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Graham Lab

Neuroblastoma and Brain Tumor Research

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Investigator / Contact Person Regina Graham

Research

My research efforts are mainly focused on pediatric cancers aiming to better understand mechanisms of treatment resistance and finding novel ways to target and induce cancer cell death.  Neuroblastoma (NB) is a cancer presumed to arise from the neural crest cells of the developing nervous system and primarily occurs in very young children. At diagnosis most children already have metastatic disease and for children with high-risk disease the prognosis is poor. Brain tumors are now the leading cause of cancer-related deaths in children and for the survivors the adverse consequences of the current treatment regimen is severe including neurological deficits and increased risk of additional cancers. 
For these diseases I am interested in testing the therapeutic potential of natural products such as curcumin and withaferin A, the repurposing FDA approved drugs such as antipsychotics and other neuroleptics as cancer treatments and developing novel treatment modalities. In addition I am interested in cancer stem-like cells since these are often treatment resistant and presumed to be responsible for tumor recurrence following therapy. I have generated several patient-derived glioblastoma (GBM) stem-like cell (GSC) lines. GBM is a rapidly proliferating, and aggressive brain tumor with a dismal prognosis for children and adults. We have found that natural products including withaferin A and curcumin inhibit GSC self-renewal and induce cell death and are now testing several curcumin analogs.


It is well known that cancer cells alter their metabolism to support rapid cell proliferation, increasing their uptake of glucose and amino acids. I am interested in targeting the pathways supporting these metabolic differences including glycolysis, NAD+ production and protein homeostasis. I have shown that the natural product Resveratrol significantly increases glycolytic inhibitor induced neuroblastoma cell death by down-regulating the PI3K/Akt pathway. Targeting NAD+ metabolism via NAMPT inhibition induced NB cell death and inhibited tumor growth. Recent evidence suggests that endoplasmic reticulum (ER) proteostasis plays a key role in tumor aggressiveness and resistance to therapy. We have found that increasing ER stress sensitizes GSCs to radiation-induced cell death. 


A major obstacle in treating brain tumors is the paucity of effective anti-cancer agents able to cross the blood brain barrier (BBB). To overcome this obstacle, I am examining the therapeutic potential of antipsychotics, which target G protein-coupled receptors (GPCRs) Although GPCR signaling controls many features of tumorigenesis; they have largely been ignored as a therapeutic target. Our research indicates that antipsychotics targeting GPCR signaling induces anti-proliferative and anti-stem cell activities in our GSC lines. 
A growing area of research is personalized medicine. Proteomic differences in receptor or antigen expression as Ill differences in the metabolic or other nutrient needs of cancer cells can be exploited to preferentially target cancer cells.


I am interested in using nanoparticles as a platform to selectively target tumor cells for fluorescent-guided surgery and to deliver anti-cancer drugs. I am focusing on carbon dots (C-Dots), a relatively new member of the carbon nanoparticle family. C-dots have emerged as an excellent choice for biomedical applications due to their high biocompatibility, fluorescence and easy functionalizability. By targeting multiple tumor specific receptors/antigens, C-Dots fluorescent probes are a promising new approach for real-time fluorescence imaging during surgery and as a drug delivery system. C-Dots can be engineered to cross the BBB and deliver anti-cancer drugs directly to tumor cells.