Experimental and Molecular Therapeutics最新文献

{"title":"Abstract 927: Gut microbiome changes are associated with the efficacy of Delta-24-RGDOX viroimmunotherapy against malignant glioma","authors":"C. Gomez-Manzano, Natalie M. Meléndez-Vázquez, Teresa T. Nguyen, Ashley Ossimetha, Hong Jiang, J. Fueyo, F. Godoy-Vitorino","doi":"10.1158/1538-7445.AM2021-927","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-927","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86653538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB136: Targeting GCN2 kinase-driven stress response inactivation by orally available small molecules to restore immune tumor microenvironment in prostate cancers","authors":"Kyle Medley, Zhaoliang Li, D. Yan, U. Swami, N. Agarwal, H. Vankayalapati","doi":"10.1158/1538-7445.AM2021-LB136","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB136","url":null,"abstract":"In patients with metastatic castration-resistant prostate cancers (mCRPC) who have previously been treated with abiraterone or enzalutamide, the median overall survival is only 14 months. Unlike many other cancers, immunotherapies have had limited successes, due to the fact that there are very few T cells in the tumor microenvironment of prostate cancer (PC) patients. Identifying ways to boost immunotherapy responses could change the paradigm of mCRPC, a disease still difficult to treat. The highly proliferative nature of tumor cells, along with infiltration of myeloid cells into the tumors, leads to depletion of nutrients such as functional/natural amino acids. This metabolically stressful milieu causes activation of nutrient stress pathways, autophagy, and repressed immune responses. A key meditator of this nutrient stress pathway is a cytoplasmic Ser/Thr protein kinase called General Control Nonderepressible 2 (GCN2), also called EIF2AK4. GCN2 switches on by a reduction of amino acids, and its activity results in T cell inactivation, T cell death, regulatory T cell expansion, and the potentiation of myeloid-derived suppressor cells (MDSCs). We have developed and synthesized a series of novel small molecule immunotherapeutic agents that reversibly bind to GCN2 kinase, competitively block the ATP site, and elicit pharmacological responses in immune cells. GCN2 cell-free kinase binding, kinome selectivity, pGCN2, pEIF2α, ATF-4 phosphorylation inhibition assays were performed and confirmed it9s on-target efficacy and potency of lead GCN2 inhibitor HCI-1046. In these studies, our lead GCN2 kinase inhibitor HCI-1046 demonstrated potent activity with an IC50 of 36 nM in inhibiting GCN2. GCN2 expression has been detected in PC-3, DU-145, and LNCap cell lines, and HCI-1046 exhibited cellular efficacy with an IC50 of 0.9 to 8 μM range, reduced phosphorylation of GCN2, ATF-4 significantly and its downstream target eIF2α. HCI-1046 inhibited pGCN2 and pEIF2α in human prostate cancer clinical patient samples derived MDSC cultured in amino-acid starved conditions. HCI-1046, in a dose-dependent fashion, restored CD8+ T cell proliferation and function in clinical samples of PC patients. Our preliminary results support the hypothesis that inhibition of GCN2 reinstates anti-tumor immunity and blocks tumor progression in PC cellular models. In vivo PK studies of HCI-1046 in rodent species showed excellent PK properties; 55% oral bioavailability, low clearance, and >5 hours half-life. HCI-1046 is nominated as a pre-clinical agent. Additional 3D cellular efficacy studies, FACS for cellular apoptosis, cell migration, live PC cells including immuno-ELISA, ELISpot experimental results for MDSCs suppressive function of T cells, and restoration by HCI-1046 will be presented at the conference. PC mouse model efficacy studies will also be discussed. Citation Format: Kyle Medley, Zhaoliang Li, Dongqing Yan, Umang Swami, Neeraj Agarwal, Hariprasad Vankayalapati. Targeting G","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86965459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1455: RLY-4008, a novel precision therapy for FGFR2-driven cancers designed to potently and selectively inhibit FGFR2 and FGFR2 resistance mutations","authors":"Jessica B Casaletto, Dejan Maglic, B. Touré, Alex Taylor, Heike Schoenherr, Brandi Hudson, Kamil Bruderek, Songping Zhao, Patrick J O'Hearn, Nastaran Gerami-Moayed, D. Moustakas, R. Valverde, Lindsey Foster, H. Gunaydin, P. Ayaz, D. Sharon, D. Bergstrom, J. Watters","doi":"10.1158/1538-7445.AM2021-1455","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1455","url":null,"abstract":"FGFR2 fusions, amplifications, and mutations are oncogenic drivers that occur across multiple tumor types. Clinical efficacy observed with pan-FGFR inhibitors has validated the driver status of FGFR2 in FGFR2 fusion-positive intrahepatic cholangiocarcinoma (ICC), however, FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) and the emergence of on-target FGFR2 resistance mutations limit the efficacy of pan-FGFR inhibitors. To overcome these limitations, we designed RLY-4008, a potent and highly selective, FGFR2 inhibitor. Despite significant investment in traditional structure-based drug design, selective targeting of FGFR2 has not been achieved. We leveraged differences in conformational dynamics between FGFR2 and other FGFR isoforms observed through molecular dynamics simulations to enable the design of RLY-4008. RLY-4008 inhibits FGFR2 with low nanomolar potency and demonstrates > 200-fold selectivity over FGFR1, and > 80- and > 5000-fold selectivity over FGFR3 and FGFR4, respectively, in biochemical assays. Additionally, RLY-4008 demonstrates high kinome selectivity for FGFR2 against a panel of > 400 human kinases. RLY-4008 has strong activity against primary and acquired FGFR2 resistance mutations in cellular assays, and potent antiproliferative effects on FGFR2-altered human tumor cell lines. In vivo, RLY-4008 demonstrates dose-dependent FGFR2 inhibition and induces regression in multiple human xenograft tumor models, including FGFR2 fusion-positive ICC, gastric, and lung cancers, FGFR2-amplified gastric cancer, and FGFR2-mutant endometrial cancer. Strikingly, RLY-4008 induces regression in an FGFR2 fusion-positive ICC model harboring the FGFR2V564F gatekeeper mutation and an endometrial cancer model harboring the FGFR2N549K mutation, two mutations that drive clinical progression on current pan-FGFR inhibitors. In the FGFR2V564F model, pan-FGFR inhibitors are ineffective, even at maximally tolerated doses. Notably, treatment of these tumors with RLY-4008 induces rapid regression and restores body weight. In rat and dog toxicology studies, RLY-4008 is well tolerated and is not associated with hyperphosphatemia or tissue mineralization at exposures significantly above those required to induce regression in all models. In contrast to pan-FGFR inhibitors, RLY-4008 is highly selective for FGFR2 and demonstrates strong activity against FGFR2 resistance mutations, suggesting that RLY-4008 may have broader therapeutic potential via preventing and overcoming therapeutic resistance. Together, these data and the favorable pharmaceutical properties of RLY-4008 strongly support its clinical development in FGFR2-altered tumors. Citation Format: Jessica Casaletto, Dejan Maglic, B. Barry Toure, Alex Taylor, Heike Schoenherr, Brandi Hudson, Kamil Bruderek, Songping Zhao, Patrick O9Hearn, Nastaran Gerami-Moayed, Demetri Moustakas, Roberto Valverde, Lindsey Foster, Hakan Gunaydin, Pelin Ayaz, Dina Sharon, Donald Bergstrom, James Watters. RLY-4","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79569704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1376: Dosing frequency/PD/efficacy relationship of MEN1611 in HER2 amplified, PIK3CA mutated, and refractory to Trastuzumab xenograft model of breast cancer","authors":"Alessio Fiascarelli, G. Merlino, S. Capano, A. Bressan, M. Bigioni, A. Pellacani, M. Binaschi, Massimiliano Salerno","doi":"10.1158/1538-7445.AM2021-1376","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1376","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91018005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1153: Targeting CA125 transcription for ovarian cancer treatment","authors":"Er Yue, Guangchao Yang, Yuanfei Yao, Guangyu Wang, Yanqiao Zhang, E. Wang","doi":"10.1158/1538-7445.AM2021-1153","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1153","url":null,"abstract":"CA125 coded by MUC16 gene is highly expressed in most ovarian cancer cells and serves as a tumor marker to monitor disease progression or response to treatment of ovarian cancer patients. However, targeting CA125 for ovarian cancer treatment has never been successful. We performed multiple steps of high-fidelity PCR and obtained a 4.2kb DNA fragment upstream of the human MUC16 gene, which included a region upstream from the transcription start site (TSS) and a region downstream from the TSS that contains both the 59 untranslated region and the first 136bp of the open reading frame. Reporter assays showed that this DNA fragment possesses strong transactivation activity in CA125-high cancer cells, but not in CA125-low cells, indicating that the DNA fragment we cloned contains the transactivation region that controls specific expression of MUC16 gene in ovarian cancer cells. We further refined the promoter and found a 1040bp fragment with similar transcriptional activity and specificity. We used this refined MUC16 promoter to replace the E1A promoter in the adenovirus type 5 genome DNA to control expression of E1A, an essential gene for adenovirus replication, and successfully generated a conditionally replication-competent adenovirus that can replicate in and lyse CA125-high-expressing cancer cells, including CAOV3, Kuramochi, MADH2774, OVCAR3, OVCAR4, and TOV112D cells, but not in CA125-low or -negative cancer cell lines, such as A2780, OVCAR5, PEO4, or SKOV3 cells. In vivo studies showed that intraperitoneal virus injection prolonged survival of NSG mice inoculated intraperitoneally with MADH2774 cells. Preliminary experiment showed that a mouse ovarian cancer cell line, ID8, infected with the virus might elicit a protective immune response to rechallenge of parental cancer cells. Our data indicate that targeting MUC16 transactivation for ovarian cancer treatment by conditionally replicative adenovirus development is feasible and practical. Citation Format: Er Yue, Guangchao Yang, Yuanfei Yao, Guangyu Wang, Yanqiao Zhang, Edward W. Wang. Targeting CA125 transcription for ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1153.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91217027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1080: Altered response to BET-bromodomain inhibitors JQ1 and I-BET-762 targeting c-Myc in erdafitinib-resistant endometrial carcinoma cell line AN3 CA","authors":"Wilhelmina E. van Riel, Janneke J. Melis, Demi H. J. Vogels, W. Mulder, J. Kooijman, R. Buijsman, G. Zaman","doi":"10.1158/1538-7445.AM2021-1080","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1080","url":null,"abstract":"The fibroblast growth factor receptors (FGFRs) 1-4 are receptor tyrosine kinases (RTKs) involved in activation of essential cellular processes such as differentiation, proliferation and migration. Since alterations in FGFRs are common in multiple cancers, including breast cancer, non-small cell lung cancer and endometrial cancer, several kinase inhibitors targeting FGFRs are in clinical development. Erdafitinib, a pan-FGFR inhibitor, has been approved as second-line treatment of locally advanced or metastatic urothelial carcinoma harboring genetic FGFR2 or FGFR3 alterations. Although erdafitinib is very effective against these tumors, progression-free survival lasts only a few months, indicating that resistance also develops fast. Insight into the evolved resistance mechanism is crucial for the development of improved therapies. In this study we generated cell lines resistant to erdafitinib by prolonged culturing of the endometrial carcinoma cell line AN3 CA, harboring FGFR2 gain-off-function mutation N549K, to increasing doses of erdafitinib. To gain insight into the developed resistance, the expression of genes that have previously been reported to be involved in resistance against FGFR inhibitors was analyzed by qPCR and immunoblot. In addition, anti-proliferative effects of target inhibition by small molecules was evaluated. To get an unbiased view on altered gene expression, RNA sequencing (RNA-seq) was performed, followed by Gene-Set-Enrichment Analysis (GSEA). Alterations in FGFR1-4 and cancer hotspot gene sequences were detected by DNA sequencing. Occurrence of resistance to erdafitinib was confirmed in proliferation assays by a decreased response of the erdafitinib-resistant cell lines compared to the parental line. In addition, cross-resistance to other FGFR inhibitors infigratinib, pemigatinib, derazantinib and AZD4547 was observed. Although mRNA expression was altered for several RTKs previously reported to be involved in resistance to FGFR inhibitors, such as EGFR, ERBB2/3 and c-MET, involvement in resistance to erdafitinib could be excluded, as no change in response was observed in proliferation assays with their associated targeted inhibitors. RNA-seq and GSEA indicated upregulation of c-Myc target genes in erdafitinib-resistant cell lines. The involvement of c-Myc in the developed resistance was further confirmed by increased response to BET-bromodomain inhibitors JQ1 and I-BET-762, which indirectly target c-Myc. Furthermore, DNA sequencing identified novel mutations in coding regions of FGFR1 and KRAS genes. In conclusion, we show that multiple factors contribute to the development of resistance against erdafitinib in an FGFR2-mutant endometrial carcinoma cell line. BET-bromodomain inhibitors are of potential interest as therapeutic agents to overcome resistance against FGFR inhibitors. Citation Format: Wilhelmina E VAN RIEL, Janneke J. Melis, Demi H. Vogels, Winfried R. Mulder, Jeffrey J. Kooijman, Rogier C. Buijsman, Guido J. Z","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89445286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1023: Understanding the anti-tumor activities of daratumumab in natural killer/T cell lymphoma (NKTCL)","authors":"Tianyuan Zhou, M. Qing, Yann Abraham, T. Perova, C. Sweeney, M. Krevvata","doi":"10.1158/1538-7445.AM2021-1023","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1023","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89516550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1056: Potentin vivoanti-tumor activity of D-1553 as a single agent and in combination with targeted therapeutics in a broad spectrum of patient-derived xenograft tumor models with KRas G12C mutation","authors":"Shi Zhe, Jifang Weng, Xiaochong Fan, Qing-Fang Zhu, Emily Robb, A. Moriarty, M. Wick, Jiang Yueheng, Ling Zhang, D. Xing, Wang Yaolin","doi":"10.1158/1538-7445.AM2021-1056","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1056","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89667889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 43: Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer","authors":"Lawrence Snyder, T. Neklesa, Xin Chen, Hanqing Dong, C. Ferraro, D. Gordon, Jennifer Macaluso, J. Pizzano, Jing Wang, Ryan R. Willard, N. Vitale, R. Peck, Marcia Dougan Moore, C. Crews, J. Houston, A. Crew, I. Taylor","doi":"10.1158/1538-7445.AM2021-43","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-43","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89680592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 930: Production of functionally active recombinant FOXA1: The first step towards targeted drug discovery","authors":"Hariprasad Thangavel, Ying Zhu, K. Christensen, Xiaoyong Fu, D. Edwards, R. Schiff, Meghana V. Trivedi","doi":"10.1158/1538-7445.AM2021-930","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-930","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76881214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}