Targeting MYCN in Pediatric High-Grade Gliomas Using Combinatorial Approaches
Abstract
FY21 RCRP Focus Area: Biology and Etiology: Identify disease-defining molecular pathways, cell context, and microenvironment. Research Model: Developing and validating rare tumor-specific models that can support clinical trial readiness. Therapy: Identify novel therapeutic strategies, including drug repurposing. Scientific Background and Rationale: Pediatric high-grade gliomas (pHGGs) are a rare cancer with an approximate incidence of 0.85 per 100,000. pHGGs are a histologically and molecular heterogeneous group of tumors varying from anaplastic astrocytoma (WHO grade III) to glioblastoma (GBM) (WHO grade IV). The outcome for this rare cancer is particularly poor, with pHGGs patients having a 5-year survival rate of only 20%. The MYCN molecular subtype represents one such fatal subgroup of pHGG with an unmet need of therapeutics. There are no direct inhibitors of MYCN that are in clinical trial, and MYCN is currently considered undruggable, posing a large challenge in treating cancer patients whose cancer expresses MYCN. The lack of MYCN pHGG models presents a barrier to understand the biology and etiology of the disease and test novel clinically relevant therapies. The main objectives of the proposed study are to determine exactly how MYCN, currently undruggable, can be therapeutically targeted using a combinatorial approach to target treatment resistance and through dietary modulation. Taking advantage of our model, we have now identified that these cancer cells are sensitive to a drug class targeting the PI3K-AKT-mTOR (or PI3K-mTOR) pathway. This pathway consists of a series of checks and balances important for cell growth. In cancer, these checks and balances are broken, leading to uncontrolled growth, and can contribute to strengthening MYCN. While therapies targeting this pathway are initially effective, these MYCN cancer cells develop resistance. Therefore, monotherapy will be ineffective in cancer patients with poor outcomes, and the need to identify combinations is important. By using our novel model, we have identified that stopping both the PI3K-mTOR pathway and the insulin growth factor pathways can selectively kill these cancer cells, but not normal cells. Near-Term Applicability of this Proposal Toward Research and the Ultimate Relevancy for Patients: Collectively, this proposal integrates and utilizes a broad array of state-of-the-art approaches from novel mouse model generation to pioneering gene-therapy approaches by bringing together a highly collaborative and productive interdisciplinary team with unique areas of expertise. We anticipate that our research outcomes will provide key advances that are readily translatable into the clinic and provide multiple avenues that can be pursued for further clinical applications. First, by validating our MYCN model, it will be freely shared in the scientific community for discovery and pre-clinical testing of promising therapeutic agents. Second, by defining the regulators of MYCN protein stability, we can identify available small molecule inhibitors that can be directly tested for their therapeutic efficacy. Specifically, we have identified the combination of PI3K-mTOR and insulin signaling inhibitors that cross the blood-brain barrier, which we will test in our mouse and human patient-derived models. Third, we have identified that dietary intervention may augment the synergy of these inhibitors. Tumors depend on nutrients, and alterations to diet can change nutrient availability in the tumor microenvironment. This presents an innovative and underexplored promising strategy for inhibiting tumor growth. We will explore how dietary modifications can exploit metabolic vulnerabilities of these tumors to enhance the cytotoxicity of anti-cancer drugs. In addition to these clinically applicable outcomes, the proposed studies utilize and develop cutting-edge tools, including among the first gene-directed enzyme pro-therapy targeting MY
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210604
Entities
People
- Sameer Agnihotri
Organizations
- United States Army
- University of Pittsburgh