XPO1 as a Therapeutic Target in ZFTA-RELA-Driven Ependymoma
Abstract
Our proposal aligns with the fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Area(s) on (i) brain cancer, and (ii) pediatric brain tumors and the FY22 PRCRP Military Health Focus Area Gaps in cancer research that may affect mission readiness. The lead scientific investigators of this proposal, Dr. Mack and Dr. Roussel, study a type of aggressive pediatric brain tumor called ependymoma. Treatment for ependymoma has not changed in the last 20 years. In collaborative studies they have identified that ependymoma cells depend on two novel proteins to grow, called XPO1 and SMARCA4. Critically, drugs are available to target these two proteins, with XPO1 inhibitors in further clinical development and capable of crossing the blood brain barrier. Our Overall Objective Is To: (1) Rigorously test drugs that block the Xpo1 and Smarca4 pathway across specific types of ependymoma in multiple animal models. (2) Identify drug combinations that may be rapidly transitioned to phase 1 clinical trials in ependymoma. Our research will help children with a type of pediatric brain tumor called ependymoma. However, more broadly scientific findings from our research have the potential to inform treatment of other cancer types driven by the same pathway. Furthermore, the innovative framework we have developed to identify druggable targets using multiple technologies could readily extend to other pediatric and adult cancer types. The ultimate goal of our research is to take findings from each of our objectives and directly translate these to a clinical trial in patients St. Jude. Critically, XPO1 inhibitors are currently being evaluated in clinical trials at St. Jude for another pediatric brain tumor type called ATRT. If findings from our proposal are successful, we seek to leverage this data to expand our St. Jude clinical trial to include ependymoma patients, making a near-term and immediate impact on patient care. We would anticipate translating these findings to clinical trials in patients in approximately 2 years. While this appears as an accelerated timeline, we have already defined clinical dosing in patients for XPO1 inhibitors along with safety and toxicity considerations. This will provide patients and their families an option to enroll on a clinical trial that evaluates XPO1 therapy. This is particularly relevant since there few clinical trials open across the U.S. for this patient population and even fewer ependymoma-focused trials. Our proposal will address the specific FY22 PRCRP overarching challenge to Transform cancer treatment through the identification of new targets, especially for advanced disease and metastasis. XPO1 and SMARCA4 pathway is a novel target that we have discovered in ependymoma using distinct methods. Our research proposal seeks to rigorously test XPO1 and SMARCA4 drugs and to identify rationale drug combinations so we can target drug-resistant cells with alternate therapies. FY22 PRCRP Military Health Focus Area: Our research grant would directly affect Gaps in cancer research that may affect mission readiness, specifically the treatment and health of military members, Veterans, their beneficiaries, and the general public. Our strategy to identify combination therapy using proteomics profiling and CRISPR-CAS9 KO screening has potential to broadly apply to the study of other cancer types and improving our understanding of cancer toward new therapeutic development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310624
Entities
People
- Stephen Mack
Organizations
- United States Army