• Wade Clapp, MD (IU) – PD/PI, Basic Science Co-Leader

  • Lu Le, MD, PhD (UVA), Basic Science Co-Leader

  • Brigitte Widemann, MD (NCI), Clinical Co-Leader

  • Jaishri Blakeley, MD (JHU), Clinical Co-Leader

  • Luis Parada, PhD (MSKCC), Basic Co-Investigator

  • Michael Fisher, MD (CHOP), Clinical Co-Investigator

  • Stephen D. Rhodes, MD, PhD, Co-Investigator

  • Dana K. Mitchell, MD, Co-Investigator

  • Eva Dombi, MD (NCI), Imaging/MRI, Collaborator

  • Jack F. Shern, MD (NCI), Collaborator

Description

Project 1 seeks to reduce illness and death from two NF1-associated peripheral nerve sheath tumors: plexiform neurofibroma (PNF) and malignant peripheral nerve sheath tumor (MPNST).

  • Aim 1: Develop improved treatments for plexiform neurofibromas (PNFs). PNFs are common tumors in persons with NF1 that greatly reduce their quality of life and are difficult to treat. DHART SPORE researchers are asking whether drugs that inhibit the protein SOX2 can slow PNF tumor growth and improve treatment responses.

  • Aim 2: Determine whether immunotherapy and targeted therapies can prevent precancerous PNF tumors from progressing to MPNSTs. MPNST is an aggressive cancer that is very difficult to cure. Strains of mice with an NF1 gene mutation develop cancers that are very similar to human MPNST. DHART SPORE scientists are evaluating strategies to block PNFs at an early stage before they become MPNSTs.

  • Aim 3: Evaluate promising new therapies for MPNST that target the Ras signaling pathway. Many pharmaceutical companies are developing drugs to inhibit the active form of Ras or key proteins such as Raf and MEK that Ras “turns on” in cancer cells. NF1 gene mutations also activate Raf and MEK in tumor cells. DHART SPORE researchers are investigating DLK1 - a protein found in MPNST but not in PNF tumors - as a potential therapeutic target and marker of cancer progression.

  • Aim 4: Assess DLK1 as both a diagnostic biomarker and therapeutic target. DHART SPORE researchers will determine whether DLK1 can be detected in tumor tissue and blood samples to identify tumors at risk of becoming cancerous and to improve patient monitoring. In addition, an early-phase clinical trial will evaluate ADCT-701, a novel therapy designed to target DLK1-positive cancer cells in patients with advanced MPNST.

Translational Impact: Project 1 integrates laboratory discoveries with preclinical and clinical studies to improve the treatment of early-stage tumors and aggressive NF1-associated cancers, explore ways to prevent PNF tumors from progressing to MPNSTs, and advance new diagnostic tools and treatments. Together, these novel therapeutic efforts have the potential to improve the lives of persons with NF1, PNF, and MPNST.

Publications

  • Luis Parada, PhD (MSKCC), Basic Science Co-Leader

  • Ingo Mellinghoff, MD (MSKCC), Clinical Co-Leader

  • Anna F. Piotrowski, MD, Co-Investigator

  • Katherine S. Panageas, DrPH, Collaborator

Description

Project 2 focuses on an aggressive brain cancer called glioblastoma (GBM). Some persons with NF1 develop GBM, and the NF1 gene is also mutated in many GBM tumors in patients who do not have NF1. Studies carried out by DHART SPORE investigators support the idea that GBM tumors with NF1 gene mutations are unlike other types of GBM and will therefore respond to different treatments. The central hypothesis is that NF1 gene mutations cause abnormal cell-growth signals that promote tumor development and that blocking these signals will slow the growth of GBMs or kill these cancers. To better understand how NF1 loss contributes to glioblastoma, DHART SPORE researchers are studying mice that develop GBM tumors, tumor cells from GBM tumors that grow in mice, and human GBMs removed during surgery.

  • Aim 1: Evaluate the safety and effectiveness of mirdametinib, a targeted therapy that can enter the brain, in patients with GBM tumors that have NF1 mutations. Mirdametinib is an inhibitor of a protein called MEK that is abnormally activated by the Ras protein when NF1 is mutated. Through a clinical trial, DHART SPORE investigators are determining if this drug can safely reduce tumor growth and identify factors that predict which patients are likely to respond.

  • Aim 2: Use laboratory and animal models to better understand how mirdametinib and other promising therapies affect GBM tumors with NF1 mutations. These studies examine the biological effects of treatment in greater detail than is possible in patients and test promising new drugs to block the abnormal growth signals in GBMs. Findings from these studies will help guide the development of future clinical trials for GBM and other brain tumors with NF1 gene mutations.

Translational Impact: These studies have the potential to rapidly advance new treatments for patients with brain tumors. By combining clinical and preclinical research, this project will generate the evidence needed to move promising treatments into larger clinical trials and establish a foundation for precision medicine approaches tailored to NF1 mediated brain cancers.

  • Kevin Shannon, MD (UCSF)–PD/PI, Basic Science Co-Leader

  • Elliot Stieglitz, MD (UCSF), Co-Investigator

  • Benjamin J. Huang, MD (UCSF), Co-Investigator

  • Yueh-Yun Chi, PhD (TACL, Lead Clinical Stats)

Description

Project 3 aims to develop more effective and less toxic treatments for juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemias (AMLs) with NF1 gene mutations by conducting clinical trials informed by our research. We previously showed that the drug trametinib, an inhibitor of a protein called MEK was effective in JMML patients who had not responded to other treatments. MEK is abnormally activated in JMML cells when RAS or NF1 are mutated.

  • Aim 1: Conduct innovative clinical trials for patients with JMML. DHART SPORE investigators are conducting a national clinical trial that builds on their data showing that trametinib is active in JMML patients that did not respond to other treatments. They used the discovery that DNA methylation patterns can be used to identify JMML patients who have an excellent chance of being cured (low risk group) and other patients who are very hard to cure with standard treatments (high risk group) to design this trial. Lower-risk patients only receive trametinib and another targeted therapy and may avoid hematopoietic stem cell transplantation (HSCT), while higher-risk patients are treated with trametinib and chemotherapy drugs before HSCT to cure as many children as safely as possible. The goal is to personalize treatment intensity based on each child's risk profile.

  • Aim 2: Use advanced laboratory, patient-derived, and genetically engineered models of NF1-mutant JMML and AML to identify and test promising new therapies. These studies will also investigate why some patients develop resistance to treatment and evaluate strategies to overcome that resistance, providing critical data to guide future clinical trials.

Translational Impact: This project will translate biological discoveries into more personalized treatment strategies for JMML and pediatric and adult AMLs with NF1 mutations. By identifying patients who may benefit from less intensive therapy while improving outcomes for those with high-risk disease, these studies have the potential to reduce treatment-related toxicity, improve survival, and establish new therapeutic approaches for JMML, AML, and other NF1-associated cancers.

Publications