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Developmental and Hyperactive Ras Tumor (DHART) SPORE

Indiana University and the University of California San Francisco

Principal Investigators

 

D. Wade Clapp, M.D.
Interim Director, IU Simor Comprehensive Cancer Center
Professor of Pediatrics, Microbiology & Immunology
Indiana University School of Medicine
1130 W Michigan St.
Fesler Hall 320
Indianapolis, Indiana 46202
317-278-5809

 

Kevin Shannon, M.D.
American Cancer Society Research Professor
Auerback Distinguished Professor of Molecular Oncology
University of California, San Francisco, Mission Bay Campus
1450 3rd Street; Room 263
San Francisco, CA 94158-9001
415-476-7932

Overview

The DHART SPORE: Advancing Treatments for Cancers with Germline and Somatic NF1 Mutations

Neurofibromatosis type 1 (NF1) is one of the most common inherited conditions that increases a person's risk of developing tumors and cancer. These tumors can occur in the skin, muscles, nerves, brain, blood vessels, and other tissues, and are often diagnosed in children, teens, and young adults. People with NF1 have a mutation in one copy of the NF1 gene in every cell, and tumors mutate or lose the normal copy. The protein made by the NF1 gene helps to “turn off” a protein called Ras that stimulates cell growth when it is turned on.    

The Developmental and HyperActive Ras Tumor (DHART) SPORE is a national research program focused on developing more effective, targeted treatments for associated tumors and cancers with NF1 gene mutations. The program brings together scientists, physicians, and patient advocates from leading institutions to better understand how these tumors develop, why some treatments work while others fail, and how resistance to therapy occurs.

Through three integrated Research Projects and specialized Research Cores, DHART investigators study the genetic and biological changes that drive tumor growth and are working to use this knowledge to identify biomarkers that can be used to diagnose tumors when they are small and easier to treat and to implement new therapies by performing innovative clinical trials.  Achieving the goals of the three DHART SPORE Projects will not only improve the outcomes for specific cancers with NF1 gene mutations but also has the potential to inform new therapeutic approaches for the substantial proportion of human cancers with RAS gene mutations.

Translational Impact: By accelerating the development of targeted therapies for rare NF1-associated tumors, DHART SPORE aims to improve outcomes and quality of life for children, adolescents, and adults living with NF1. Because many common cancers share the same abnormal growth pathways seen in NF1, discoveries from this program may also lead to better treatments for many cancer patients.

Project 1: From neurofibroma to MPNST: models, biology and translation to clinic

Project Co-Leaders

Specific Aims

Project 1 seeks to reduce illness and death from two NF1-associated 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 will test whether SOX2 inhibitors alone or in combination can improve PNF 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. Mice with an NF1 mutation develop cancers that closely resemble 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 investigators are using novel PDXs and GEMMs to test novel Ras and Ras pathway combinations. 
  • 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 combines lab discoveries with preclinical and clinical studies to enhance treatment for early-stage tumors and aggressive NF1-associated cancers, prevent PNF tumors from progressing to MPNSTs, and develop new diagnostic tools and therapies. These innovative efforts aim to improve the lives of those with NF1, PNF, and MPNST.

Project 2: NF1-associated glioblastoma

Project Co-Leaders

Specific Aims

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.

Project 3: A high content clinical trial of the MEK inhibitor Trametinib in JMML

Project Co-Leaders

Specific Aims

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.

Administrative and Biostatistics Core

Core Directors

Specific Aims

The DHART SPORE is a national research program dedicated to improving treatments for cancers and tumors that harbor germline of somatic mutations in the NF1 gene, which can lead to uncontrolled cell growth. The program brings together scientists, physicians, and patient advocates from leading institutions across the country to develop new targeted therapies for rare NF1-associated diseases, particularly those affecting children, adolescents, and young adults.

The program supports three major research projects focused on understanding how NF1-mutant tumors are initiated and evolve, identifying new treatment strategies, and advancing promising discoveries through clinical trials. By studying different tumor types that share the same underlying genetic cause, researchers aim to accelerate progress and improve patient outcomes.

The Administrative and Biostatistics Core serves as the program’s coordinating center, supporting collaboration, data management, statistical analysis, and communication across all projects.

Impact: The Administrative and Biostatistics Core provides the foundation that enables researchers to work together effectively, accelerating the discovery, testing, and delivery of new treatments for persons with NF1-associated tumors.

Biospecimen and Pathology Core

Core Co-Directors

Specific Aims

The DHART Biospecimen and Pathology Core (Core C) brings together a team with expertise across all relevant subspecialties of pathologic analysis and diagnostics, as well as in the collection, storage, and sharing of blood and tissue samples to advance the scientific goals of the DHART SPORE.

Core C collects, stores, tracks, and distributes blood and tissue samples from patients and research models, ensuring that investigators have access to high-quality specimens for study. The Core also applies standardized pathology procedures to accurately characterize tumors and other samples, helping researchers compare results across projects and institutions. In addition, Core C maintains the DHART SPORE website as a resource for communication and collaboration among researchers, clinicians, patients, and advocacy groups.

Impact: By providing high-quality biospecimens, expert pathology support, and coordinated data sharing, Core C enables researchers to better understand NF1-associated cancers and accelerates the development of more accurate diagnostics and more effective treatments for patients.

Omics Core

Core Director

Specific Aims

The DHART SPORE Omics Core supports research aimed at developing new treatments for neoplasms and cancers caused by germline and somatic mutations in the NF1 tumor suppressor gene.  When the NF1 gene is damaged, important growth-control signals become overactive, allowing tumors to develop and progress.

Core B uses advanced technologies to study tumor samples at the genetic, molecular, and protein levels. By examining how tumors differ from patient to patient and how they respond to treatment, researchers can identify biomarkers that predict treatment response and uncover new targets for therapy.

Core B works closely with other DHART SPORE teams to analyze tumor samples, integrate complex data, and create detailed molecular profiles of NF1-mutant cancers. These data are shared through a secure research platform, allowing investigators across the program to collaborate and accelerate discoveries.

Impact: By helping researchers understand the biological drivers of NF1-related tumors and why some treatments work better than others, Core B plays a critical role in advancing more precise, personalized therapies for patients with NF1-associated cancers.

Developmental Research Program

Program Director

Specific Aims

The DHART SPORE Developmental Research Program (DRP) supports early-stage research aimed at improving the diagnosis, prevention, and treatment of neoplasms characterized by germline and somatic NF1 gene alterations.  The program provides funding for promising pilot projects that explore new scientific ideas, develop research tools, and test potential therapies.

A goal of the DRP is to help researchers generate preliminary data to obtain follow-on federal research grants and to advance discoveries toward clinical application. The program places special emphasis on high-risk, high-reward projects that have the potential to transform care for patients with NF1-mutant tumors. Novel DRP projects have the potential to be incorporated into the SPORE in the future.

The DRP also helps attract established investigators from diverse scientific fields into NF1 research and encourages collaboration among researchers, clinicians, and specialized DHART SPORE Cores. Projects are selected through a competitive review process and receive funding and oversight to ensure scientific rigor and progress.

Impact: By supporting innovative research at its earliest stages, the DRP helps generate new ideas, technologies, and treatment strategies that can ultimately lead to better therapies for NF1-mutant neoplasms and cancers. 

Career Enhancement Program

Program Co-Directors

Specific Aims

The DHART SPORE Career Enhancement Program (CEP) supports early-career scientists and physicians who are committed to improving the diagnosis and treatment of cancers associated with neurofibromatosis type 1 (NF1) and cancers with somatic NF1 driver mutations.

CEP participants receive funding, mentorship, training, and access to specialized research resources from leading cancer centers across the country. They work closely with experienced scientists and clinicians who provide guidance on research design, career development, and securing future research funding. The program also offers opportunities for collaboration across institutions and disciplines, helping young investigators build the skills and networks needed for long-term success.
By supporting new investigators and encouraging innovative ideas, the CEP helps ensure a strong pipeline of talented researchers dedicated to advancing NF1 cancer research.

Impact: The CEP invests in the next generation of scientists whose discoveries may lead to better diagnostics, new therapies, and improved outcomes for people living with NF1-mutant neoplasms and cancers. By fostering career development and scientific innovation, the program will support progress in NF1 research for years to come. 

 Institutional SPORE Website

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