作者: Rodriguez, Rene ; Ramos-Mejia, Veronica ; Huergo, Carmen ; Ayllon, Veronica ; Estupinan, Oscar ; Rodriguez, Aida ; Gallego, Borja ; Tornin, Juan ; Gonzalez, Jessica ; Murillo, Dzohara ; Moris, Francisco ; Victoria Gonzalez, M. ; Blanco-Lorenzo, Veronica ; Rey, Veronica ; Bigas, Anna

Osteosarcomas are frequently associated to a poor prognosis and a modest response to current treatments. EC-8042 is a well-tolerated mithramycin analog that has demonstrated an efficient ability to eliminate tumor cells, including cancer stem cell subpopulations (CSC), in sarcomas. In transcriptomic and protein expression analyses, we identified NOTCH1 signaling as one of the main pro-stemness pathways repressed by EC-8042 in osteosarcomas. Overexpression of NOTCH-1 resulted in a reduced anti-tumor effect of EC-8042 in CSC-enriched 3D tumorspheres cultures. On the other hand, the depletion of the NOTCH-1 downstream target HES-1 was able to enhance the action of EC-8042 on CSCs. Moreover, HES1 depleted cells failed to recover after treatment withdrawal and showed reduced tumor growth potential in vivo. In contrast, mice xenografted with NOTCH1-overexpressing cells responded worse than parental cells to EC-8042. Finally, we found that active NOTCH1 levels in sarcoma patients was associated to advanced disease and lower survival. Overall, these data highlight the relevant role that NOTCH1 signaling plays in mediating stemness in osteosarcoma. Moreover, we demonstrate that EC-8042 is powerful inhibitor of NOTCH signaling and that the anti-CSC activity of this mithramycin analog highly rely on its ability to repress this pathway.

2021-02-05·EMBO Molecular Medicine1区 · 医学

Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor

1区 · 医学

ArticleOA

作者: Grohar, Patrick J ; Foxa, Gabrielle E ; Kang, Min H ; Boguslawski, Elissa A ; Kitchen‐Goosen, Susan M ; Beddows, Ian ; Rosien, Jessica E ; Chasse, Maggie H ; Williams, Bart O ; Johnson, Benjamin K ; Reynolds, C Patrick ; Triche, Timothy J ; Sorensen, Katie M ; Heo, Lyong ; Madaj, Zachary B

Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. Here we use unbiased screening of cell line panels to identify a heightened sensitivity of rhabdoid tumor to mithramycin and the second-generation analogue EC8042. The sensitivity of MMA and EC8042 was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion. Mithramycin blocks SMARCB1-deficient SWI/SNF activity and displaces the complex from chromatin to cause an increase in H3K27me3. This triggers chromatin remodeling and enrichment of H3K27ac at chromHMM-defined promoters to restore cellular differentiation. These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes. Importantly, a single 3-day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice.

2019-07-01·European Urology Oncology2区 · 医学

Transcriptional Reprogramming and Inhibition of Tumor-propagating Stem-like Cells by EC-8042 in ERG-positive Prostate Cancer

2区 · 医学

Article

作者: Catapano, Carlo V ; Mutti, Azzurra ; Shinde, Dheeraj ; Carbone, Giuseppina M ; Merulla, Jessica ; Mapelli, Sarah N ; Civenni, Gianluca ; Kokanovic, Aleksandra ; Costales, Paula ; Albino, Domenico ; Morìs, Francisco ; Perez-Escuredo, Jhudit ; Zoma, Marita

BACKGROUNDThe TMPRSS2-ERG gene fusion is the most frequent genetic rearrangement in prostate cancers and results in broad transcriptional reprogramming and major phenotypic changes. Interaction and cooperation of ERG and SP1 may be instrumental in sustaining the tumorigenic and metastatic phenotype and could represent a potential vulnerability in ERG fusion-positive tumors.OBJECTIVETo test the activity of EC-8042, a compound able to block SP1, in cellular and mouse models of ERG-positive prostate cancer.DESIGN, SETTING, AND PARTICIPANTSWe evaluated the activity of EC-8042 in cell cultures and ERG/PTEN transgenic/knockout mice that provide reliable models for testing novel therapeutics in this specific disease context. Using a new protocol to generate tumor spheroids from ERG/PTEN mice, we also examined the effects of EC-8042 on tumor-propagating stem-like cancer cells with high self-renewal and tumorigenic capabilities.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSISThe efficacy of EC-8042 was determined by measuring the proliferative capacity and target gene expression in cell cultures, invasive and metastatic capabilities in chick chorioallantoic membrane assays, and tumor development in mice. Significance was determined using statistical test.RESULTS AND LIMITATIONSEC-8042 blocked transcription of ERG-regulated genes and reverted the invasive and metastatic phenotype of VCaP cells. EC-8042 blocked the expansion of stem-like tumor cells in tumor spheroids from VCaP cells and mouse-derived tumors. In ERG/PTEN mice, systemic treatment with EC-8042 inhibited ERG-regulated gene transcription, tumor progression, and tumor-propagating stem-like tumor cells.CONCLUSIONSOur data support clinical testing of EC-8042 for the treatment of ERG-positive prostate cancer in precision medicine approaches.PATIENT SUMMARYIn this study, EC-8042, a novel compound with a favorable pharmacological and toxicological profile, exhibited relevant activity in cell cultures and in vivo in a genetically engineered mouse model that closely recapitulates the features of clinically aggressive ERG-positive prostate cancer. Our data indicate that further evaluation of EC-8042 in clinical trials is warranted.

项与 AIT-102 相关的新闻（医药）

2024-02-16

·GlobeNewswire-Health Care

OrphAI Therapeutics receives Orphan Drug Designation for AIT-101 as a treatment for amyotrophic lateral sclerosis in the European Union

Feb. 15, 2024 -- OrphAI Therapeutics Inc. (“OrphAI”), a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today that it has received Orphan Drug Designation (ODD) in the European Union (EU) for the treatment of amyotrophic lateral sclerosis (ALS). AIT-101 previously received ODD from the U.S. FDA in June 2023 for the treatment of ALS. “OrphAI Therapeutics now has orphan designation for AIT-101 both in the US and the EU for the treatment of ALS, an important step toward bringing the drug to patients suffering from this neurodegenerative disorder,” said Dr. Brigette Roberts, CEO and Director of OrphAI. “AIT-101 has demonstrated compelling activity in its ability to clear toxic aggregates, which are a hallmark of ALS and other neurodegenerative diseases. We look forward to moving AIT-101 into the next stage of clinical development." AIT-101 is a first-in-class, potent and highly selective inhibitor of the lipid kinase PIKfyve. Inhibition of PIKfyve leads to activation of the transcription factor TFEB which drives the increased clearance of toxic protein aggregates via the lysosomal autophagy pathway. AIT-101 has now been demonstrated to reduce aggregates in human subjects, to improve the survival of motor neurons in in vitro models of familial and sporadic ALS, and to ameliorate functional deficits in a mutant TDP-43 animal model of ALS. AIT-101 is the most clinically advanced PIKfyve inhibitor in development. OrphAI Therapeutics’ mission is to transform the lives of patients with rare diseases. The company is currently developing three investigational therapies across multiple orphan indications: AIT-101, a first-in-class PIKfyve inhibitor, which recently completed a Phase 2a clinical trial in amyotrophic lateral sclerosis (ALS); LAM-001, a proprietary inhaled form of rapamycin, currently in Phase 2 for Group 1 and 3 pulmonary hypertension and bronchiolitis obliterans syndrome (BOS); and AIT-102, a proprietary analogue of mithramycin, in preclinical development, for the treatment of SWI/SNF mutated or dysregulated tumors. The content above comes from the network. if any infringement, please contact us to modify.

孤儿药临床结果

2024-01-24

·GlobeNewswire-Health Care

OrphAI Therapeutics Announces Appointment of Jay Fine to Board of Directors

Seasoned leader in drug discovery and developmentGUILFORD, Conn., Jan. 24, 2024 (GLOBE NEWSWIRE) -- OrphAI Therapeutics Inc. (“OrphAI”), a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today the appointment of Jay S. Fine, Ph.D. to its Board of Directors. Dr. Fine has a strong track record of drug discovery and development leadership in respiratory diseases, oncology, immunology and fibrotic disease indications. His leadership has contributed to the progression of over 30 new molecular entities into clinical development, leading to the commercial launch of multiple products including Skyrizi™ for Plaque Psoriasis, Psoriatic Arthritis and Crohn’s Disease and Spevigo™ for Generalized Pustular Psoriasis. He has chaired various governance and steering committees at several global pharmaceutical companies. Dr. Fine currently serves as President of Research and Development at EvolveImmune Therapeutics, a development-stage company focused on advancing differentiated immunotherapeutic approaches for the treatment of cancer. Previously, he served as Senior Vice President and Global Therapeutic Area Head for Immunology and Respiratory Diseases Research at Boehringer Ingelheim and as the Discovery Research Site Head at their Ridgefield, CT location. Dr. Fine also served as Head of Translational Biology at Roche Pharmaceuticals, was a Director in the Inflammation department at Schering-Plough and worked in the Biologic Response Modifiers Program at the National Cancer Institute. He holds a B.S. degree from Cornell University and a Ph.D. from the University of Rochester School of Medicine. Dr. Fine has authored over 75 scientific publications and patents and has been the recipient of numerous honors and awards during his career. “Jay Fine represents an extraordinary resource both for the Board as well as for the OrphAI management team, given his years of experience and success in the operational leadership of drug discovery and development. I am personally excited to work with him in this capacity,” said Dr. Brigette Roberts, CEO and Director of OrphAI. “I am very pleased to join the OrphAI Therapeutics’ Board of Directors,” said Dr. Fine. “The company has established an exciting product pipeline which holds tremendous potential to meaningfully improve the lives of patients with rare diseases. I look forward to working closely with the OrphAI team and its board to accelerate the progress of its promising pipeline.” “We are excited to welcome Jay Fine to our Board of Directors,” said David Scheer, Chairman of the Board of Directors at OrphAI. “Jay’s extensive leadership experience and drug development insights will be especially valuable to OrphAI and our Board as we collectively embark on this next stage of the company’s growth.” About OrphAI Therapeutics OrphAI Therapeutics’ mission is to transform the lives of patients with rare diseases. The company is currently developing three investigational therapies across multiple orphan indications: AIT-101, a first-in-class PIKfyve inhibitor, which recently completed a Phase 2a clinical trial in amyotrophic lateral sclerosis (ALS); LAM-001, a proprietary inhaled form of rapamycin, currently in Phase 2 for bronchiolitis obliterans syndrome (BOS) and pulmonary arterial hypertension (PAH); and AIT-102, a proprietary analogue of mithramycin, in preclinical development for the treatment of SWI/SNF mutated or dysregulated tumors. To learn more, please visit: OrphAI-Therapeutics.com

临床2期高管变更

2023-10-02

·BioSpace

OrphAI Therapeutics Announces Oral Presentation and Posters at the 22nd Annual NEALS Conference

GUILFORD, Conn., Oct. 02, 2023 (GLOBE NEWSWIRE) -- OrphAI Therapeutics Inc., a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today data presentations at the 22nd Annual NEALS (Northeast ALS Consortium) meeting being held October 4 - 6, 2023 in Clearwater Florida. Oral Presentation: October 5, 2023, 11:10 a.m. ET Title: Results of the Phase 2a clinical trial of LAM-002A (apilimod dimesylate) in C9orf72 ALS Presenters: Dr. Suma Babu, Sean M. Healey Center for ALS at MGHl; Peter Young, Ph.D. Chief Scientific Officer, OrphAI Therapeutics. Location: Opal Ballroom Poster Presentations: Title: AIT-101 Improves Functional Deficits in a Human TDP-43 Animal Model of ALS Presenter: Peter Young, Ph.D., Chief Scientific Officer, OrphAI Therapeutics Location and Time: Poster Session 1, Abstract:4, October 4, 2023, 5:15p – 7:15p ET Title: Results of a double blind, placebo-controlled clinical trial of AIT-101 (LAM-002A) in C9ORF72 ALS- A biomarker driven Phase 2a clinical trial targeting PIKfyve inhibition Presenter: Dr. Suma Babu, Sean M. Healey Center for ALS at MGH Location and Time: Poster Session 2, Abstract:136, October 5, 2023, 4:30p - 6:30p ET About OrphAI Therapeutics OrphAI Therapeutics’ mission is to transform the lives of patients with rare diseases. The company is currently developing three investigational therapies across multiple orphan indications: AIT-101, a first-in-class PIKfyve inhibitor, which recently completed a Phase 2a clinical trial in amyotrophic lateral sclerosis (ALS); LAM-001, a proprietary inhaled form of rapamycin, currently in Phase 2 for bronchiolitis obliterans syndrome (BOS) and pulmonary arterial hypertension (PAH); and AIT-102, a proprietary analogue of mithramycin, in preclinical development for the treatment of SWI/SNF mutated or dysregulated tumors. To learn more, please visit: OrphAI-Therapeutics.com MEDIA CONTACT: info@orphai-therapeutics.com

临床2期临床结果

100 项与 AIT-102 相关的药物交易

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