Current Research
Our long-term research interest is focused on understanding the biology of clinically aggressive, high-risk neuroblastoma to develop more effective, targeted treatment strategies. One aspect of our research is investigating the role of tumor microenvironment and angiogenesis in neuroblastoma pathogenesis. Our lab has determined that Schwann cells, derived from low-risk, stroma-rich neuroblastoma tumors, produce Secreted Protein Acidic and Rich in Cysteine (SPARC). We characterized SPARC as a potent inhibitor of angiogenesis and demonstrated its strong anti-tumor effect in preclinical models of neuroblastoma. Our recent studies indicated that SPARC may represent a new class of scavenger chaperones, which mediate degradation, remodeling and repair of the extracellular matrix. Understanding this novel mechanism provides insight into the pathogenesis of matrix-associated disorders and may lead to new treatment strategies.
To translate these discoveries into clinical use, we designed a short peptide FSEC, which corresponds to the epidermal growth factor-like module of the follistatin domain of SPARC. The peptide was tested in pre-clinical models of neuroblastoma and several adult cancers. Strong anti-tumor effect of peptide FSEC in all cancer models positions it as a highly promising therapeutic candidate with unique and novel properties. It targets tumor microenvironment, which is critical for cancer progression and its modulation represents a new strategy in the drug design and the treatment of cancer.
We have also shown that treatment with a number of other anti-angiogenic agents is capable of “normalizing” the architecture and function of neuroblastoma blood vessels, suggesting that this treatment strategy may also allow for more efficient cytotoxic drug delivery
Recently, we have evaluated the role of race and ethnicity in children with neuroblastoma and show, for the first time, that black children with neuroblastoma are statistically significantly more likely to present with clinically aggressive disease than white children and have significantly worse outcome. Germline genetic variations can account for racial and ethnic diversity in drug effectiveness and, toxicity. Next generation sequencing technologies will be used to identify rare, heritable variants, associated with event-free survival using germline DNA samples from black children with neuroblastoma.
We are also interested in identifying molecular classifiers that will detect “ultra high-risk” neuroblastoma patients who will not respond to current therapies and may benefit from alternative new strategies. With the use of the nCounterTM Analysis System we are uncovering a prioritized gene list that identifies this subset of neuroblastoma patients with very dismal prognosis. Tumor samples from high-risk patients with linked clinical and outcome data are being analyzed using the nCounterTM, and the prognostic value of the molecular signature evaluated. Our goal is to establish a robust genome-based outcome prediction system that could be incorporated into the clinical settings and used to develop more effective, individualized therapy.
We anticipate that these studies will improve scientific knowledge in the broad fields of pharmacogenomics, pharmacoethnicity, and genomics, and may ultimately lead to a refinement of how drugs are delivered in the clinic based on a patient’s unique genetic profile, maximizing response and minimizing adverse drug reactions. Further, the genetic variants we identify in tumor tissue may prove to be driving mutations that can be exploited therapeutically.
