The Development Programs (Career Enhancement Program [CEP] and the Developmental Research Program [DRP]) are components of the multi-institutional Developmental and Hyperactive Ras Tumor (DHART) SPORE. The primary focus of this SPORE is to improve the diagnosis and management of tumors arising in persons with neurofibromatosis type 1 (NF1) and other inherited “Rasopathy” syndromes through basic, translational, and clinical research. These tumors include plexiform neurofibroma, malignant peripheral nerve sheath tumor (MPNST), optic pathway and other gliomas, juvenile myelomonocytic leukemia (JMML), and subsequent malignant neoplasms caused by prior exposure to mutagenic chemotherapy and/or radiation. Research proposals investigating the role of somatic NF1 mutations in cancers such as glioblastoma multiforme, adenocarcinoma of the lung, melanoma, and myeloid leukemia will also be considered for support through this program

Please direct any questions about the CEP/DRP to Kevin Shannon, MD, University of California: Kevin.Shannon@ucsf.edu.

Career Enhancement Program (CEP)

  • Kevin Shannon, MD (UCSF), Director

  • Jaishri Blakeley, MD (JHU), Associate Director

The Career Enhancement Program (CEP) supports early-stage investigators (ESIs) who engage in translational research focused on NF1- and Ras-associated tumors as well as sporadic cancers characterized by somatic NF1 mutations. An essential component of the DHART SPORE CEP is an emphasis on recruiting and supporting ESIs from historically disenfranchised racial, ethnic, sexual orientation and disability groups that are under-represented in health sciences. Identifying, recruiting, and mentoring ESIs who will work to implement more effective and less toxic therapies for neoplasms and cancers characterized by NF1 mutations is intrinsic to the discovery and clinical missions of each collaborating institution.

CEP Eligibility

CEP Proposals are accepted from clinical or basic science investigators at any DHART SPORE institution as well as from other academic institutions. Application is limited to faculty who are scientifically independent by the criteria of eligibility to apply for NIH R01 awards, but who do not currently hold R01 or equivalent funding for NF1-related research. Faculty members with NIH career development awards (K08; K23) are encouraged to apply for CEP funds. Faculty members from under-represented in medicine (URM) groups are strongly encouraged to apply. All applicants for a CEP award must identify a mentor who can assist with their NF1 or Rasopathy focused project. Mentors can be identified from within the DHART SPORE. A list of potential mentors associated with the DHART SPORE, their contact information and areas of expertise is provided on the DHART SPORE Mentorship List. Mentors can be from outside of the DHART SPORE, but must have expertise in NF1 or Rasopathy focused translational research.

CEP Application Information

DHART SPORE CEP 2022 Guidelines

DHART SPORE CEP Proposal Form

2022-2023 CEP Awardees

Project Abstract. Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive form of soft tissue sarcoma that represents the leading cause of premature death in individuals with neurofibromatosis type 1 (NF1). The malignant transformation of benign plexiform neurofibromas (PNF) often occurs through the development of atypical neurofibroma/atypical neurofibromatosis neoplasms of uncertain biological potential (ANF/ANNUBP), which are characterized by distinct histopathological features and proclivity for CDKN2A copy number loss. Informed by these clinical observations, our laboratory has developed novel genetically engineered mouse models (GEMMs) harboring conditional inactivation of Nf1 and Cdkn2a (Ink4a/Arf) in Schwann cell precursors, which spontaneously develop ANF/ANNUBP reminiscent of human patients and transform to MPNST with high penetrance. Emerging data suggests that the Nf1+/- microenvironment may act as a double-edged sword, promoting outgrowth of benign NF1 associated tumors such as PNF, while on the other hand acting as a safeguard to forestall malignant transformation. Spatial profiling of a series of human NF1-associated peripheral nerve sheath tumors conducted collaboratively through the DHART SPORE suggests that ANNUBP are heavily infiltrated by T cells and exhibit enhanced signatures of immune surveillance. However as malignant transformation ensues, T cells become excluded from the microenvironment and dysfunctional. We hypothesize that the Nf1+/- microenvironment, and specifically Nf1+/- T cells, are critical to constraining the outgrowth of malignant clones of disease within PNF and ANF/ANNUBP precursor lesions harboring Nf1 and Cdkn2a (Ink4a/Arf) loss. To test this hypothesis, in Aim 1, we will establish the impact of a WT vs Nf1+/- microenvironment in modulating the rate of MPNST progression in our fully immunocompetent Nf1-Ink4a/Arf mutant GEMMs. In Aim 2, we will define the functional consequences of depletion of specific T cell subsets on progression of tumors along the neurofibroma to MPNST continuum in Nf1-Ink4a/Arf mutant mice using neutralizing antibodies to CD4, CD8 or the combination. Collectively, these data will provide a novel window of insight into the role of the Nf1+/- microenvironment and T cell subsets in governing the natural history of neurofibroma progression and malignant transformation in NF1.

Clinical Impact. MPNST is a rapidly fatal form of sarcoma that evolves from benign PNF and ANF/ANNUBP precursors in persons with NF1. Aside from wide marginal excision, there are no curative therapies. A primary objective of DHART SPORE Project 1 is to gain insight into how Nf1 and Cdkn2a inactivation in Schwann cell precursors prompts the progression of tumors along the neurofibroma to MPNST continuum to mechanistically inform the development of new and effective targeted therapies. The studies proposed here leverage GEMMs harboring these key genetic driver events developed by our laboratory, and further build upon recent findings by Dr. Lu Le and colleagues in Project 1 suggesting that the Nf1+/- microenvironment promotes PNF growth, yet paradoxically protects against malignant transformation. Collectively, these studies will directly contribute to the goals of Project 1 by characterizing at single cell resolution how Nf1 heterozygosity shapes the immune landscape across PNF, ANF/ANNUBP and MPNST. By establishing the functional role of Nf1+/- T cells in forestalling malignant transformation of PNF and ANF/ANNUBP precursors, the proposed translationally based studies have the potential to directly inform future investigation of immunotherapy-based approaches for MPNST chemoprevention in ANF/ANNUBP lesions that are not amenable to surgical resection.

Project Abstract. NF1 is a modulator of ERK signaling in NF1-associated and sporadic glioma. While targeted therapies have successfully impacted some ERK-dependent gliomas (those with BRAF mutations), current targeted therapies are inadequate for other ERK-dependent glioma. We and others have previously demonstrated somatic NF1 loss in glioma neurosphere models confers an ERK-dependent phenotype that is sensitive to MEK inhibition (MEKi), though the effects are not durable. Interestingly however, inhibition of ERK signaling may unmask other potentially-targetable vulnerabilities in NF1-deficient cancers. Specifically, ERK signaling appears to modulate DNA damage repair (DDR), particularly homologous recombination (HR). We have generated preliminary data suggesting HR is dependent on ERK signaling and downregulated in the presence of MEKi. Here, we propose to study the effect of MEKi on DDR pathways, with a focus on HR expression and the potential for exploitation of decreased HR expression in NF1-/- glioma cell lines using a combination of targeted therapies. We will identify the effect of MEKi on DDR pathway activity in NF1-mutant and wild-type glioma neurosphere lines. We will determine whether the addition of a PARP inhibitor to a MEK inhibitor effectively inhibits DNA repair and increases cell death in those same cell lines. Lastly, using in vivo models of NF1-/- glioma we will confirm the combination of a PARP and MEK inhibitor decreases tumor growth. Through a well-characterized panel of glioma neurospheres and adherent lines with varied expression of NF1 we will use molecular biology techniques to define the role of ERK dependence in maintaining DNA repair genes in glioma. The outcomes of these studies have direct implications for patients with NF1 mutant low and high grade glioma that is sporadic or NF1-associated.

Clinical Impact. The proposal “Exploiting ERK-dependence with combination targeted therapy in NF1-/- glioma” directly supports the goals of the DHART SPORE by interrogating mechanisms that may be specific to NF1 loss and associated cellular dysregulation that may enable novel therapies for tumors driven by NF1-loss leading to ERK-dependence. The proposal is specifically focused on NF1-associated gliomas, a rare and often fatal diagnosis in desperate need of new, rational therapies. The results from this work have the potential to be broadly applicable to gliomas with NF1 mutations (somatic or germline) as well as other cancers with NF1-loss that leads to ERK-dependence. The proposed experiments are complementary, but not overlapping, with the work ongoing in project 2, for which the project mentor, Dr. Jaishri Blakely, is a co-investigator. Finally, the proposal seeks to maximize the use of DHART SPORE cores via exploring the response to targeted therapy in glioma with NF1-loss utilizing the Omics Core in collaboration with Drs. Yiu and Angus, and commitment to share in vivo samples with the Biospecimen/Pathology Core.

Project Abstract. Neurofibromatosis Type 1 (NF1), which arises from mutation of the NF1 tumor suppressor, is one of the most common genetic cancer predisposition syndromes. Approximately half of individuals with NF1 develop benign peripheral nerve sheath tumors called plexiform neurofibromas (PNF), a subset of which undergo transformation into malignant peripheral nerve sheath tumors (MPNSTs). MPNST is a highly aggressive, treatment refractory form of sarcoma and is the leading cause of death in NF1 patients. There are currently no targeted therapies for MPNST, and complete surgical resection remains the sole curative option. Predictive biomarkers to identify PNF with malignant potential are urgently needed, as are molecular targets for the development of effective therapies to treat MPNSTs. Our recent work defining the spatial transcriptomic profile of the PNF-to-MPNST continuum revealed that malignant transformation of PNF coincides with a striking increase in the expression of the mitotic protein CENPF. Importantly, upregulation of CENPF has been found by others to promote tumor progression of various cancer types and portends poor prognosis. Further, recent studies have shown that tumor-derived CENPF can trigger production of CENPF-specific autoantibodies detectable in the sera of a subset of cancer patients. Together, these findings suggest that CENPF is a potential predictive biomarker to implement in the screening of NF1 patients for early detection of MPNST, either through immunohistochemical evaluation of biopsy samples or through minimally invasive serological detection of CENPF autoantibodies. In addition, we found that siRNA-mediated silencing of CENPF significantly impaired the growth of human MPNST cell lines, indicating that CENPF may represent a therapeutic target for the treatment of surgically unresectable or metastatic MPNST. The work outlined in this proposal will evaluate the utility of CENPF as a biomarker for the prediction of malignant potential of PNF and directly assess the efficacy of CENPF as a therapeutic target for the treatment of MPNST.

Clinical Impact. The dismal 5-year survival rates of 20-40% for MPNST highlight an urgent need for biomarkers to enable screening of NF1 patients for early detection of MPNST and for the development of targeted therapies. The goal of this proposal is to evaluate the potential of the CENPF protein to serve both these functions. We will (1) validate our transcriptomic data that implicate overexpression of CENPF in the malignant transformation of PNF and (2) evaluate the in vitro and in vivo therapeutic efficacy of targeting CENPF for the treatment of MPNST. Further, this work will evaluate CENPF autoantibodies as potential serological biomarkers for noninvasive detection of MPNST. At the mechanistic level, these studies will employ functional kinome profiling to identify therapeutically targetable kinases that mediate the antitumor effect of CENPF silencing that we have observed in MPNST cell lines. Together, these studies will directly address the goals of the DHART SPORE Projects 1 and 2, defining a genetic determinant of the PNF-to-MPNST progression and testing the utility of CENPF as a therapeutic target.

CEP Past Awards

Developmental Research Program (DRP)

  • Kevin Shannon, MD (UCSF), Director

  • Jaishri Blakeley, MD (JHU), Associate Director

The DRP funds innovative pilot projects led by established investigators that will advance the overall goal of the DHART SPORE, which is to implement better treatments for neoplasms and cancers with germline and somatic NF1 mutations or related to Rasopathies in general. The DRP supports innovative pilot projects focused on tumors characterized by germline and somatic NF1mutations through rigorous translational research in the areas of population science, therapeutics, and mechanisms of disease and by facilitating collaborative interactions between DRP-funded scientists and other SPORE investigators. Advancing this area of cancer science has important implications beyond NF1-associated tumors as it is also relevant to understanding both the relationship between normal human development and cancer and the fundamental therapeutic problem of therapeutically targeting hyperactive Ras signaling in a range of human cancers. An essential component of the DRP is to attract and support underrepresented minority (URM) investigators.

Please direct any questions about the CEP/DRP to Kevin Shannon, MD, University of California: Kevin.Shannon@ucsf.edu.

DRP Eligibility

Proposals are accepted from clinical or basic science investigators at any DHART SPORE institution as well as from other academic institutions. Application is limited to faculty who are scientifically independent by the criteria of eligibility to apply for NIH R01 awards, but who do not currently hold R01 or equivalent funding for NF1-related research. Faculty members with NIH career development awards (K08; K23 or similar) are not eligible to apply for DRP funds.

DRP Application Information

DHART SPORE DRP 2022 Guidelines

DHART SPORE DRP Proposal Form

2022-2023 DRP Awardee

Project Abstract. Neurofibromatosis type 1 (NF1) is a cancer-predisposition syndrome characterized by pleiotropic secondary manifestation, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are a leading cause of death in individuals with NF1. Despite attempts at surgical resection, few therapeutic options are available to treat MPNSTs, highlighting the critical need for new therapeutic opportunities. With prior DRP support from the DHART SPORE (2019-2020), we demonstrated that aberrant MET splicing (METDJMD) was enriched in a subset of NF1 patient MPNSTs. Expression of the METDJMD allele leads to splice-exclusion of the MET juxtamembrane domain (JMD), resulting in ligand-dependent gain-of-function. Expression of the METDJMD allele has been studied extensively in lung cancer, including metastatic disease, and leads to a “MET addiction” phenotype in the tumor. Thus, tumors that express the METDJMD allele are exquisitely sensitive to MET inhibitors, which was recently demonstrated in multiple phase 2 lung cancer clinical trials. Moreover, we tested the hypothesis that expression of the MetDJMD allele in a mouse model of spontaneous MPNST formation (cisNP mice) would alter the development of MPNSTs in vivo. Indeed, we showed that tumor formation and lethality were significantly accelerated in cisNP;Met+/DJMD mice compared to cisNP;Met+/+ mice (hazard ratio=10.36; p<0.0001). Building on this exciting preliminary data, the study proposed here will investigate the molecular basis for the accelerated tumor formation in these mice (Aim 1) and will test whether MetDJMD-expressing tumors are sensitive to MET inhibitors in vivo (Aim 2). First, we will utilize the DHART Omics core to perform comprehensive kinome, transcriptome, and mutation analyses of existing S100+ MPNSTs from cisNP;Met+/+ and cisNP;Met+/DJMD mice (i.e. collected from our 2019 DRP study). Second, we will test the potential for the MET inhibitor Capmatinib to treat MetDJMD-expressing MPNSTs. Our laboratory is committed to investigating a potential therapeutic role for MET inhibitors in this novel sub-class of NF1 MPNSTs. At the completion of this study, we will be positioned to begin testing patient-derived samples using in vitro and in vivo (i.e. xenograft) approaches (see support letter from Dr. Angela Hirbe).

Clinical Impact. MPNSTs are the primary cause of death in individuals with NF1, and new therapeutic strategies are urgently needed. The study proposed here builds on the success of our previous DRP award (2019) in which we 1) identified a molecularly-defined subset of MPNSTs predicted to be sensitive to MET inhibitor therapy, and 2) successfully demonstrated that expression of the MetDJMD allele leads to advanced disease progression and significantly reduced survival in mice. Here, we will leverage the infrastructure of the DHART Omics core facility to determine the molecular basis for the advanced MPNST progression in cisNP;Met+/DJMD mice. As well, we will test whether expression of the MetDJMD allele sensitizes MPNSTs to the MET inhibitor Capmatenib, as was recently demonstrated in clinical trials for human METDJMD-expressing non-small cell lung cancer. Taken together, we will both leverage the infrastructure of the DHART SPORE and build on our previous DHART SPORE DRP award to implicate a novel therapeutic strategy for a molecularly-defined subset of NF1 MPNSTs.

DRP Past Awards