Game-Changer Archives - Page 45 of 45

Michael Armstrong, M.D., Ph.D.

Funded by the Apple Gold Group

Neuroblastoma is the third most common childhood cancer. Unfortunately, despite intensive treatment, two-thirds of children with advanced neuroblastoma succumb to their disease. New treatment options must be developed to improve outcomes in this devastating disease. This requires a better understanding of how neuroblastoma cells survive in the face of these intensive therapies. N-Myc is a member of a family of proto-oncogenes (genes capable of leading to cancer development) implicated as a cause of several cancers. N-Myc plays a central role in the aggressiveness of neuroblastoma tumors. Children whose neuroblastoma tumors have extra copies of the N-Myc gene (N-Myc amplification) fare worse than children whose tumors have the normal number of N-Myc genes. However, it is unknown why extra N-Myc leads to poor outcomes. Mxi1 is a protein related to the Myc family, however, it counteracts the ability of N-Myc to cause cell growth. Mxi0 is a similar protein, but it does not inhibit N-Myc like Mxi1. In this proposal, we will test the hypothesis that the balance of Mxi1 and Mxi0 expression is important for maintaining normal growth, and that N-Myc alters this balance, leading to treatment resistance. To accomplish this, we developed a new kind of mouse which has its Mxi1 or Mxi0 genes removed. In this project, we will examine the impact of decreasing Mxi1 or Mxi0 expression on neuroblastoma tumor formation and response to treatment, with the overall goal of finding a mechanism to bypass the effects of N-Myc and improve the outcomes of children with neuroblastoma.

Ash Alizadeh, M.D., Ph.D.

V Scholar Plus Award- extended funding for exceptional V Scholars

Aggressive lymphomas are cancers of white blood cells. The most common type is called diffuse large B cell lymphoma (DLBCL). Most patients with DLBCL can be cured by chemotherapy, but some patients either do not respond to treatment or the disease comes back after a certain time (‘relapse’). If we can identify those patients likely to relapse earlier, we hope to improve their chance of survival. Circulating tumor DNA (‘ctDNA’) is DNA that comes from tumor cells and gets in the blood stream. CtDNA in the patient’s blood can be analyzed to get more information about the tumor. In this study, we developed a blood test to profile ctDNA at different stages of the disease and to identify patients at risk for relapse. We found that ctDNA in the patient’s blood contains information that can be used to tell how well the patients will do with chemotherapy. We also observed that analysis of ctDNA over the course of treatment could show how their lymphomas change over time. For example, we detected new mistakes (‘mutations’) in ctDNA that could be used as an early signal to predict that certain treatments would no longer work in these patients. Also, we found that ctDNA in the blood after treatment predicts disease relapse months earlier than any other clinical method. Our test can also give physicians early warning that the tumor is changing from a slow growing to a fast growing lymphoma type. All this information in ctDNA can be used to learn more about lymphoma biology and to find patient groups with high risk for relapse.

Mazhar Adli, Ph.D.

V Scholar Plus Award- extended funding for exceptional V Scholars

Gene regulation is vital for our health and abnormal regulations lead to many diseases, including cancer. There are two mechanisms that control genes: Genetic info and epigenetic. Genetic alterations are stable and we cannot target them. However, epigenetic is dynamic as it changes over time. Epigenetic can control gene expression in tissues. It is the loss of this control that causes cancer. In cancer, only select genes are abnormal while the rest are normal. We need to target only abnormal genes. Current therapy is based on chemicals that target all of the genes in the cell. Thus they have side effects. This proposal develops a novel tool that can target a specific gene. Thus, it can correct an aberrant gene only. The tool also has strong therapeutic potential. This will be very valuable for basic research.

Bradley Bernstein, M.D., Ph.D. and John Mullen, M.D.

Support for the Liposarcoma Genome Project was funded by

Alex Gould and Friends in memory of Kathryn Gould.

Liposarcoma Genome Project –
Liposarcoma is the most common type of cancer that arises in soft tissue. These tumors often present as low grade tumors initially, but a subset of patients will experience recurrence of a higher grade tumor. Those patients who recur with higher grade tumors do poorly. Therefore, our research focuses on understanding these high grade tumors. We will explore the genetic changes between the low grade and high grade tumors in order to understand the molecular features that underlie high grade transformation. We will begin by sequencing gene mutations in these tumors and surveying gene activity in each tumor type (Aim 1). Mechanisms that govern which genes are on and off frequently involve how the DNA is packaged and structurally arranged in the cell. Therefore, we will characterize the packaging (chromatin) and structure (topology) of the genomic DNA in these tumors (Aim 2). By elucidating mechanisms by which tumor cells alter gene expression, we will better understand the genes and pathways that sustain them. Finally, we will develop models of these tumors (Aim 3). We can use these models to test driver genes and candidate therapeutic targets identified in our study. We believe that our interdisciplinary team of clinicians and scientists is poised to complete the proposed aims, which should yield important insights into liposarcoma biology and guide future clinical strategies.