The Children's Tumor Foundation is delighted to announce the funding of nine Young Investigator Awards (YIA) for 2013. YIA recipients focus on using animal models and cell and tissue cultures to advance understanding of the biology of NF1, NF2, and schwannomatosis, which is the first step toward better treatments for neurofibromatosis.
The 2013 YIA recipients include seven post-doctoral and two pre-doctoral awardees.
2013 POSTDOCTORAL AWARDEES
Lu Zhou, Peninsula School of Medicine and Dentistry, UK
KSR1 as a Potential Therapeutic Target for Both NF1 and NF2
NF1 patients can develop plexiform neurofibromas (benign tumors that grow along nerves) which can become malignant peripheral nerve sheath tumors (MPNST) in 10% of cases. NF2 patients are likely to develop tumors of the Schwann cells called schwannomas, which lead to significant medical problems. Currently, there is no approved drug therapy for these complications of NF1 and NF2. This project will use cell cultures to explore the tumor-suppressing activity of Kinase Suppressor of Ras 1 (KSR1) as a new approach for the treatment of both NF1 and NF2.
Kairong Li, University of Alabama
Characterizing Novel NF1 Mouse Models and Developing New Therapeutic Interventions
The approach of using drugs that interact with a mutated gene or its gene product, with the goal of restoring gene function, has proved feasible in genetic disorders such as cystic fibrosis and Duchenne muscular dystrophy. This project will develop new mouse models mimicking human NF1 mutations to enable preclinical testing of such gene or protein-targeted NF1 therapeutics. It will focus on mice with mutations like those in NF1 patients in which there is a premature "stop signal." This type of mutation occurs in approximately 20% of people with NF1. The researchers will study mice with premature stop mutations, and test the ability of a group of drugs called "nonsense suppressors" to allow normal protein to be produced in these mice.
Su Ting, University of Chicago
Dissecting Merlin-mediated Regulation of the Hippo Growth Control Pathway Using FRET-based Biosensors
Loss of the NF2 tumor suppressor protein Merlin leads to tumor formation in humans and mice, and tissue overgrowth in Drosophila (fruitflies). Merlin is thought to regulate the activity of the Hippo growth control pathway that controls organ size and tissue stability. Due to a lack of laboratory methods for studying Hippo pathway kinase activity, we do not know exactly how Merlin regulates the Hippo pathway. The researchers plan to develop optical biosensors that measure the activity of Hippo pathway kinases with high resolution. They will use these to explore the role of Merlin in regulating the Hippo pathway during normal development, and in suppressing tumor formation in humans.
Christine Chiasson MacKenzie, Harvard University, Massachusetts General Hospital
Mechanical Organization of the Cell Cortex by the Tumor Suppressor NF2/Merlin
This researcher's group has recently discovered that the protein that is missing in NF2, Merlin, helps to organize the physical properties of the cell by restricting the function of the ERM family of proteins. Based on these findings, the researcher proposes a novel and unifying hypothesis: that the multiple features of NF2 are related to a failure of cells to appropriately respond to mechanical stimuli. She will use innovative bioengineering approaches to manipulate the mechanical environment experienced by cells and investigate how mechanical stimuli impact the activity of known Merlin-regulated signaling pathways in the presence or absence of Merlin. These studies will set the stage for future efforts to match the appropriate therapeutic strategy to a specific tumor type.
William Guerrant, The Scripps Research Institute, Florida
Small Molecule Inhibition of the Hippo-YAP Pathway as a Therapeutic Strategy in NF2
Currently, treatment options for NF2 are scarce. There is a pressing need for NF2 drugs. The Hippo-Yap pathway is involved in NF2 and has recently been shown to interact with many other important pathways that can cause cancer. It has therefore become an important new target for cancer researchers. The project will screen a 640,000 plus "library" of chemical compounds to identify inhibitors of the pro-growth signaling Hippo-Yap pathway and test the most promising inhibitors of human NF2 tumors in mouse models, with the goal of developing validated drugs for NF2 treatment.
Shuning He, Harvard University, Dana-Farber Cancer Institute
In Vivo Analysis of the NF1 Tumor Suppressor in Neurofibromatosis
It is known that part of the NF1 protein down-regulates the function of another protein, called RAS, which can promote tumor formation when it is expressed at high levels. However, the functions of other regions of the NF1 protein have yet to be discovered. This project will study new functions of NF1 and how NF1 is involved in neurofibromatosis formation using a zebrafish model. When the functions of NF1 proteins are inhibited in zebrafish, they develop abnormally with defects that mirror the human disorder. The zebrafish model promises to be meaningful for the study of NF1 in humans and the development of improved therapies for patients with NF1.
Wei Mo, University of Texas Southwestern Medical Center
MPNST, a Disease of the Stem Cell?
Recently, the concept of cancer stem cells has arisen in multiple professional journals in the biomedical field and has been widely discussed as an important topic of public health. The traditional tumor growth model holds that every cancer cell has unlimited dividing and metastasis potential. However, it is difficult to explain tumor relapse after classical anti-tumor treatments such as chemo- and radiotherapies because the majority of the highly proliferative cancer cells are killed upon treatment. The cancer stem cell hypothesis can better explain tumor recurrence following treatment. Cancer stem cells (CSCs) represent a small population in cancers with self-renewal capability and maintain tumor heterogeneity. Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and lethal tumors that develop in 2-5% of NF1 patients. There is now opportunity to develop innovative and novel therapies for these tumors, if the CSC model is applicable to MPNST growth. The identification of CSCs in MPNSTs would suggest that a more aggressive treatment plan targeting the CSCs would be effective, and could lead to improved treatments for NF1 patients who develop MPNSTs.
2013 PREDOCTORAL AWARDEES
Christine Kivlin, University of Texas, MD Anderson Cancer Center
PARP Inhibitors for the Treatment of NF1-associated MPNST
A malignant peripheral nerve sheath tumor (MPNST) is the most aggressive consequence of NF1. Currently, the only treatment for MPNST is surgery, if feasible. Additionally, about 50% of the patients develop metastases, which have a poor survival rate (20-50% five-year survival rate). This project will evaluate the use of Poly ADP Ribose Polymerases, or PARP, inhibitors to treat MPNSTs. PARP inhibitors are proteins that play an essential role in the repair of DNA damage. Recent evidence suggests that cancers have specific defects in DNA repair pathways that may predispose for sensitivity to various classes of cytotoxic agents, such as PARP inhibitors. Preliminary data from this laboratory strongly suggest that an MPNST is sensitive to the effects of AZD2281, a PARP inhibitor. The goal of this project is to further evaluate the effects of PARP inhibition on MPNSTs in cell lines and animal models. It also aims to identify why MPNST cells are sensitive to PARP inhibition. Understanding the mechanisms responsible for sensitivity would enhance our ability to identify MPNST patients that will most benefit from treatment with PARP inhibitors.
Matthew Karolak, Vanderbilt University
FGFR1 and Neurofibromin Interactions During Endochondral Bone Formation
Approximately 30% of NF1 patients will have some type of abnormality related to skeletal development, bone remodeling, and bone fracture repair. Following fracture, these NF1 patients typically have healing abnormalities. In some cases, they are required to undergo multiple surgeries to achieve fracture healing. Frequently these attempts are still unsuccessful, may require limb amputation, and are associated with high morbidity. The molecular mechanisms underlying many of the skeletal aspects of NF1 remain unknown, and largely untreatable with drugs. This project will test the hypothesis that FGF Receptor 1 signaling in chondrocytes (the bone cells contributing to bone elongation during growth and the first steps of bone repair following fracture) is under the control of neurofibromin (the protein mutated in NF1 patients). If correct, this will identify a novel target against which pharmacological drugs targeting FGFR1 could be used to promote proper fracture healing in NF1 patients. In this study, tissue culture experiments will examine which FGFR1 signaling events are regulated by neurofibromin. A second part of this study will test whether inhibiting FGFR1 in a mouse model promotes bone healing. It will use a newly developed method to deliver an FGFR1 inhibitor at the fracture site in a controlled (slow release) and local manner. Overall, this study will determine the feasibility of the approach of blocking FGFR1 during the early phases of bone healing in NF1 patients in order to promote proper fracture healing and stable bone union following fracture.