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:

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 2024 Guidelines


2023-2024 CEP Awardees

Project Abstract. : High-grade gliomas are incurable brain tumors that are more prevalent in individuals with NF1 than in the general population. These tumors are particularly challenging to treat due to their lack of chemo responsiveness and the immune-suppressive microenvironment. This proposal seeks to modulate this immune microenvironment through the use of bispecific T-cell engagers, or BiTEs, which bind both native immune cells and antigens on the surface of glioma, thereby activating the T-cell and leading to immune clearance of tumor. Both NF1-associated and, more broadly, NF1-mutant, high-grade gliomas have been shown to express several cell-surface markers, including B7-H3, HER2, IL13Ra2, GD2, and EphA2 at a higher rate compared to normal brain, suggesting that these markers represent potential targets for BiTE therapy. Furthermore, these antigens are in clinical trials for CAR-T therapy. Using cell culture assays and live imaging technology, five distinct BiTEs will be evaluated for their ability to kill each of five NF1-mutant high-grade glioma cell lines when compared to a CD19 (B-cell) control. The linker length between the two antibody fragments will also be optimized via evaluation of killing in BiTEs with short, intermediate, and long linkers, as this can impact the overall binding and, therefore, killing capacity of a BiTE as well as its expression as a payload in cellular delivery systems. Given that Blinatumomab, a BiTE targeting CD19, has been approved for use in the treatment of refractory B-ALL and several trials are ongoing for additional BiTEs, effective BiTEs could be rapidly tested in pre-clinical models and subsequently advanced to clinical trials.

Clinical Impact. NF1-mutant high-grade gliomas are Ras-driven malignancies with a high mortality rate and limited therapeutic options. This project has the capacity to identify therapeutic targets for a novel immunotherapy approach in NF1-mutant HGG using bispecific T-cell engagers (BiTEs) against several antigens that are highly expressed in HGG but have not been validated within NF1-mutant tumors. Early-phase clinical trials for CAR-T cells are either completed or ongoing for all the antigens to be evaluated in this proposal, thereby eliminating the need to optimize targeted tumor binding of the antibodies selected for tumor antigens. Furthermore, BiTEs such as Blinatumomab are already FDA-approved for use in the treatment of other malignancies, thereby suggesting that any effective BiTE identified in this proposal would also have the potential to be rapidly translated into clinical trials if the efficacy holds in pre-clinical studies.

Project Abstract. Malignant peripheral nerve sheath tumor (MPNST) is characterized as a rare sarcoma responsible for the highest sarcoma-specific deaths and a five-year survival rate between 20-50%. Surgical resection with wide margins is the main treatment option but is often limited due to the location and size of the tumor. Further, this procedure is commonly followed by postoperative morbidity and relapse due to metastasis. Single agents against MPNST often fail clinically due to an interplay between tumor and tumor microenvironment (TME). Therefore, to meet the urgent need for MPNST therapeutics, combinatorial targeting of key signaling mechanisms necessary for MPNST progression is warranted. Nf1 (Neurofibromatosis type I)gene encodes a Ras-GTPase activating protein that negatively regulates the Ras signaling pathway. Following the loss of the Nf1 gene and the subsequent activation of the Ras pathway, several Ras-regulated metabolic signaling cascades are dysregulated within MPNST disease stages. Some of these oncogenic Ras-dependent metabolic processes include glutaminolysis, glycolysis, tricarboxylic acid (TCA) cycle, and macropinocytosis. Hence, developing novel treatment strategies and early therapeutic interventions that target these metabolic dependencies of MPNST will improve survival, reduce suffering, and alleviate the burden of care for persons with NF1. Redox Factor-1 (Ref-1) is highly expressed in MPNST patient samples, and its expression increases as the disease progresses toward malignancy. Our published data demonstrated that Ref-1 regulates mitochondrial metabolism, and we have preliminary data demonstrating that inhibition of Ref-1 downregulates mitochondrial gene expression and impacts the Tricarboxylic Acid (TCA) cycle in MPNST cells. Based on existing studies and our preliminary data, we hypothesize that dual metabolic inhibition with Ref-1 alone and in combination with preclinically tested glutaminolysis inhibitor (JHU395) will dramatically affect MPNST growth and disease progression in vivo. Hence, we designed the following aims to test our hypothesis: Investigate the role metabolism plays in driving MPNST disease progression in vivo using a high penetrance Nf1flox/flox; Arfflox/flox; PostnCre(+) genetically modified mouse model that recapitulates the progression of Plexiform Neurofibromas (PNF) to MPNSTs (AIM1) and against MPNST growth using a syngeneic orthotopic model from Trp53tm1TyjNf1tm1Tyjmice (AIM2).

Clinical Impact. Currently, no treatment options are available to prevent the malignant transformation of precancerous neurofibromas to MPNST. Ras pathway upregulation in MPNST promotes glycolytic and glutaminolytic metabolism, enabling cancer cells to prioritize glucose and glutamine for anabolic purposes. Therefore, in this proposal, perturbation of metabolism at an early stage of PNF will be evaluated for impact on malignant transformation of these precancerous tumors to ANNUBP and further to MPNST. NF1-derived MPNSTs became the focus of my research interests due to the impact of this cancer on children, and the importance of every life lost to it without ongoing research. I have worked alongside my mentor, Dr. Melissa Fishel (former DRP recipient), to demonstrate the effect of Ref-1’s redox inhibition on MPNST growth, which was published recently in the British Journal of Cancer. Further expanding on these results, I am investigating the metabolic dependencies of MPNST patient-derived cells, thereby initiating my career path as an independent NF1-MPNST researcher. This award would give me an opportunity to develop my career, establish deeper collaborations with Dr. Steven Rhodes, and generate data for higher funding. Finally, the new knowledge gained from this proposal will inform the field of novel MPNST therapeutics while using physiologically relevant tumor models.

Project Abstract. Germline NF1 alterations result in a tumor predisposition syndrome with an increased likelihood of developing brain tumors. A study from the EORTC and NCIC Clinical Trials Group established the clinical utility of nomograms to predict the survival of patients with newly diagnosed glioblastoma. Improved outcomes confirmed the association with prognostic factors, including MGMT promoter methylation status, combined treatment with radiation and temozolomide, extensive tumor resection, younger age, or favorable KPS. Because NF1 gliomas are rare and there has been a lack of systematic studies for this population, established prognostic factors such as age and KPS cannot be applied to patients with NF1-associated glioma. We and others completed a retrospective case series of 45 adult patients with NF1 and non-optic pathway glioma. Surprisingly, we observed worse-than-expected outcomes, with a median overall survival of 23 months despite a median age of 37 years, KPS of 80%, and 46% histologically low-grade tumors. This data indicates that in adults with NF1 who develop glioma, there is a critical need to learn what drives the behavior of these tumors, enables more accurate prognostication, and guides the best treatment options. Sporadic glioma with intratumoral NF1 mutation is a unique population of patients without a tumor predisposition syndrome. We found that 15% of non-NF1 patients sporadic glioblastoma, have an intratumoral, somatic NF1 mutation and present a mesenchymal phenotype with poor outcomes. Of those with multiple tumor biopsies, NF1 alterations are late and persistent, implying that it is a candidate tumor driver. Leveraging the comprehensive knowledgebase for adults with NF1 gliomas built via the SPORE-sponsored Glioma DHART board ( a registry of adult patients with full clinical, pathological, and imaging annotation), we now aim to 1) study the correlation between longitudinal precision volumetric imaging with disease outcomes in somatic and in germline NF1 gliomas; and 2) identify a comprehensive panel of imaging and molecular biomarkers for somatic and germline NF1 gliomas. The overarching goal of this project is to define key imaging and molecular features associated with disease status and survival for this rare population of patients with a clear unmet need.

Clinical Impact. This project shares many common goals with the DHART SPORE: improved prognostication, prioritization of treatment regimens, and recommendations for clinical trial participation. With central, quantifiable MRI analysis over time, we aim to use imaging and molecular features to identify prognostic markers for NF1-driven non-optic pathway gliomas. In the long-term, we envision that this will foster a framework that could: 1) provide a powerful resource for prospective patient identification for enrollment into appropriate clinical trials; 2) improve current clinical care and trial design paradigms for patients with germline and somatic NF1 mutant glioma; and 3) serve as a valuable foundation for additional data curation and analysis over the next several years.

Project Abstract. Approximately 10-15% of individuals with NF1 will develop a malignant peripheral nerve sheath tumor (MPNST), which is thought to arise from the malignant progression of pre-existing neurofibromas. Once diagnosed, MPNST has a five-year survival rate as low as 20%. A major challenge in caring for individuals with MPNST in the setting of NF1 is the inability to track disease burden reliably. This is partly because imaging modalities have low sensitivity and specificity to differentiate MPNST from other concurrent tumors in individuals with NF1. We have recently developed a blood-based assay, coined Safer-SeqS, that combines the detection of tumor-derived DNA using somatic mutations (ctDNA) and chromosomal copy number changes that can detect MPNST in the background of concurrent tumors that affect individuals with NF1 (e.g., neurofibromas) with high specificity. With this proposal, we will determine if our multi-analyte assay can detect minimal residual disease (MRD) after surgical resection of MPNST. We aim to retrospectively measure the level of ctDNA before and after surgical resection in MPNST patients to correlate the extent of resection and the presence of MRD. In addition, we will monitor MPNST progression after resection by using Safer-SeqS to quantify the biomarker level changes 3-6 months after surgery and at tumor recurrence. We will retrospectively analyze cases from our Johns Hopkins NF1 Biospecimen Repository and test the plasma from these individuals at different clinically relevant time points. With the support of the DHART CEP, Dr. Rincon-Torroella will acquire research and clinical skills from leaders in the neurofibromatosis and cancer genomic fields while assisting in her career development as a member of the under-represented medicine community. In the future, Dr. Rincon-Torroella can contribute to and benefit from the sizeable multi-omics data integration of the DHART Spore Omics Core. She can then use the results of this study and the collaboration with the Omics Core to prepare an R01 proposal based on prospective clinical analysis of ctDNA as a liquid biopsy to follow MPNST management, the response to therapy, and to limit unnecessary radical surgery.

Clinical Impact. MPNSTs are a major source of morbidity, mortality, and healthcare costs for individuals with NF1. However, current MPNST diagnosis and follow-up tools, including PET scans, are hindered by low specificity, high cost, and radiation exposure. Therefore, there is no reliable and cost-effective method to monitor malignant transformation, residual disease, or MPNST status, including progression. This is especially challenging for clinicians when we treat MPNST with neoadjuvant chemotherapy or radiation with an unclear response, and we are faced with challenging decisions such as radical resections that will burden our patients with life-long morbidity or disabilities. Our approach has the potential to generate a novel, specific, and less-invasive technology to diagnose, test, and follow individuals with NF1 and MPNST. The proposed biomarker, ctDNA, which combines mutation burden and aneuploidy, could eventually be used to diagnose MPNSTs earlier, when the chances for cure are highest and could track disease burden and response to treatment in real-time. Starting with the retrospective detection of minimal residual disease after surgery, this assay can open the door to a more extensive prospective interventional study where we can track response to therapy or monitor for recurrence. Such a biomarker is critical for precision-based oncological management of individuals with NF1.

Project Abstract. Gliomas are the most common tumor of the central nervous system in Neurofibromatosis type 1(NF1), seen in approximately 20% of patients. Most gliomas affect children and have a predilection for the optic pathway and brainstem. While many gliomas are low-grade, there is a 50-fold increase in the risk of developing high-grade glioma (HGG) in NF1 patients compared to the general population. Recent genomic studies have demonstrated a higher mutation burden in NF1-associated HGG compared to low-grade glioma (LGG). A large proportion of HGGs harbor CDKN2A and ATRX loss, akin to the LGm6 subgroup of sporadic gliomas described in the Cancer Genome Atlas. However, the mechanism by which these mutations functionally drive the process of gliomagenesis in human cells in the context of NF1 loss is poorly understood. There is a critical need for human neural stem cell intermediates for functional interrogation of mutations found in NF1-associated HGG. Our long-term goal is to develop a novel platform for the identification of drug targets using human stem cell models of NF1-associated glioma. Previously, we derived human neuroepithelial stem (NES) cells that represent the developing neural tube from patient-derived induced pluripotent stem (iPS) cells. NES cells are long-term self-renewing neural stem cell intermediates that can be differentiated towards brainstem neuroglial lineages. They provide powerful tools for studying putative cells of origin of tumors arising in the brain stem and the functional effects of mutations on neural and glial proliferation, differentiation, and tumorigenicity. Moreover, they can provide in vitro screening tools for drug targets in cells with defined genetic backgrounds. The objective of this study is to develop NES cells with heterozygous NF1 mutations in the germline from patient-derived iPS cells and to define the functional effects of the two most common genetic aberrations seen in NF1-associated HGG: 1) NF1 loss of heterozygosity and 2) loss of CDKN2A. Our hypothesis is that these mutations are sufficient to drive the proliferation of neuroglial progenitors and initiate the development of HGG following orthotopic transplantation. These stem cell models will provide new insight into the origins of NF1-associated gliomagenesis and novel tools for drug discovery.

Clinical Impact. This proposal is highly relevant to the goals of the DHART SPORE Career Enhancement Program. Firstly, the principal investigator of this proposal, Dr. Jignesh Tailor, is a junior faculty neural stem cell researcher who is relatively new to the NF1 field. Dr. Tailor has experience modeling other cancer predisposition syndromes with human stem cells, including Gorlin syndrome and NF2, and would like to develop these stem cell techniques and models in the NF1 space. This program will investigate new relationships between Dr. Tailor, his mentors, Drs. Wade Clapp (IU), Lu Le (UTSW), and Luis Parada, who are senior scientists in the NF1 tumorigenesis field. We anticipate these collaborations will lead to new ideas and directions related to gliomas in NF1 while also contributing to Dr. Tailor’s career development. Dr. Tailor has a special interest in brain cancer predisposition and tumorigenesis and would like to build on his prior research in human brain cancer stem cell modeling. This proposal focuses on the development of high-grade glioma in NF1, which is one of the focus areas of the DHART SPORE program.

Project Abstract. Patients with neurofibromatosis type 1 (NF-1), caused by loss of the tumor suppressor gene NF1 encoding neurofibromin, develop both benign plexiform neurofibromas (pNF)and malignant peripheral nerve sheath tumors (MPNSTs). Although the MEK inhibitor selumetinib is FDA-approved for pNFs in patients with NF-1, partial responses are common, and MPNSTs are resistant to MEK inhibition. Given that pNFs cause significant morbidity and MPNSTs are the most common cause of death in adults with NF-1, there is an urgent, unmet clinical need for novel therapies. My preliminary data demonstrates repression of NF2, encoding the tumor suppressor Merlin,inNF1 mutant neurofibroma cells is sufficient for selumetinib resistance. In NF1 mutant neurofibroma cells, CRISPRi NF2 repression leads to loss of Schwann cell differentiation and robust induction of phospho-PAK with no significant effect on Ras/Raf/MEK/ERK. The central focus of this proposal is to understand how NF2 loss underlies resistance in NF1-deficient tumors. In particular, the key knowledge gap addressed by this proposal is to shed light on the critical signaling intermediates, biochemical mechanisms, and druggable dependencies underlying cooperation between NF1 and NF2 loss. In order to address this gap, we propose to (i) define ifRAC1 mediates the functional effects of NF2 loss inNF1 mutant neurofibroma cells and (ii) determine if direct Merlin effectors differentially bind Merlin in NF1 intact versus NF1 deficient peripheral nerve cells. The technical innovation lies in the integration of validated genetic systems with cutting-edge proteomic approaches to define the functional and biochemical network connecting neurofibromin and Merlin. The biological innovation is the elucidation of a functional link between the NF1 and NF2 tumor suppressors, which cause overlapping cancer syndromes defined by peripheral nervous system tumors. In sum, we will leverage a multidisciplinary approach combining CRISPR interference, pharmacology, biochemistry, and proteomics to understand Merlin function in pNF and MPNST model systems and identify new therapeutic approaches for patients.

Clinical Impact. Peripheral nervous system tumors such as plexiform neurofibromas (pNFs) and malignant peripheral nerve sheath tumors (MPNSTs) are significant sources of morbidity and mortality in persons with neurofibromatosis type 1 (NF1). The goal of this project is to identify novel therapeutic approaches beyond the MEK inhibitor selumetinib, which is the only FDA-approved molecular therapy for pNFs. Given the lack of approved second-line therapies, understanding why some patients with pNFs do not respond to MEK inhibitors is critical, and moreover, the lack of any molecular agents for MPNSTs comprises an unmet clinical need. This proposal builds on my prior work integrating human pNF and MPNST samples with biochemical and functional genomic studies in cell lines and mice to nominate NF2 loss as a potential driver of MEK inhibitor resistance. However, the mechanisms underlying this functional relationship are unclear, and by leveraging the biochemical and pharmacologic expertise of my mentor, Dr. Frank McCormick, we aim to understand the signaling alterations and druggable dependencies following NF2 loss in NF1 mutant peripheral nervous system tumors with the goal of identifying new treatments for pNF and MPNSTs. Thus, our proposal is well aligned with the DHART SPORE’s emphasis on tumors arising in persons with NF1.

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:

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 2024 Guidelines


2023-2024 DRP Awardee

No DRP awardee for 2023-2024

DRP Past Awards