Investigating the Mechanisms Underlying ATRX Mutant Neuroblastoma
Abstract
My lifelong passion and goal is to better elucidate the mechanism(s) that drive cancer progression and translate these findings to improve patient outcomes. As a predoctoral candidate, I have developed a strong research background that I aim to build on. This Horizon Award will significantly help my training to becoming a successful independent investigator in the field of neuroblastoma by providing me resources to help address the scientific questions as outlined in this proposal. With the combined guidance of my mentor, Dr. Emily Bernstein, and the support available at Icahn School of Medicine at Mount Sinai, I will be able to work diligently towards attaining my goal of contributing novel and clinically relevant discoveries that help to better comprehend neuroblastoma disease management. Neurons are nerve cells that populate regions of the human body and are responsible for transmitting chemical signals back and forth to the brain to regulate several functions. A deadly form of pediatric cancer, known as neuroblastoma, occurs when these neurons start to proliferate uncontrollably. These cancer cells can go on to migrate and spread throughout the body, making it very challenging to treat with currently available drugs. This highly aggressive form of neuroblastoma occurs frequently in children who are older than 18 months. At such an early age, this disease can be quite devastating, and there is an imperative need to better understand how this form of neuroblastoma progresses. Neuroblastoma is hypothesized to arise from alterations to the DNA template within a cell, known as genetic mutations. These mutations result in changes in expression of genes to escalate cellular growth, migration, and invasion. The DNA is wrapped around a core of proteins, called histones, and this complex is packaged and regulated in a form termed chromatin. The alterations that occur to chromatin structure that don t affect the DNA sequence are referred to as "epigenetics," and these variations also contribute to cancer cell growth. Therefore, it is believed that neuroblastoma arises from a combination of genetic and epigenetic events. Recent work has identified mutations in distinct specialized proteins that regulate gene expression, known as chromatin remodelers, in several pediatric cancers, notably neuroblastoma. One such protein, ATRX, was recently found to be mutated frequently in tumors identified in adolescent and young adult patients, which have lower survival. The functional significance of these ATRX mutations in promoting aggressive neuroblastoma is currently unclear. I favor the hypothesis that ATRX mutations alter gene expression at candidate genes to promote cancer growth. In this proposal, I aim to elucidate the consequences of ATRX mutations in neuroblastoma progression thorough innovative approaches. I will map and compare ATRX genomic localization in a panel of patient-derived ATRX wild-type and ATRX mutant neuroblastoma cells. Simultaneously, I will utilize functional studies to investigate novel candidate genes whose expression we have identified to be altered in ATRX mutant neuroblastoma cell lines. Excitingly, these genes could serve as therapeutic targets to treat this specific type of neuroblastoma and improve patient outcomes. The prognosis for neuroblastoma patients who are diagnosed after 18 months of age is exceptionally poor. There is an imperative need to design new rational treatments for this disease. Ultimately, I hope to generate critical information to help in the fight against neuroblastoma so that military personnel directly affected by this disease don t have additional battles at home when they return from active duty. I anticipate that my studies will provide (i) insight on the mechanism of how ATRX mutations promote migration and invasion in aggressive neuroblastoma and (ii) new therapies for children diagnosed with this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610365
Entities
People
- Zulekha Qadeer
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army