In addition to all of programs that we fund, Make Your Mark also supports research done by some of the brightest physicians and scientists. Currently, we are collaborating with faculty at Northwestern Memorial Hospital, Lurie Children’s Hospital, and Comer Children’s Hospital. Below, you can get a glimpse into the exciting work that these brilliant scientists are doing to combat neuroblastoma and other cancers that affect children.
Dr. Mary Beth N Madonna, from Lurie Children’s Hospital, is one of the recipients of Make Your Mark Research Grants. Here are some more details on it: Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15 percent of all cancer-related deaths in children. Although many factors contribute to the high mortality, resistance to chemotherapeutic drugs is a major factor. Our lab has made considerable progress pursuing different avenues of research, highlighted below, to determine better treatment for children with drug-resistant neuroblastoma. This work has resulted in multiple publications in prominent scientific journals.
1) Overcoming drug resistance through inhibiting glycolysis (the metabolic pathway that generates cancer cells’ main source of energy).
Most cancer cells exhibit increased glycolysis and use this metabolic pathway to generate energy. There are alterations in the metabolic needs of tumor cells which allow cells to survive the stress of chemotherapy. This inherent difference between malignant and non-malignant cells offers a unique approach for drug treatment of chemotherapy resistant cells. 3-Bromopyruvate (3-BrPA) is an inhibitor of glycolysis and has been shown in other tumors to be a potent chemotherapeutic agent. Our preliminary data shows that there is an enhanced response in doxorubicin resistant neuroblastoma cells when they are treated with 3BrPA. Currently we are working on determining the mechanism of this action. In addition, we are beginning animal studies to confirm this phenomenon is reproducible in vivo. The advantage of this particular drug is that it is already commercially available.
2) Identifying the Receptor(s) of Midkine in conferring drug resistance
Previous work in our laboratory has identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma cells. This finding has been confirmed in an animal model. Our current work is trying to identify the pertinent receptor(s) and downstream signaling pathways so that we can find novel therapeutic agents targeting these pathways. To date we have ruled out many of the commonly known midkine receptors. Using whole genome analysis, we have identified some potential receptors. Notch is one such receptor. We have confirmed that this receptor is present in drug-resistant neuroblastoma cells and that there is increased expression of many of the proteins in pathway downstream to this receptor. Currently we are working to block this receptor to determine if the cytoprotective effect is lost. If this is confirmed then we will use this blocking agent in animal studies to confirm it is a potential agent in vivo.
Dr. Susan L. Cohn, from Comer Children’s Hospital at University of Chicago, is the latest of the recipients of Make Your Mark Research Grants. Here are some more details on it:
Mark Staehely Neuroblastoma Research Fund was established this year at the University of Chicago Medicine Comer Children’s Hospital. The Fund supports Dr. Susan Cohn and her team’s studies, with colleagues in Chicago and around the world, to better understand the biology of neuroblastoma in order to develop more effective treatments.
Dr. Cohn’s team has nearly completed construction of a special room at Comer Children’s Hospital to provide a new, targeted radiotherapy for children with neuroblastoma that is called MIBG (meta-iodomethylguanidine) treatment. This treatment has been shown as effective in killing cancer in approximately 30% of children with relapsed neuroblastoma. Until recently, this treatment has only been used in patients whose disease has relapsed. However, based on the significant activity of this drug in relapsed patients, clinical trials are now testing the efficacy of MIBG in newly diagnosed patients. They anticipate that the MIBG room at Comer Children’s Hospital will be open in early spring 2014. Dr. Cohn’s team plans to open a number of clinical trials for children with neuroblastoma that will incorporate MIBG treatment this year. The Mark Staehely Fund will support these very important and exciting new studies, the only of their kind in Illinois.
In addition, Dr. Cohn’s team is working on several of the following ongoing studies made possible by philanthropic gifts:
- They are expanding a database, the Interactive International Neuroblastoma Risk Group Database (iINRGdb), with clinical and genetic information from over 12,000 neuroblastoma patients from around the world. The data collected on these patients are available to investigators internationally, and numerous data mining studies have been published that would not have been possible without this unique resource. They have now linked the clinical data with data from the Children’s Oncology Group Tumor Bank and are poised to link genomic data that have been generated in laboratories globally to the clinical data, enhancing this tool’s application for investigators around the globe. (Reference: Cohn SL, et al., J. Clin. Oncol., 2009, Schleiermacher G et al., Br J Cancer. 2012 )
- They are investigating the genetic factors that contribute to racial disparities in outcome in children with neuroblastoma. They have previously shown that African Americans with neuroblastoma have worse outcomes than Caucasian children (Henderson TO, et al., J. Clin. Oncol., 2011). More recently, they have identified the genetic variants that contribute to the increased prevalence of high-risk neuroblastoma in the African American population (Gamazon E, et al., J. Natl. Cancer Inst., 2013). They are now conducting experiments to determine how these genetic variants contribute to the development of chemotherapy-resistant neuroblastoma.
- They are collaborating with Dr. Lucy Godley, a medical oncologist at the University of Chicago, to investigate the role that epigenetic changes in neuroblastoma play in determining the clinical behavior of the tumor (Ostler KR, et al., Cancer Res., 2012). There are a number of drugs currently in clinical trials that can reverse these changes. Thus, learning more about how epigenetic aberrations occur in neuroblastoma will provide important clues to inform new therapies.
- They are continuing their long-term interest in studying the angiogenesis (new blood vessel formation) in neuroblastoma and investigating a number of agents that will inhibit blood vessel growth. Their studies indicate that by inhibiting the growth of blood vessels, that bring nutrients and oxygen to the tumor, they are able to block tumor growth (Chlenski A, et al., Mol. Cancer, 2010; Chlenski A, et al., PLoS One, 2011).
Dr. John A. Kalapurakal, from Northwestern Memorial Hospital, is one of the recipients of Make Your Mark Research Grants. Here are some more details from his ongoing neuroblastoma research and the work that is being done in conjunction with the lab of Dr. Gayle Woloschak at Feinberg School of Medicine at Northwestern University.