Targeting Chromothripsis in Malignant Glioma
Abstract
Clinical biomarker detection has paved the way in determining the patient population that will most benefit from a specific treatment. In this way, there will be fewer unnecessary side effects as a patient determined as a non-responder – via biomarker presence or absence – would not be selected to receive this treatment. A classic example is the expression of the HER2 receptor in breast cancers. If a patient is HER2 positive, they will receive the HER2-targeting drug, Herceptin. However, a non-HER2 positive patient would not receive Herceptin, as they do not have the drug target expressed. Here, HER2 is a positive selection biomarker that dictates treatment therapeutic options to prevent over-treatment and assist in positive patient selection. While other cancers, like breast, have well-defined biomarkers that dictate drug options, the brain cancer glioblastoma (GBM) is lagging. GBM is the most common and deadly brain cancer in adults, with an average survival post-diagnosis of ~14-16 months. This survival time greatly decreases once a patient becomes resistant to the current first line therapeutic option, temozolomide (TMZ). For these reasons, we are proposing to elucidate a biomarker of TMZ-resistant GBM, as well as better understand the disease, to determine the best second-line therapeutic option for these patients. Our proposal seeks to assist in patient selection via biomarker detection for a compound currently in GBM clinical trials called Selinexor. Selinexor is a brain penetrant compound that affects the localization of proteins within the cell. In our research, we found differences in the types of DNA damage that occur in TMZ-sensitive vs TMZ-resistant disease. One of these alterations is that protein localization changes occur more frequently in the TMZ-resistant disease, which may be correlated to the DNA shattering phenomenon termed chromothripsis. In chromothripsis bits and pieces of DNA can be lost, flipped, duplicated, or misplaced within the genome. This inherently changes many signaling and regulatory pathways within the cell, as well as the potential to disrupt normal protein docking sites within those misplaced segments of DNA. In our proposed work, we seek to better understand if TMZ treatment is able to induce chromothripsis and protein localization changes and how TMZ treatment affects DNA regions that normally protect against chromothripsis, called telomeres, where proteins also have been shown to dock. In this way, we can use DNA sequencing and downstream computational analyses to determine if a patient displays chromothripsis or telomere changes and then correlates the type of DNA damage signature to Selinexor response. This would be accomplished on pre-existing biopsies, thereby preventing the need for more invasive measures or increased hospital visits. Finally, we have kept the Fiscal Year 2021 (FY21) Rare Cancers Research Program (RCRP) Overarching Challenges in mind when developing our proposal and will address the following two FY21 RCRP Overarching Challenges: (1) the Biology and etiology of TMZ-resistant GBM: We propose to elucidate the role of chromothripsis in disease progression, and (2) Therapy: we seek to test using DNA damage signatures (like chromothripsis and telomere changes) to assist with patient selection for the brain-penetrant Selinxor, which is already in clinical trials and has been shown to be safe in humans. We have assembled a strong team of scientists to tackle this task including basic (Deanna Tiek, Ph.D.; Principal InvestigatorPI), clinical (Craig Horbinski, M.D.; a neuropathologist), and translational (Priya Kumthekar, M.D.; Selinexor Trial PI, a neuro-oncologist) with the overall goal being to improve GBM patient overall survival and clinical care, especially in the post-TMZ resistant setting.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210373
Entities
People
- Deanna Tiek
Organizations
- Northwestern University
- United States Army