Research

Our lab focuses on uncovering the pathways by which high-risk neuroblastoma develops and resists treatment. Earlier work done in our lab led us to focus particularly on how tumor cells repair their DNA, enabling them to resist cell death in the presence of DNA-damaging chemotherapeutic agents.

In high-risk neuroblastoma that is resistant to treatment or that relapses, we hypothesized that it is these DNA repair pathways, specifically an alternative nonhomologous end-joining (alt-NHEJ) pathway, that acts as the survival mechanism for these cells, giving them an enhanced ability repair DNA double-strand breaks (DSB).

We are also interested in studying the impact of low socioeconomic status on neuroblastoma progression and therapy resistance.

The strategies we use to investigate high-risk neuroblastoma and neuroblastoma treatment are three-fold:

• Identifying the developmental and repair pathways involved in high-risk neuroblastoma
• Creating new, reliable preclinical models, including models derived from patient tumors that closely resemble in situ tumor biology and genetics
• Actively identifying and screening potential compounds to inhibit implicated pathways

Our work revealed the mechanism by which the oncogene MYCN confers neuroblastoma cells with a distinct survival advantage: through the alt-NHEJ DNA repair pathway. We found that efficient but faulty repair through alt-NHEJ is the primary pathway neuroblastoma cells with high-risk genotypes use to address DSB.

These findings led us to investigate differences in protein and gene expression of important NHEJ components in high-risk tumor cells. Through this work, we demonstrated that particular NHEJ repair proteins — the enzymes Ligase I, Ligase IIIa and PARP1 — were overexpressed during development in high-risk neuroblastoma. Clinically, patients with these forms of the disease have lower overall survival rates than patients whose tumors express low levels of these repair proteins.

Experiments with a knockdown model that silenced these alt-NHEJ components showed decreased expression of key neuroblastoma markers TH, Phox2b and TRKB, suggesting that alt-NHEJ components might be highly promising targets for new therapies that inhibit their activity.
In fact, experimental data from additional work show that inhibiting alt-NHEJ components in high-risk neuroblastoma cells impedes cells' DNA repair response, leading to the accumulation of DNA DSB and to cell death in vitro and to slowed tumor progression in vivo. We are now actively engaged in identifying and screening potential compounds that target and inhibit these alt-NHEJ components.

Our work also focuses on optimizing solid tumor cancer models. Using patient tumor samples, our lab has developed a successful method to create reliable preclinical xenograft models that can be used to screen new compounds as well as guide patient-specific treatment. The models created are the first to closely resemble the many biological and genetic factors and processes of patients' original tumors, including metastasis. To date, we've created models of both neuroblastoma and Ewing's sarcoma.

We created devised a method to develop metastatic preclinical models using patient tumor samples, while patients are still alive, enabling them to potentially benefit, and we are currently identifying and screening ligase-inhibiting compounds. Since patients with tumors that show patterns of alt-NHEJ overexpression tend to fare worse, our findings not only point to previously unrecognized targets for therapy but also may help stratify individuals most likely to respond. And, by more closely targeting implicated pathways, we can better spare normal cells from the toxic effects of chemotherapy.

The Newman Lab collaborates with Block Out Cancer program at the University of Michigan. We also work with Dr. Nouri Neamati, Dr. Patrick O’Brien, Dr. Gary Hammer and Dr. Sunitha Nagrath.