Mechanisms of PPM1D in Growth and Treatment Responsiveness of Pediatric DIPGs
Abstract
Military Relevance Focus Area: Gaps in cancer diagnosis or treatment that may affect the general population but have a particularly profound impact on military health. Rationale: Brain tumors are one of the most common cancers that occur in children. Diffuse intrinsic pontine glioma (DIPG), one of the most deadly childhood brain tumors, arises in the middle of the brain, in an area that controls functions crucial to life, such as your heart rate and breath. Thus, this tumor cannot be removed and is rarely biopsied because of its location. Despite our best efforts, no treatments today have improved the prognosis of DIPG. All these children die of disease within 1-2 years of diagnosis. If we can improve our understanding of how DIPGs develop and progress, we can cure children that suffer from this horrible disease. Objective: Recent scientific studies show that the gene called PPM1D is altered such that it can promote formation of an aggressive brain tumor in children. These studies also show that 25% of DIPGs have this gene alteration at the time of diagnosis. We propose to study how an alteration in the PPM1D gene encourages DIPG cancer cells to grow and how drugs that specifically prevent PPM1D from working can be used to treat DIPGs. Applications, Benefits, and Risks: This research will help young children diagnosed with DIPG. We propose to study how certain types of DIPG grow and how novel drugs can be used to kill DIPG tumors. The major benefit to our approach is that we will be able to test the safety and efficacy of novel treatments before novel drugs are tested in patients with DIPG. Recent scientific studies show that some breast and ovarian cancers have the same PPM1D gene alterations seen in DIPG tumors. Thus, we may be able to translate our findings to patients with other cancers that have an alteration in the PPM1D gene. One risk is that our findings in a dish or in a mouse will not be the same as in human subjects. It is also possible that while preventing PPM1D from working, our novel drugs might cause children to become sick from its effects in other organs of the body. However, these are risks faced by all cancer experiments outside a human being. Although our research may be too basic for immediate clinical applicability, we believe that over the course of the 2-year grant period, our work has the potential to (1) improve understanding of what causes DIPG and to (2) find effective new drugs for DIPG. Because there are no cures currently available for DIPG, promising results from our studies might be able to be tested in DIPG patients within the next 5-8 years. Military Relevance: The diagnosis of a brain tumor in a child is usually devastating to most families. However, this may assume additional significant in military families, who often are already dealing with numerous emotional or financial challenges as a consequence of military service obligations. Until recently, our understanding of DIPG had been limited and treatments ineffective. There are still no effective treatments for DIPG. However, the findings of recent scientific studies have generated great excitement, as they have uncovered novel gene changes in DIPGs, including alteration of the cancer-promoting gene PPM1D in at least one-quarter of DIPGs. Scientific studies suggest an important role for drugs that prevent PPM1D from working in cancer cells. We have shown that PPM1D-inhibiting drugs are effective at stopping both the growth and invasion of cells from another aggressive childhood brain tumor, medulloblastoma. With unique DIPG models, we will be well positioned to provide preclinical evidence for efficacy and toxicity of PPM1D inhibitors against DIPG. Interestingly, alterations in the PPM1D gene have also been identified in adult breast and ovarian cancers. Thus, findings from our proposed research may have a significant impact on the health and treatment of adult members of the military and others
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510132
Entities
People
- Robert Castellino
Organizations
- Emory University
- United States Army