Biochemical Pathology Section

David D. Roberts, Ph.D.

Primary Research Areas

Areas of expertise
Tumor vascular biology Tumor immunology Signal transduction Extracellular matrix biology Redox and radiation biology Glycobiology Stem cell biology Candidia pathogenesis

Technologies / approaches / methodologies

Cell biology: angiogenesis, autophagy, cell motility, stem cell reprogramming, radiation responses Biochemistry: cell surface receptor signaling, metabolomics Molecular biology Transgenic mice Mouse tumor models including treatment and imaging

Targeting CD47 in tumors and their microenvironment Stroma:

CD47 blockade increases cell survival via: Nitric oxide signaling Autophagy c-Myc and other stem cell factors Metabolic reprogramming Increased repair of DNA damage
Tumor vasculature T cells Macrophages

Irrad.

Genotoxic stress Irrad.+ CD47M

Tumor:
Mean tumor volume (cm3)

CD47 blockade increases tumor cell death via:

Decreasing protective autophagy Resistance to c-Myc regulation
Tumor cells

1.5 1.2 .9 .6 .3 0 0

Tumor Tumor+Irrad. Tumor+Irrad+CD47M Tumor+CD47M

Decreased resistance to innate and adaptive immunity

Genotoxic stress

6 12 18 24 30 Time after radiation (days)

Research Implications
How does your research fit in LP and the broader context? We are developing new insights into the pathogenesis of cancer that can be applied for improving diagnostic and prognostic evaluation (e.g. CD47 expression) We are developing new treatment modalities for improving the responses of cancer patients to radiotherapy and chemotherapy How does your research translate into potential clinical applications? We are using animal models to evaluate and optimize novel therapeutics targeting CD47 that can improve patient survival and increase curative responses

Future Directions
Where do you see your research going in the next 5-10 years?

Preclinical and clinical development of antisense and small molecule CD47 inhibitors Applications to cancer radiotherapy, chemotherapy, and immunotherapy Basic research addressing CD47 signaling to regulate angiogenesis, autophagy, immunity, stem cell reprogramming, and cancer stem cells
What are the current challenges & obstacles?

Preclinical pharmacology to support an IND for translation of CD47-based therapeutics to clinical trials Establishing clinical collaborations to initiate clinical trials

Collaborators partial list

Laboratory of Pathology
Maria Merino molecular markers and metabolism in familial kidney cancers David Levens & Eric Batchelor cMyc regulation by thrombospondin-1 and CD47

CCR NIH
David Wink, RBB (radioprotection and radiosensitization by modulating CD47) Marc Nicklaus, Chemical Biology Laboratory (design of small molecule CD47 inhibitors) Jay Berzovsky, Vaccine Branch (regulation of adaptive tumor immunity by CD47)

Chengyu Liu, iPSC and Genome Engineering Core, NHLBI (stem cells) Abdel Elkahloun, Cancer Genetics Branch, NHGRI (stem cells and cancer stem cells) Satya Singh, Laboratory of Molecular Immunology, NIAID (immune regulation) Michail Lionakis, NIAID (Candida pathogenesis) Martin Lizak, NINDS (MRI imaging)

Extramural
Jeff Isenberg, University of Pittsburgh (CD47 signaling and animal models) Maria Tsokos, Harvard (animal model pathology) Chris Kevil, LSU (hydrogen sulfide signaling) Ken Nickerson, University of Nebraska (Candida pathogenesis)