R01NS116421

Developmental Origin, Injury, and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors - Project Abstract

Individuals with Neurofibromatosis Type 1 (NF1) have an approximately 160-fold increased risk of developing Malignant Peripheral Nerve Sheath Tumor (MPNST). MPNST, as a leading cause of death for NF1 patients, has no effective therapy, and thus there is an urgent need for new therapies.

The dramatically increased risk of developing MPNSTs is caused by the presence of Plexiform Neurofibromas (PNFs), the major benign precursor lesion for NF1-MPNST. It has been proposed that PNFs are congenital lesions, arising from the early stages of nerve development when neural-crest stem cells differentiate into Schwann cell (SC) lineages, which give rise to either myelinating or nonmyelinating SCs (MSCs or NMSCs).

In the normal nerve, unmyelinated axons are sorted and ensheathed by NMSCs into individual pockets, forming Remak bundles. Whereas no defect in SC precursors or MSCs was observed, NF1 loss (NF1-/-) during early nerve development induced a pocket defect in Remak bundles, characterized by abnormally sorted unmyelinated axons. These abnormal Remak pockets progress to a stage with axonal degeneration and abnormal proliferation of dissociated SCs, leading to the formation of PNFs. Axonal degeneration may contribute to PNF formation by inducing a nerve injury environment, a concept supported by the observation that NF1 loss in mature SCs is not sufficient to induce PNFs unless an injury to the nerve occurs.

Malignant transformation of PNFs to MPNSTs requires at least two additional genetic alterations: sequential inactivation of CDKN2A, and then either SUZ12 or EED - two essential components of Polycomb Repressive Complex 2 (PRC2). PRC2 catalyzes histone modification H3K27me3 to repress gene expression throughout the genome. Loss of PRC2 specifically observed in MPNSTs, but not in benign tumors, suggests that PRC2-mediated H3K27me3 normally represses expression of the oncogenic drivers responsible for malignant transformation of PNFs to MPNSTs. However, EED/PRC2 is dispensable during normal mouse SC development and myelination. Further, loss of the EED/PRC2 tumor suppressor unexpectedly inhibits proliferation of injury-induced reprogrammed SCs, accompanied by derepression of CDKN2A expression.

Here, we propose to test two related hypotheses: (1) the developmental NF1-/- Remak pocket defect and its associated axonal degeneration (nerve injury) drive NF1-/- SCs to form PNFs and (2) nerve injury response induces an epigenomic switch, rendering reprogrammed PNFs or SCs susceptible to malignant transformation by sequential loss of CDKN2A and PRC2. We will determine the role of the developmental Remak pocket defect in NF1-MPNST formation (Aim 1), investigate tumor suppressive mechanisms in injury-induced reprogrammed SCs (Aim 2), and develop therapeutic strategies based on the injury-induced epigenomic switch in reprogrammed SCs (Aim 3). We will identify injury-induced and PRC2-repressed oncogenic drivers for MPNST formation via epigenomic approaches, develop synergistic therapies using a high-throughput drug repurposing screen, and test them in gem- and patient-derived preclinical models.

The University Of Texas Southwestern Medical Center

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Dallas, Texas 753907208 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 03/31/26 to 02/28/27 and the total obligations have increased 366% from $723,312 to $3,373,546.