Nathan Dolloff, PhD
2001 B.S., Gettysburg College
2007 Ph.D., Drexel University College of Medicine
2010 Postdoctoral Fellow, University of Pennsylvania
Office: Drug Discovery Building 407
Lab: Drug Discovery Building 426
Drug Discovery Focus in B and Plasma Cell Malignancies
Efforts in the Dolloff Laboratory are aimed at discovering and developing new targeted therapies for the treatment of incurable hematologic malignancies. The primary disease focus is Multiple Myeloma (MM) with a general interest in cytogenetically related B and plasma cell cancers that include non-Hodgkins Lymphoma, plasma cell leukemia, and others. Major objectives of the lab are to identify and validate new molecular targets and establish high throughput drug screening assays for screening large chemical libraries. Lead compounds that are discovered are then used as tools to better understand the biology of new targets and/or are selected for further drug development toward the ultimate goal of clinical translation.
(1) Targeting IgH Gene Enhancers. B and plasma cells are specialized for the production of mass amounts of immunoglobulins (antibodies). An integral step in their differentiation program is the transcriptional activation of immunoglobulin genes, which include the heavy chain (IgH) and light chain (IgL) genes. In addition to their critical role in normal B and plasma cell biology, errors in Ig gene rearrangement, particularly the IgH gene (chromosome 14q32), are the most common genetic aberrations in MM and nearly every malignancy that arises from this cell lineage. Structurally, these translocations juxtapose oncogenes with potent transcriptional enhancer sequences (i.e., IgH gene enhancers) found within the IgH gene locus. This leads to transcriptional up-regulation of the oncogene, which drives the process of malignant transformation. The activity of IgH enhancers is tightly regulated by a specific set of transcription factors whose expression is restricted to B and plasma cells. This specific regulation and cell type restriction coupled with their role in the pathogenesis of multiple clinically distinct blood cancers, makes IgH gene enhancers attractive new drug targets. Ongoing efforts in the lab focus on the pursuit of compounds that selectively inhibit their activity and block the expression of oncogenes that are overexpressed due to IgH gene translocations. Given the prevalence of blood cancers with IgH translocations (i.e., roughly 100,000 new cases each year in the U.S.), this work has significant translational implications.
(2) Overcoming Proteasome Inhibitor Resistance: The development of novel classes of agents such as proteasome inhibitors (PI) has significantly improved survival times for patients with MM. Despite these improvements, resistance to these therapies is an emerging clinical challenge as nearly every patient progresses to a treatment refractory stage and the disease remains largely incurable. We have developed a cell-based drug screening platform that uses isogenic models of PI resistance for discovering compounds and molecular mechanisms that selectively kill PI resistant MM cells or restore sensitivity to the FDA-approved PIs bortezomib/VELCADEâ and carfilzomib/KYPROLISâ. Screening projects in the lab using shRNA and chemical libraries are aimed at identifying genes and compounds that mediate PI resistance or can be used to overcome it, respectively.
(3) Targeting Redox Regulation: Maintaining redox homeostasis and neutralizing harmful levels of Reactive Oxygen Species (ROS) is critical to all cells. This is especially true in plasma cells where basal levels of ROS are elevated due to mass production of immunoglobulins. Large proteins like immunoglobulins have hundreds of disulfide bonds per molecule, the formation of which generates equimolar amounts of ROS. MM plasma cells are therefore, by nature, highly susceptible to even the slightest disruption in redox balance. As part of the South Carolina Center of Biomedical Research Excellence (COBRE) in Oxidants, Redox Balance and Stress Signaling, the Dolloff Lab is investigating new ways to disrupt redox balance for therapy of MM and other plasma cell malignancies.
Recent Publications/Additional Publications
- Stessman HA, Lulla A, Xia T, Mitra A, Harding T, Mansoor A, Myers CL, Van Ness BG, Dolloff NG. High throughput drug screening identifies compounds and molecular strategies for targeting proteasome inhibitor resistant multiple myeloma. Leukemia 2014 [Epub ahead of print]
- Stessman HA, Baughn LB, Sarver A, Xia T, Deshpande R, Mansoor A, Walsh SA, Sunderland JJ, Dolloff NG, Linden MA, Zhan F, Janz S, Myers CL, Van Ness BG. Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol Cancer Ther 2013;12:1140-50.
- Dolloff NG, Talamo G. Targeted therapy of multiple myeloma. Adv Exp Med Biol. 2013;779:197-221.
- Talamo G, Dolloff NG, Sharma K, Zhu J, Malysz J. Clinical features and outcomes of plasma cell leukemia: a single-institution experience in the era of novel agents. Rare Tumors 2012;4:e39.
- Dolloff NG, Allen JE, Dicker DT, Acqui N, Vogl D, Talamo G, El-Deiry WS. Sangivamycin-Like Molecule 6 (SLM6) exhibits selective anti-multiple myeloma activity through inhibition of cyclin-dependent kinase-9 (CDK9). Mol Cancer Ther 2012;11:2321-30.
- Dolloff NG, Ma X, Dicker DT, Humphreys R, Li LZ, El-Deiry WS. Spectral imaging-based methods for quantifying autophagy and apoptosis. Cancer Biol Therapy 2011;12:349-56.
- Dolloff NG, Mayes PM, Hart LS, Dicker DT, Humphreys R, El-Deiry WS. Off-target Lapatinib Activity Sensitizes Colon Cancer Cells through TRAIL Death Receptor Up-regulation. Science Transl Med 2011,3(86):86ra50.
- Mayes PM*, Dolloff NG*, Liu JJ, Kuribayashi K, Jee DIH, Liu YY, Dorsey JF, Brown JM, Furth EE, El-Deiry WS. Overcoming hypoxia-induced apoptotic resistance through combined inhibition of GSK-3b and CDK1. Cancer Res 2011;71:5265-75. (*equal contribution).
- Yang W., Dolloff NG, El-Deiry W.S. ERK and MDM2 prey on FOXO3a. Nat Cell Biol 2008;10:125-126.