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3225 Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relives Differentiation Block in MDS/AML

Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes—Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, MDS, Translational Research, Chronic Myeloid Malignancies, drug development, Diseases, Therapies, Myeloid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Opeyemi Ajibade, MD, MS1*, Urszula Pakulska, PhD2*, Emma Rabinovich, MD3, Ariel Fromowitz3, Srabani Sahu4*, Sarah Aminov, MSc3, Nandini Ramachandra, MS4*, Srinivas Aluri, PhD4*, Shanisha Gordon Mitchell3*, Milagros Carbajal3*, Kinga Keska-Izworska5*, Michał Combik, PhD5*, Marta Obacz, MSc2*, Elżbieta Adamczyk, PhD2*, Jan M. Zaucha6*, Ewa Zarzycka, MD7*, Przemyslaw Juszczynski, MD, PhD8*, Jacqueline Boultwood, PhD9*, Andrea Pellagatti, PhD9*, Kith Pradhan, PhD4*, Ulrich Steidl, MD, PhD3, Aditi Shastri, MD3, Rongbao Zhao, PhD4*, Milena Mazan, PhD2*, Tomasz Rzymski, PhD5* and Amit Verma, MD10

1Blood Cancer Institute, Department of Oncology, Albert Einstein College of Medicine, Brooklyn, NY
2Ryvu Therapeutics, Kraków, Poland
3Blood Cancer Institute, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY
4Montefiore Einstein Cancer Center, Blood Cancer Institute, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
5RYVU Therapeutics, Krakow, Poland
6Medical University of Gdansk, Gdansk, Poland
7Department of Hematology and Transplantology, Medical University of Gdansk, Gdansk, Poland
8Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, POL
9Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
10Department of Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY


Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemias (AML) are characterized by a block in hematopoietic differentiation that can often be traced to aberrant stage-specific transcription. The kinase module of the mediator complex, consisting of CDK8, its paralog CDK19, Cyclin C, MED12, and MED13, have been identified as a molecular switch that regulates gene expression. A variety of cancers have exploited this mechanism to maintain stemness and an undifferentiated state. RVU120 is a first-in-class, specific, and selective inhibitor of CDK8/19, currently in Phase Ib clinical trial in patients with AML or High-Risk MDS (HR-MDS) (NCT04021368). RVU120 has been shown to stimulate erythroid differentiation in transformed CD34+ cord blood (CB) cells and in CD34+ cells from Diamond-Blackfan Anemia (DBA). To evaluate the further therapeutic potential of CDK8/19 inhibition, we confirmed aberrant expression of mediator complex components and erythroid-stimulating activity in a collection of CD34+ primary samples of AML and MDS.


We investigated the expression of mediator complex components in a large database of MDS CD34+ marrow samples and age-matched controls. Our findings revealed that MED12, a critical component of the mediator complex, was significantly overexpressed in MDS samples from refractory anemia with excess blasts (RAEB), a higher risk subset of MDS(p=0.018) (Fig A). Furthermore, we observed that this overexpression of MED12 was associated with a higher rate of transformation to AML. To delve deeper, we examined the expression of MED12 in sorted leukemic stem cells from primary AML samples and found significantly elevated levels in Long Term Hematopoietic Stem Cells from AML samples with both normal karyotype and complex karyotypes compared to healthy controls.

Next, we conducted an evaluation of the efficacy of the mediator kinase module inhibition in MDS-derived cell line (MDS-L). Inhibition of CDK8/19 with RVU120 led to increased erythroid differentiation in this model which confirmed our observations in transformed CD34+ CB cells in CB cells, these phenotypic changes were correlated with the inhibition of CDK8-dependent phosphorylation marker S726 on STAT5 and a profound increase in the expression of genes involved in erythroid commitment and hemoglobin metabolism. In order to confirm therapeutic potential of CDK8/CDK19 inhibition in MDS and AML, we performed colony-forming assay on primary samples of MDS and AML (n= 15). The treatment with RVU120 resulted in increased erythroid differentiation in a majority of samples, evident from an augmented number of colonies. Detailed analysis indicated changes in the expression of erythroid differentiation markers, including increased CD71 and Glycophorin A expression on colonies, as assessed by FACS analysis (Figure B, shows representative sample).


Our data highlight that inhibition of the overexpressed mediator complex proteins can alleviate the differentiation blocks seen in MDS/AML. These results provide a compelling rationale for further developing the CDK8/19 inhibitor RVU120 for transfusion- dependent MDS/AML patients.

Disclosures: Pakulska: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Obacz: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Adamczyk: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zaucha: Medical University of Gdańsk: Current Employment; BMS: Research Funding; Pierre Fabre, Takeda, BMS, Gilead, Novartis, Pfizer, Amgen, F. Hoffmann-La Roche Ltd, Astra Zeneca, Abbvie: Honoraria; MSD: Research Funding. Steidl: Aileron Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Stelexis Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Bayer Healthcare: Research Funding; GlaxoSmithKline: Research Funding. Shastri: Kymera Therapeutics: Honoraria, Research Funding; Gilead Sciences: Honoraria; Rigel Pharmaceuticals: Honoraria; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria. Zhao: Albert Einstein COM: Current Employment. Mazan: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Verma: Bristol Myers Squibb: Research Funding; Stelexis: Consultancy, Current equity holder in private company, Honoraria; Bakx: Consultancy, Current equity holder in private company; Janssen: Honoraria; Curis: Research Funding; GSK: Research Funding; Incyte: Research Funding; Medpacto: Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy; Acceleron: Consultancy; Throws Exception: Current equity holder in private company; Celgene: Consultancy; Prelude: Research Funding.

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