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

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

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

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

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

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

  • Ted Laetsch, MD (CHOP), Clinical Collaborator

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

  • Hao Liu, PhD (IU) Site Biostats, Co-Investigator

Description

Plexiform neurofibromas (PNF) are a hallmark disease manifestation of neurofibromatosis type 1 (NF1) that affect up to 50% of patients and cause lifelong morbidity. A subset of PNF progress to atypical neurofibroma (ANF) and/or malignant peripheral nerve sheath tumors (MPNST). These treatment refractory sarcomas represent the leading cause of death in NF1 patients. Clinical genomic studies and novel genetically engineered mouse (GEM) models, led and developed by Project 1 investigators, have provided strong evidence that loss of CDKN2A (INK4A) and/or its alternate reading frame (ARF) is a key driver event in the majority of NF1-associated ANF and MPNST.

Our studies to date have identified the first two broadly clinically effective drugs for PNF, the MEK inhibitor, selumetinib, and the multi-RTK inhibitor, cabozantinib. Mechanistic insights from preclinical models and initial phase 2 trials showed that selumetinib and cabozantinib have distinct pharmacodynamic characteristics. Collectively, these results suggest that combining these two drugs may enhance efficacy in PNF, and perhaps impede the progression to ANF and MPNST.

To inform ongoing translational efforts to develop novel therapies for NF1 patients affected by tumors across the PNF-ANF-MPNST continuum, we are: (1) Identifying actionable therapeutic targets within the tumor microenvironment that interact with neoplastic Schwann cells to accelerate PNF formation and maintenance; (2) extending preclinical studies in GEM and PDX models to investigate potential synergistic drug combinations for treating existing PNF, ANF and MPNST; (3) conducting an early phase clinical trial of MEK inhibition and cabozantinb therapy in PNF; and (4) Leveraging state-of-the-art technologies in Omics (Core B) and Biospecimen/Pathology (Core C) to define the adaptive responses of PNF, ANF, and MPNST in GEM models as well as patient biopsy specimens.

Aims

Aim 1:

To define mechanisms accelerating plexiform neurofibroma (PN) development

Aim 2:

Preclinical evaluation of MEKi in combination with cabozantinib or a BETi for the treatment and prevention of PNF, ANF, and MPNST

Aim 3:

To utilize novel PDX models to identify therapies and define mechanisms for malignant transformation into MPNST

Aim 4:

Clinical Trials/Translational Studies

Translational Impact

The overall translational impact Project 1 includes: (1) investigating a rational approach to combinatorial therapy based on simultaneously interfering with paracrine growth signals emanating from the tumor microenvironment while also targeting aberrant Ras/Raf/MEK/ERK pathway activation in tumor cells to treat PNF; (2) defining novel biomarkers in NF1 patients enrolled on combination trials by analyzing tumor specimens and blood obtained both prior to and after treatment; and, (3) identifying rational drug combinations in preclinical models that will allow treatment and/or prevention of ANF and MPNSTs that will lead to new phase I-II trials for these tumors in year 2-3 of the proposed funding period.

Publications

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

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

  • Jaishri Blakeley, MD (JHU), Co-Investigator

  • Nicholas D. Socci, PhD (MSKCC), Biostats/Bioinform, Co-Investigator

  • Andrea Schietinger, PhD (MSKCC), Collaborator

  • Mark Gilbert, MD (NCI, Neuro-Onc), Collaborator

  • Fausto Rodriguez, MD (JHU), Imaging/MRI, Collaborator

  • Robert J. Young, MD (MSKCC), Imaging/MRI, Collaborator

Description

Young adults with NF1 have a 10-50-fold increased risk of developing malignant gliomas and glioblastoma (GBM) is estimated to be 5 to 10 times more common in persons with NF1. Concurrently, NF1 is a common somatic mutation in sporadic gliomas. Additional reports indicate that NF1 mutations may define a clinically and biologically distinct subgroup of GBM. Our central hypothesis is that NF1-mutant gliomas constitute a distinct subgroup with a unique molecular pathogenesis, tumor microenvironment (TME), and tumor cell vulnerabilities. Our experimental approach includes utilizing a variety of glioma models, including genetically engineered mouse (GEM) models, patient-derived xenografts (PDX), primary cultures, and human tumor biopsies. We are pursuing three specific aims. Aim 1 exploits GEM models of germline and somatically mutated NF1 to study GBM biology and to test mechanism-based therapies. We are also examining the role of the TME - both local inflammatory microglia as well as infiltration of the immune system. Aim 2 extends the studies of Aim 1 to PDX models to orthogonally test agents found promising in GEM models. Aim 3 will increase our understanding of NF1-associated GBM from germline patients through the evaluation of clinical samples derived from an extensive international network and patient-facing portal. Through this effort, in addition to clinical annotation and histopathological analysis, we will establish patient derived cell lines and PDX models for extension of Aims 1 and 2 as new material becomes available. These studies are being performed in collaboration with Core C (Biospecimen/Pathology), as well as Core B (Omics).

Aims

Aim 1:

Functional and phenotypic characterization of germline and somatic NF1 GBM in genetically engineered mice.

Aim 2:

Functional and phenotypic characterization of human somatic NF1 mutant GBM.

Aim 3:

Characterization of NF1 associated GBM through comprehensive histological, molecular and clinical analysis.

Translational Impact

GBM pathogenesis has not previously been systematically interrogated through the lens of how NF1 mutations influence the underlying biology and therapeutic responses. Project 2 will perform in-depth characterization of this disease entity, including clinical presentation and therapy response as well as pathological and genetic characterization.

Publications

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

  • Mignon Loh, MD (USCF), Clinical Co-Leader

  • Benjamin Braun, MD, PhD (UCSF), Co-Investigator

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

  • Kim Mi-Ok, PhD (UCSF), Site Biostats, Co-Investigator

Description

Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) for which the standard of care is hematopoietic stem cell transplant (HSCT). Unfortunately, relapse rates are high after HSCT, particularly in NF1 patients. We discovered that NF1 functions as a tumor suppressor gene in hematopoietic cells and showed that NF1 inactivation results in deregulated Ras/Raf/MEK/ERK signaling. This work suggested a central role of hyperactive Ras signaling in JMML pathogenesis, and our group and others subsequently identified mutations in other Ras pathway genes including NRAS, KRAS, PTPN11, and CBL. We developed genetically engineered mouse (GEM) models of JMML and observed remarkable efficacy of MEK inhibition. These data informed an ongoing phase 2 clinical trial of trametinib for patients with relapsed/refractory JMML (ADVL1521) that includes determining the molecular mechanisms underlying clinical responses in collaboration with Cores B (Omics) and C (Pathology). We are extending our studies through the following aims: Aim 1. To conduct innovative clinical trials for patients with JMML that emanate from our laboratory and preclinical studies; and, Aim 2. To perform biologic and preclinical studies of promising therapies in JMML patient specimens and GEM models to inform clinical translation.

Our overall goal is to develop more effective and less toxic therapies for infants and children with JMML by targeting the underlying molecular pathogenesis, which also has implications for the fundamental problem of improving the treatment of other cancers driven by hyperactive Ras signaling.

Aims

Aim 1:

To conduct innovative clinical trials for patients with JMML that emanate from our laboratory and preclinical studies. We will complete the ongoing ADVL1521 trial and have developed the first interventional risk-stratified clinical trial in newly diagnosed JMML.

Aim 2:

To perform biologic and preclinical studies of promising therapies in JMML patient specimens and GEM models to inform clinical translation.

Translational Impact

The translational impact of the studies described in this project include: (1) testing signal transduction inhibition as an alternative therapeutic strategy to HSCT in JMML; (2) developing a new therapeutic paradigm for JMML based on stratifying patients according to the underlying molecular landscape of their disease and administering mechanism-based personalized therapies that are more effective and less toxic; and, (3) generating data in GEM models to identify the most promising new drugs and drug combinations that will be evaluated in “next generation” early phase clinical trials in hematologic and nonhematologic cancers characterized by germline and somatic NF1 mutations.

Publications