Francis S. Collins Scholars Program

The Francis S. Collins Scholars Program in Neurofibromatosis Clinical and Translational Research is building a community of exceptional clinician scientists who will lead neurofibromatosis type 1 (NF1) research and clinical care.

The Scholars Program is named in honor of Dr. Francis S. Collins, who led the team that discovered the NF1 gene in 1990. In addition to this work, Dr. Collins has been at the forefront of advancing translational science in his roles as Director of the National Institutes of Health (NIH) and former Director of the National Human Genome Research Institute. His leadership helped to establish the National Center for Advancing Translational Sciences (NCATS) and Brain Research through Advancing Innovative Neurotechnologies (BRAIN).

By providing the “Collins Scholars” with critical support and training in the management of NF1 and the conduct of rigorous clinical translational research, the program aims to revolutionize the field of NF1 and improve treatment options for patients now and in the future.

Explicitly designed to attract talent of the highest order to the field of NF1 and to foster life-long commitment to this syndrome, the program provides scholars with:

• 75-100% salary support for 2-3 years
• Training in the care of NF1 patients
• Tuition support and formal training in clinical translational science
• Participation in collaborative translational research programs with government, academic and industry partners
• Travel costs for scientific meetings
• Mentor and research stipends

Current  NTAP-funded Francis S. Collins Scholar projects:

Development of a Preclinical NF1-MPNST Platform Suitable for Precision Oncology Drug Discovery and Evaluation

Angela Hirbe, M.D, Ph.D., Washington University

One of the most common cancers affecting adults with neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive tumor. Sadly, for those individuals with NF1 who develop these cancers, there are limited treatment options, and the vast majority of people with these malignancies will die within 5 years of diagnosis. Over the past decade, research has revealed that NF1-MPNSTs represent a group of diverse cancer types, characterized by different genetic changes. In this respect, there are likely different subtypes of MPNSTs that each harbor distinct sets of molecular changes, and thus have different responses to rationally-chosen treatments. Unfortunately, current small-animal models of NF1-MPNST used to discover and evaluate new therapies are largely engineered with one set of genetic changes, limiting their ability to fully represent the human condition. For this reason, Dr. Hirbe believes that the failure to discover effective treatments is partly due to the inability of these preclinical models to accurately model the genetic landscape of the human tumors. To address this problem, Dr. Hirbe and her team proposes to develop and characterize a set of ten patient-derived MPNST xenograft lines directly obtained from actual human tumors. These lines should more fully represent the genetic diversity seen in patients, and therefore be more likely to identify promising treatments for human clinical trials.

Narrative: Read about the project’s background, goals, specific aims, methods, preliminary results, and impact (auspices of Dr. Angela Hirbe, hirbea@wustl.edu)

Novel Therapeutics in Malignant Peripheral Nerve Sheath Tumor (MPNST)

Ping Chi, M.D., Ph.D., Memorial Sloan Kettering Cancer Center

Malignant Peripheral Nerve Sheath Tumor (MPNST) arising from the cellular component of the peripheral nerves represents a group of highly aggressive soft tissue sarcomas with limited treatment options. They can occur in the setting of type I neurofibromatosis (NF1-associated), or sporadically or in association with prior radiotherapy (RT-associated). Using comprehensive genomic approaches, Dr. Chi and others have discovered that the majority of MPNSTs have inactivation of three tumor suppressor pathways, including the NF1, the CDKN2A (INK4A/ARF) and the Polycomb repressive complex 2 (PRC2) pathways. Here, Dr. Chi proposes to use multidisciplinary approaches to establish authentic MPNST model systems for preclinical investigation. Dr. Chi and her team will also evaluate a combination treatment strategy of trametinib (a MEK inhibitor) and ribociclib (a CDK4/6 inhibitor) in various cell line and animal models of MPNST. Lastly, Dr. Chi and her team will conduct a screen using RNA interference technology to identify and characterize the genes that are important for MPNST growth and survival when the PRC2 pathway is inactivated. These studies will build important resources for the NF1-research community and can identify novel treatment strategies and streamline clinical therapeutic development for patients with NF1-associated MPNSTs.

Narrative: Read about the project’s background, goals, specific aims, methods, preliminary results, and impact (auspices of Dr. Ping Chi, chip@mskcc.org)

Neurofibromatosis Type 1 Dermal Neurofibroma Longitudinal Natural History Study and Selumetinib Clinical Trial

Ashley Cannon, Ph.D., M.S., University of Alabama

The overall goal of Dr. Cannon’s project is to complete a longitudinal natural history study of dermal neurofibromas to enhance current knowledge of dermal neurofibroma development as well as improve the design, implementation, and interpretation of clinical trials targeting DNs. To address the clinical trial facet of this project, a trial using the MEK1/2 inhibitor selumetinib will be piloted. Dr. Cannon will also evaluate the quality of life impact of dermal neurofibromas before and during Selumetinib treatment. For both facets of this study, she and her team will examine genomic alterations that correlate with DN development and selumetinib response.

NarrativeRead about the project’s background, goals, specific aims, methods, preliminary results, and impact (auspices of Dr. Ashley Cannon, ashleycannon@uabmc.edu)

Development of a novel treatment approach to Neurofibromatosis Type 1-related MPNST using genetically engineered Clostridium novyi-NT

Verena Staedtke, M.D., Ph.D. Johns Hopkins University

The overall goal of Dr. Staedtke’s project is to explore C. novyi-NT as a novel therapeutic for NF1-associated MPNSTs and to gather preclinical evidence substantiating clinical trial for for C. novyi-NT therapy in NF1 patients with MPNSTs.

Narrative: Read about the project’s background, goals, specific aims, preliminary results, and impact (auspices of Dr. Verena Staedtke, vstaedt1@jhmi.edu)

Publication 1: Roberts NJ, Zhang L, Janku F, Collins A, Bai RY, Staedtke V, et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med 6 (249), 249ra111 (2014)

Publication 2Staedtke V, Bai RY, Laterra JJ. Investigational new drugs for brain cancer. Expert Opin Investig Drugs. 2016 Aug;25(8):937-56. doi: 10.1080/13543784.2016.1182497. (Review)

Publication 3Staedtke V, Robert NJ, Bai RY, Zhou S. Clostridium novyi-NT in cancer therapy. Journal for Genes and Disease: Volume 3, Issue 2, June 2016, Pages 144–152 (Review)

Publication 4: Bai RY, Staedtke V, Xuwei X, Riggins GJ. Prevention of tumor seeding during needle biopsy by chemotherapeutic-releasing gelatin sticks. Oncotarget. 2017 Feb; 8(16): 25955-25962.

Publication 5:  Staedtke V, Bai RY, Blakeley JO. Cancer of the peripheral nerve in neurofibromatosis Type 1. (Review). Neurotherapeutics. 2017, 14: 298-306.

The Role of MEK-inhibitors for the Prevention and Treatment of Optic Pathway Gliomas in an NF1 Deficient Mouse Model

Miriam Bornhorst, M.D., Children’s National

Proving that treatment with MEKi in established tumors can provide therapeutic benefits, delaying expansion of the tumor by either decreasing or delaying immune cell response, axonal injury, and RGC loss. The goals of Dr. Bornhorst’s study are to 1) identify a potential developmental time window when low dose MEKi can be used to prevent OPG formation all together and 2) provide critical information about optic nerve changes that are responsible for vision loss during OPG formation, and how MEKi can be used to improve visual deficits.

Narrative: Read about the project’s background, goals, specific aims, highlights, and preliminary results (auspices of Dr. Miriam Bornhorst, mbornhorst@childrensnational.org

Publication 1: Bornhorst M, Hwang EI. Experimental Therapeutic Trial Design for Pediatric Brain Tumors. J Child Neurol. 2016 Oct;31(12):1421-32.

Publication 2: Packer RJ, Pfister S, Bouffet E, Avery R, Bandopadhayay P, Bornhorst M, Bowers DC, Ellison D, Fangusaro J, Foreman N, Fouladi M, Gajjar A, Haas-Kogan D, Hawkins C, Ho CY, Hwang E, Jabado N, Kilburn LB, Lassaletta A, Ligon KL, Massimino M, Meeteren SV, Mueller S, Nicolaides T, Perilongo G, Tabori U, Vezina G, Warren K, Witt O, Zhu Y, Jones DT, Kieran M. Pediatric low-grade gliomas: implications of the biologic era. Neuro Oncol. 2016 Sep 28

Imaging Biomarkers of Neurofibromatosis Type 1-Associated Optic Pathway Glioma

Peter de Blank, M.D., Cincinnati Children’s Hospital Medical Center

The main goals of the project is the interrogation of 2 two promising advanced magnetic resonance techniques, DTI and MRF, investigating tissue microstructure in OPG

Narrative: Read about the project’s background, goals, specific aims, and preliminary results (auspices of Dr. Peter de Blank, Peter.deBlank@UHhospitals.org)

Publication 1: de Blank PM, Fisher MJ, Lu L, Leisenring WM, Ness KK, Sklar CA, Stovall M, Vukadinovich C, Robison LL, Armstrong GT, Krull KR. (2016). Impact of Vision Loss Among Survivors of Childhood Central Nervous System Astroglial Tumors. Cancer 2016 Mar 1;122(5):730-9.

Publication 2: de Blank P, Berman JI, Fisher MJ. (2016). Systemic Chemotherapy and White Matter Integrity in Tracts Associated with Cognition Among Children with Neurofibromatosis Type 1. Pediatric Blood & Cancer 2016 May; 63(5):818-24

Publication 3: de Blank P, Ellika S, Kader M, Fisher MJ. Advanced Imaging in Optic Pathway Gliomas. In press (Journal of Pediatric Neuroradiology)

Targeting the mechanisms underlying cutaneous neurofibroma formation in NF1: a clinical translational approach

Matthew R. Steensma, M.D., Spectrum Health

To mitigate the morbidity and disfigurement attributable to CNFs arising in NF1, in this project, Steensma’s objective is to improve health and quality of life (QOL) by targeting essential mechanisms of CNF initiation and progression. In doing so, we will define a molecular pathogenesis specific to CNFs that encompasses existing knowledge regarding CNF cell-of-origin, as well as new knowledge regarding the role of cellular intrinsic factors such as DNA damage repair mechanisms, secondary mutations, epigenetic regulation of gene expression, and aberrant oncogene activation; extrinsic factors such as autocrine/paracrine feedback loops; and environmental factors such as ultraviolet radiation..

NarrativeRead about the project’s background, goals, aims, methods, and impact (auspices of Dr. Matthew Steenma’s, steensma@spectrumhealth.org)

Current Francis S. Collins Scholars:

Miriam Bornhorst, M.D., 2015

Miriam Bornhorst, M.D., received training in Pediatrics and Hematology/Oncology through the University of Michigan followed by a Neurooncology fellowship at Children’s National Health System. She currently works as an assistant professor in Oncology and Cancer Genetics at Children’s National Health System in Washington, DC. Under the mentorship of Dr. Yuan Zhu, her primary research focus is the use of preventative therapy for optic pathway gliomas. She was awarded the Neurofibromatosis Therapeutic Acceleration Program’s Francis S. Collin’s Scholarship in 2016 and plans to use this opportunity to enhance her clinical and research knowledge in NF1. Through her work, her overall goal is early detection and management of tumors in patients with cancer predisposition syndromes. Outside of work, she spends most of her time with family, particularly enjoying outdoor activities (hiking, camping, fishing, canoeing)

Verena Staedtke, M.D., 2015

Dr.  Verena Staedtke received her MD/PhD from the Charite, Medical School of the Humboldt and Free University in Berlin (Germany).  Currently an Assistant Professor and Director of pediatric Neurofibromatosis at Johns Hopkins, she completed her pediatric neurology residency and UCNS neuro-oncology fellowship at Johns Hopkins. Dr. Staedtke’s spearheaded the use of the therapeutic “anti-cancer” agent Clostridium novyi-NT (C. novyi-NT), a genetically modified anaerobic bacterium, for the use in nervous system cancers, particularly glioblastomas and malignant peripheral​ nerve sheath tumors, the most common malignancy in NF1 patients. In addition, she is interested in immunotherapies and chemoprevention in NF1. In her free-time, Dr. Staedtke is an avid swimmer, painter and plays the piano, flute and ping-pong.

Ashley Cannon, Ph.D., M.S., 2016

Ashley Cannon, PhD, MS, CGC is an Assistant Professor at the University of Alabama at Birmingham in the Department of Genetics. Dr. Cannon was named to the Francis S. Collins Scholars Program in 2016. She is a neuroscientist and certified genetic counselor. Her previous research experience at Mayo Clinic Florida encompassed molecular genetics, neuropathology, and mouse modeling of neurodegenerative diseases. This research exposed her to the significance of genetic counseling for individuals and families affected by genetic conditions and motivated her to become trained as a genetic counselor. She received an MS in Genetic Counseling at UAB in 2015. She currently provides genetic counseling for the Neurofibromatosis Clinic and Undiagnosed Diseases Program. Her current research comprises the longitudinal quantification, treatment, and psychosocial impact of cutaneous neurofibromas in individuals with NF1. She is a native of Jacksonville, Florida and loves science fiction novels and movies.

Ping Chi, M.D., Ph.D., 2017

Dr. Ping Chi is an Assistant Member in the Human Oncology and Pathogenesis Program (HOPP), and an Assistant Attending Physician in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City. Dr. Chi completed clinical training in internal medicine at the Brigham and Woman’s Hospital and Medical Oncology at Memorial Sloan-Kettering Cancer Center, and a concurrent postdoctoral training in epigenetics and chromatin biology in the C. David Allis’ lab at the Rockefeller University. Dr. Chi’s current laboratory research focuses on understanding the genetic and epigenetic mechanisms of transcriptional activation of novel oncogenic transcripts and oncogenic transcription factors in solid tumor malignancies. Through mechanistic studies, she aims to identify novel therapeutic strategies to target oncogenic transcription factors and aberrant transcriptional activation of oncogenes. Dr. Chi also maintains an active academic clinical practice, leads early phase clinical trials, and works with a multidisciplinary team to care for patients with sarcomas, with the goal to expedite clinical translation of laboratory research.

Angela Hirbe, M.D., Ph.D., 2017

Dr Angela Hirbe is a graduate of the Washington University M.D. Ph.D. program and completed her residency in Internal Medicine and fellowship in Oncology as part of the Physician Scientist Training Program.   Dr. Hirbe has had a longstanding interest in Neurofibromatosis research and her post-doctoral work was performed in the laboratory of Dr. David Gutmann where she used next-generation sequencing technologies to identify b-III spectrin as a protein involved in malignant peripheral nerve sheath tumor (MPNST) pathogenesis and developed a mouse model for this deadly type of sarcoma.  This work has transitioned into her own lab when she joined the faculty at Washington University.  Dr. Hirbe is currently an Assistant Professor in the Division of Medical Oncology in the Department of Medicine at Washington University in St. Louis.  Clinically, Dr Hirbe treats patients with sarcoma and has a strong clinical interest is in the care of patients with NF1-MPNST.  Her laboratory continues to use genomics to identify drivers in MPNST pathogenesis and further develop mouse models for preclinical studies and therapeutic drug testing.

Former Francis S. Collins Scholars:

Peter de Blank, M.D., M.S.C.E., 2014

Peter de Blank, MD, MA, MSCE was a Francis S. Collins Scholar in NF Clinical and Translational Research from 2014-2016 and continues to receive funding for ongoing projects from NTAP.  He is also a current St. Baldrick’s Scholar.  He graduated from the University of California, San Francisco School of Medicine in 2005, and completed a Masters of Arts in English and American Literature at Stanford University, and a Master’s of Science in Clinical Epidemiology and Biostatistics at the University of Pennsylvania.  He completed residency in Pediatrics, and fellowships in Pediatric Hematology & Oncology and Pediatric Neuro-Oncology at the Children’s Hospital of Philadelphia. Dr. de Blank was a member of the faculty at Rainbow Babies & Children’s Hospital from 2012-2016 where he served as Scientific Director of the NF Clinic from 2014-2016. He joined the faculty at Cincinnati Children’s Hospital Medical Center in 2017 where is an Associate Professor in the division of Neuro-Oncology and leads efforts on cancer imaging in the Cancer & Blood Diseases Institute. His research focuses on the application of advanced MR techniques in children with NF1 and brain tumors.  He is interested in the characterization of novel MR sequences to investigate brain tumors, and the development of early radiographic biomarkers of functional complications of brain tumors and brain tumor therapy.  Dr. de Blank has two wonderful girls (Casey 8 years and Reed 6 years) and a wife he doesn’t deserve (Robin).  When he has free time, he remembers that he liked to play Ultimate Frisbee.

Matthew R. Steensma, M.D., 2014

Dr. Matthew Steensma received his B.A. from Hope College in Holland, Mich., and his M.D. from Wayne State University School of Medicine in Detroit, Mich. He subsequently completed internship and residency training in the Grand Rapids Orthopaedic Surgery Residency Program. After completing residency, he trained in the laboratories of Drs. George Vande Woude and Rick Hay at VARI under an Orthopaedic Research and Education Foundation training award. Subsequently, Dr. Steensma was admitted into the prestigious fellowship program in Musculoskeletal Surgical Oncology in the Department of Surgery at Memorial Sloan Kettering Cancer Center in New York where he obtained sub-specialty training in the surgical management of musculoskeletal tumors. His fellowship in New York also provided Dr. Steensma with the opportunity to work in the laboratory of Dr. Steve Goldring, Chief Scientific Officer of the Hospital for Special Surgery (HSS) in New York. Dr. Goldring is one of the world’s leading orthopaedic researchers and has a particularly strong reputation for training leading clinician-scientists. During his training with Dr. Goldring, Dr. Steensma further developed his interests in understanding the molecular and cellular mechanisms underlying the development of bone and soft-tissue sarcomas. Dr. Steensma joined Van Andel Research Institute in 2010 as an Associate Scientific Investigator in the Center for Skeletal Disease Research.

 

Dr. Collins honoring all of the Francis S. Collins Scholars (left to right “Dr. Angela Hirbe, Dr. Ping Chi, Dr.  Peter de Blank, Dr. Francis Collins, Dr. Matthew R. Steensma, Dr. Ashley Cannon, Dr. Miriam Bornhorst, Dr. Verena Staedtke”)