The Final Evolutionary Trajectory of End-Stage Glioma
Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in adults, and also the most lethal—the average time from diagnosis to death is 12-16 months. Glioblastomas harbor mutations in multiple core signaling pathways. Unfortunately, attempts to target these signaling pathways have been unsuccessful so far. This is perhaps due to a lack of fundamental understanding of the selective pressures related to the emergence of dominant lethal clone(s), which possess infiltrative properties leading to the rapid clinical decline seen in end-stage disease. To date, there has been no comprehensive effort to understand the breadth of clones present at the lethal stage of disease. Using a series of rapid autopsy cases, I propose to (1) identify the lethal clone(s) present in GBM; (2) track their emergence and trajectory; (3) determine the effect of tumor-directed therapy on which clones survive; (4) identify molecular features in the primary tumor that can help clinicians identify the lethal clone(s) at the time of diagnosis. The work outlined in this grant proposal will better guide treatment for GBM patients and accelerate drug development by establishing which molecular targets to focus on and how best to use molecular information obtained at diagnosis to guide treatment. This proposed work is most directly related to GBM, but it will also provide a framework to better understand the evolution of growth factor signaling pathways and the factors that affect these dynamic changes. This is applicable to almost every type of cancer, including colorectal cancer, melanoma, pancreatic cancer, and stomach cancers. This work could therefore benefit many cancer patients beyond those suffering from brain tumors, including patients who are active duty Service members, Veterans, and their family members. Understanding how to use molecular information from the primary tumor to predict which molecular alterations will drive the lethal progression of disease will likely impact clinical trial design within the next 5 years. This research stands to make a positive contribution to those efforts, as well as further my own career goals to become an independent clinician-scientist whose work will inform clinical trial design for glioma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010664
Entities
People
- Alexandra Miller
Organizations
- Sloan-Kettering Institute
- United States Army