wen Li. Antitumor effects of ensartinib in non-small cell lung cancer harboring MET exon 14-skipping mutations [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 4131.
Abstract 4183: Differential modulation of tumor versus T cell oxidative phosphorylation potentiates anti-tumor immunity
Authors: Bhanu Krithikaa Rajkumar , Jayaprakash Priyamvada , Rice Meghan , Morrow Brittany , Marszalek Joseph R. , Gay Jason P. , Vellano Christopher P. , Cowen Benjamin R. , Welsh Dean J. , Curran Michael A. 
Published: June 2022

Abstract
We sought to determine whether various inhibitors of Oxidative Phosphorylation (OxPhos) could restore tumor infiltrating T cell functionality and longevity while compromising metabolic fitness of tumor cells. Using a combination of in vitro metabolic profiling with the Seahorse XFe96 Analyzer and in vivo tumor immunotherapy in the immunocompetent TRAMP-C2 prostate adenocarcinoma model, we determined the differential impact of multiple OxPhos inhibitors on both tumor immune metabolic fitness and functional capacity. Impact on the tumor immune microenvironment of TRAMP-C2 tumors was assessed through high parameter flow cytometry on a BD X-30. While OxPhos inhibition compromised initial T cell activation, we found that two of the inhibitors increased the glucose uptake, proliferation, and activation status of effector T cells. In contrast, the same two inhibitors decreased the mitochondrial fitness, proliferation and OxPhos metabolic capacity of TRAMP-C2 tumor cells themselves. To determine whether this selective inhibition of tumor versus T cell metabolic function could improve immunotherapy responses in vivo, we implanted TRAMP-C2 tumors and treated them with these OxPhos inhibitors with or without concomitant immune checkpoint blockade (ICB). The combination of ICB and OxPhos inhibition achieved highly significant and durable rates of tumor control and regression suggesting that these approaches are potentially synergistic. Analysis of the tumor microenvironment has identified the cellular mechanisms underlying these therapeutic effects which may provide useful biomarkers as this novel combination is translated to the clinic.
Citation Format: Krithikaa Rajkumar Bhanu, Priyamvada Jayaprakash, Meghan Rice, Brittany Morrow, Joseph R. Marszalek, Jason P. Gay, Christopher P. Vellano, Benjamin R. Cowen, Dean J. Welsh, Michael A. Curran. Differential modulation of tumor versus T cell oxidative phosphorylation potentiates anti-tumor immunity [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 4183.