Tomoo Iwakuma, MD, PhD
Doctoral Research Faculty; Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Research Professor of Cancer Biology, University of Kansas School of MedicineFull Biography
The mission of Alex’s Lemonade Stand Foundation is to change the lives of children with cancer through funding impactful research, raising awareness, supporting families, and empowering everyone to help cure childhood cancer. The funds for this Research Catalyst award were made possible thanks to passionate advocacy of local Alex’s Lemonade Stand Foundation affiliates, including the generous support of the annual ALSF Lemon Mixer in Kansas City. To date, the Kansas City ALSF Lemon Mixer has helped raise more than $185,000 for pediatric cancer research initiatives at Children’s Mercy.
The funding will help Dr. Iwakuma’s project titled, “Identifying Drugs That Specifically Kill MDM2-Overexpressing Pediatric Cancers” by helping to purchase a multifunctional plate reader. This piece of equipment is essential for Dr. Iwakuma and his team to be able to perform screening and validation.
Osteosarcoma is a type of bone cancer that begins in the cells that form bones. As Dr. Iwakuma explains, combination treatment of surgery and chemotherapy improve the 5-year survival rates for children and adolescents. However, the prognosis for high-grade osteosarcoma patients with macrometastasis and recurrence remains poor with long-term survival below 20%. To overcome this poor prognosis, researchers must learn about the genetics and molecular pathogenesis of osteosarcoma and identify the vulnerabilities.
Several mutations and genetic abnormalities are found in osteosarcoma. Of these, abnormalities in tumor suppressor p53 is one of the most frequent events in osteosarcoma, which is correlated with poor outcome in patients. The p53 activity is regulated by an oncogene MDM2 which acts as an E3 ubiquitin ligase for p53 to induce p53 degradation. MDM2 is overexpressed in ~30% of human osteosarcoma. Although overexpressed MDM2 inhibits p53 activity and promotes cancer progression, increasing evidence indicates that MDM2 has p53-independent cancer-promoting activities. However, no drug that inhibits p53-independent MDM2 function is clinically available.
“Such a drug would significantly improve prognosis of patients with osteosarcoma and other pediatric cancers that overexpress MDM2, including rhabdomyosarcoma and Ewing sarcoma,” said Dr. Iwakuma.
The goal of Dr. Iwakuma’s study is to identify clinically available drugs that specifically kill MDM2-overexpressing cancer cells. He hopes to also discover a new p53-independent function of MDM2, which could provide novel therapeutic targets for these MDM2-overexpressing cancers as novel vulnerabilities.