Identifying Novel Candidate Therapies for SEGAs Using Quantitative Single-Cell Assays
Abstract
Nearly all patients with tuberous sclerosis complex (TSC) are thought to develop subependymal nodules (SENs) -- small, benign tumors that present around the lateral ventricles, where cerebrospinal fluid flows through the brain. These tumors are usually asymptomatic. A smaller percentage of patients (~15%) go on to develop subependymal giant cell astrocytomas (SEGAs) -- larger tumors that grow near a specific spot in the ventricles. Critically, these tumors require clinical intervention, as their larger size and positioning mean that they obstruct the flow of cerebrospinal fluid and are lethal if untreated. Patients who develop SEGAs must undergo many months of treatment with everolimus or similar drugs, and they may experience tumor regrowth if they choose to stop treatment. Detecting SEGA development, and preventing or blocking the growth of these tumors, is therefore a paramount concern for many TSC patients. However, we still do not understand what factors predispose particular patients to develop SEGAs and why these tumors present in a very specific location while SENs are widely distributed. A better understanding of the factors that drive SEGA development will be essential for developing new therapies that selectively and permanently target these tumors without adversely affecting related healthy cells. Both SENs and SEGAs are thought to develop from the same cell type: the stem cells surrounding the lateral ventricles. My laboratory is expert in the targeting and study of these cells in the mouse and human brain, including the pediatric brains which are highly relevant to TSC biology. Until recently, it was thought that all stem cells had identical potential: any given stem cell could make many types of neurons and was as "plastic" as the stem cells of the embryonic brain. During the past decade, we have realized that this model is incorrect; in fact, neural stem cells are specialized, and a stem cell in one location does not have the same properties as a stem cell found in a different subregion around the lateral ventricles. This discovery led my lab to hypothesize that SEGAs might originate from a specific subgroup of neural stem cells. During the last 2 years, we have been testing this hypothesis in the mouse, and we have made several observations that suggest a specific subgroup of stem cells are particularly susceptible to the mutations that arise in TSC patients and can generate SEGAs while other cells do not. As part of our studies, we found that one subgroup of neural stem cells (ventral) shows persistently higher mTOR pathway activation under multiple conditions, including some that approximate conditions in TSC patients, and that this subgroup of cells is more resistant to a compound related to everolimus (rapamycin). Our preliminary data also suggest that these ventral cells are the primary cells responsible for SEGA growth. Therefore, in this application we are proposing to test factors that may switch the subgroup identity of ventral stem cells to a different identity (dorsal). We hypothesize that changing the intrinsic developmental programming of these cells will also change their levels of mTOR pathway activation, slowing their growth, making them more susceptible to existing therapies, and potentially stopping tumor growth. We will first test three molecules developed by a colleague at Vanderbilt, which are known to switch dorsal and ventral identity in other tissues and are currently being considered as candidates for clinical development. We will then expand our experimental techniques to screen over 25,000 compounds available at Vanderbilt, with the goal of identifying new small molecules that have the potential to be developed into novel treatments for TSC patients. Although we plan to test a wide variety of molecules, we will begin with those that have a history of use in clinical trials and/or are Food and Drug Administration-approved, as these have the greatest potential f
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610171
Entities
People
- Rebecca A. Ihrie
Organizations
- United States Army
- Vanderbilt University