Pharmacology

Intercellular Communication During Adult Tissue Repair

Faculty Mentor’s Name: Dr. Daniel Kopinke
Email: dkopinke@ufl.edu
Phone Number: (352) 294-5355
Project Category: Basic
International Component or Travel: No

Research Project Description:
Our lab studies how stem cells sense and communicate with their surroundings to build, maintain and repair adult tissues including skeletal and cardiac muscle using sophisticated mouse genetics, state of the art cell biological tools and fluorescent microscopy. If you are excited about top-notch biomedical research and are highly self-motivated, we have several ongoing projects in which you would be involved in preparing, analyzing and presenting primary data. You would use techniques such as cryosectioning, immunostaininig, RT-qPCR and confocal microscopy to collect, ImageJ and Graphpad to analyze and Powerpoint to present the data. For more information, visit our website @ www.kopinkelab.com and check out our recent publications: https://pubmed.ncbi.nlm.nih.gov/32540122/ ; https://pubmed.ncbi.nlm.nih.gov/31761534/; https://pubmed.ncbi.nlm.nih.gov/28709001/

Novel Combinatorial Treatment Approaches to Augment Sensitivity to Cytarabine in Acute Myeloid Leukemia With DNMT3A Mutations

Faculty Mentor’s Name: Dr. Olga Guryanova
Email:oguryanova@ufl.edu
Phone Number: (352) 294-8590
Project Category: Translational
International Component or Travel: No

Research Project Description:
The primary objective of the proposed study is to evaluate the efficacy of a novel combined treatment consisting of cytarabine, a nucleoside analog that stalls DNA replication commonly used in AML patients, potentiated by Nutlin-3a, which facilitates activation of the tumor suppressor p53 for enhanced cell killing, in a pre-clinical model of acute myeloid leukemia with DNMT3A mutations.

Mutations in the DNA methyltransferase 3A (DNMT3A) gene are recurrent in de novo acute myeloid leukemia (AML) and are associated with poor prognosis. Although studies demonstrated survival benefit of induction chemotherapy dose intensification, outcomes remain unsatisfactory in most patients due to advanced age, comorbidities, and hence inability to tolerate treatment. Research in Dr. Guryanova’s laboratory is dedicated to identification of new targets, elucidation of the molecular basis of chemotherapy sensitivity and resistance, and development of mechanistically-informed strategies for cancer cell re-sensitization. We discovered disordered chromatin remodeling and a defect in DNA damage signaling in AML cells with a poor-prognosis mutation in DNMT3A (Guryanova et al., Nature Medicine, 2016). Cytarabine-based low-intensity regimens appear safe and effective, and in clinical trials tend to benefit patients with DNMT3A mutations. Consistently, our prior studies demonstrated increased sensitivity to nucleoside analogs in multiple models with mutant DNMT3A in vitro and in vivo, which is attributable to prolonged, elevated p53 signaling after DNA damage. We hypothesize that further unleashing p53 activity by Nutlin-3a thus augments cytarabine efficacy in these patients. Indeed, the recent BeatAML precision oncology clinical trial demonstrated preferential sensitivity to the cytarabine/nutlin-3a combo in DNMT3A-mutant patient AML cells. The objective of this study is to provide granular investigation of the molecular mechanisms defining cytarabine/nutlin-3a sensitivity in the DNMT3A mutant setting, and to conduct preclinical evaluation of the combo.

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