2019 Game Changer Grant

Stefanie Galban, Recipient

University of Michigan

Targeting Cancer Stem Cells in DIPG.

Abstract:

Diffuse intrinsic pontine glioma (DIPG) is a rare, but lethal childhood cancer with a 5-year survival rate of less than 1% and most commonly diagnosed in children between the ages of 5 and 10 years. Radiation therapy (RT) remains the only form of treatment offering temporary tumor control. Chemotherapy with or without radiation has not provided any survival benefit and novel therapeutic approaches are desperately needed. Recent studies of DIPG tumor material have identified several genes, which are mutated or deregulated. Among those, mutation of a kinase protein molecule (known as PI3K) or overabundance of a receptor (known as PDGFR) are common. Both of these events, function as a molecular switch that activates a cascade of events. Molecularly, these events include activation of another protein signal, AKT resulting in uncontrolled tumor growth. Our initial studies identified a small sub-population of DIPG cancer cells known as stem cells, which have unique characteristics. These cancer stem cells contained specific genes that provided them protection from radiation treatment permitting them to grow which resulted in tumor recurrence. These cells exhibit high levels of AKT and are especially sensitive to a drug which targets AKT and MAPK, a pathway often upregulated in resistant tumor
cells. The goal of this proposal is to target the signaling axes in cancer stem cells responsible for protecting them from radiation treatment as a new therapeutic strategy for DIPG. We will use a combination of existing, FDA-approved drugs to inhibit these key targets. Our proposal aims to address important needs: Determination of the key target(s) in DIPG stem cells by which molecularly targeted therapies can be directed against to sensitize them to radiation therapy. Use this information as the scientific rationale for combining specific molecularly targeted drugs with radiotherapy to eliminate cancer stem cells to improve patient time to progression.