Loma Linda University

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David Weldon, PhD
Assistant Professor, Pharmaceutical and Administrative Sciences
School of Pharmacy
Member, Pharmaceutical Science, SP, Faculty of Graduate Studies
Research & Grantsmanship    Funded Research Project (PI)
  • Title: Natural Product Therapy to Inhibit B Cell Precursor Proliferation

    $50,000 - Funded  3/2011-2/2012

     

    David J. Weldon, PhD

    Assistant Professor of Medicinal Chemistry 

    Department of Pharmaceutical Sciences

    School of Pharmacy

     

    Kimberly J. Payne, PhD

    Assistant Professor

    Dept. of Pathology and Human Anatomy

    Center for Health Disparities and Molecular Medicine

    School of Medicine

    ( 3/2011 - 2/2012 )

    B cell progenitor acute lymphocytic leukemia (B-ALL) is the most common childhood malignancy. Interleukin-7 receptor (IL-7R) signaling has recently been implicated as a key player in the production of normal and malignant B cells. Current therapies for childhood B-ALL have many side effects and are ineffective in approximately 20% of B-ALL, including those with overexpression of IL-7R signaling components. Understanding the role of IL-7 in normal and malignant B cell production will be important for developing combination therapies with fewer side effects and greater efficacy in treating B-ALL. The natural product, kalanchosine, has been shown to block the development of mouse B cell progenitors by selectively inhibiting proliferation that occurs following IL-7-induced IL-7R signaling. Kalanchosine spares mature B cells which are no longer responsive to IL-7R signaling. This is the first report of a natural product that selectively inhibits IL-7R signaling. The impact of IL-7R inhibition by Kalanchosine during normal and malignant B cell development in humans has not been examined. It is not known whether kalanchosine can inhibit IL-7R signals induced by the alternative IL-7R ligand, TSLP (Thymic Stroma-derived LymphoPoietin). The overall goal of the proposed studies is to evaluate the potential of kalanchosine as a potential component of combination therapy for B-ALL and as a tool for studies of IL-7R signaling in immune development and response. We hypothesize that 1) naturally occurring kalanchosine will inhibit the IL-7R-mediated proliferation of human B cells induced by both the IL-7 and TSLP ligands and that 2) the naturally occurring stereoisomer of kalanchosine can be identified and synthesized for biological evaluation as a therapeutic agent. These hypotheses will be tested through the following specific aims: 1) Determine the relative stereochemistry of naturally occurring kalanchosine and define its effect on IL-7R-mediated signals in normal malignant human B cell development; 2) Synthesize and determine IL-7R inhibitory activity of the stereoisomer(s) present in naturally occurring Kalanchosine. Dr. Payne has extensive experience in human B cell biology and in developing translational models of human B cell development.  Dr. Weldon has expertise in the total synthesis of small molecules and peptides for therapeutic applications. These qualifications along with the clinical samples and research facilities available at LLU provide a unique combination of expertise and resources to achieve the goals of the proposed project. Successful completion of the proposed project will provide preliminary data for subsequent external funding applications aimed at the development and testing of natural product analogues with the potential to break new ground in the treatment of B-ALL by providing a combination therapy component that can effectively target malignant cells while reducing immune system toxicity and other side effects. In addition, this project will provide a unique tool for applications aimed at dissecting the role of IL-7R signaling in the normal and diseased immune system development and function.

  Grant Proposals--Submitted
  • Isolation of the Natural Product Kalanchosine from 10 Species of Kalanchoe Plants.

    The American Association of Colleges of Pharmacy

    2011-2012 New Pharmacy Faculty Research Awards Program for Pharmacy

    ( 9/2010 - Present )
  • Total Synthesis of the Natural Product Kalanchosine and Kalanchosine Stereoisomers for Biological Evaluation as a Potential Therapeutic in pre-B Acute Lymphoblastic Leukemia.

    The American Association of Colleges of Pharmacy

    2010-2011 New Pharmacy Faculty Research Awards Program for Pharmacy

    ( 9/2009 - Present )