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#10 - A new compound for treatment of Neurofibromatosis Type 1
Long Title: Novel synthetic analogues of Schweinfurthin A for the treatment of Neurofibromatosis type 1.
NIH Reference No.: E-183-2009
Executive Summary
General Description
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant genetic disorder affecting one in 3000[1]-5000[2] people, and is clinically defined by a variety of lesions including the presence of six or more café-au-lait spots, two or more neurofibromas or one plexiform neurofibroma, or optic glioma. NF1 patients are at an increased risk of developing malignant peripheral nerve sheath tumors (MPNSTs), malignant astrocytomas, sporadic glioblastomas as well as tumors not associated with the nervous system, such as myeloid leukemia and pheochromocytoma.
The prognosis is difficult to predict and can manifest differently even among family members. In children, NF1 can progress rapidly and is associated with learning disabilities, low average IQ and behavioral problems[3]. Treatment options depend on the symptoms that a person exhibits[4]. Aside from surgical removal of cancer tumors, chemotherapy and radiation therapy, there are no effective treatments for NF1 patients. Thus, there remains a significant unmet need for therapies to treat NF1 and malignant tumors carrying NF1 mutations, Current drugs used in clinical trials target the RAS signaling pathway. In contrast, this invention may serve as a lead molecule in developing novel therapies targeting an alternative signaling pathway
Scientific Progress
The invention describes using schweinfurthin A and synthetic schweinfurthin analogs to inhibit growth of a range of NF1 mutant cells, specifically anaplastic astrocytoma cells and malignant peripheral nerve sheath tumor cells. It has been shown that NF1 inhibits RAS activity and that NF1 loss leads to accumulation of RAS and hyper-stimulation brought by many growth factors, which ultimately leads to tumor formation. However, the inventors discovered that schweinfurthin A does not inhibit growth of the A549 lung tumor cell line, which carries an activating mutation in RAS, suggesting schweinfurthin A, and its analogs may inhibit NF1 tumors through a distinct signal pathway. Furthermore, the inventors discovered that schweinfurthin A does not have appreciable activity against NF1 heterozygous primary astrocyte cells as reported in the patent. This differential activity in NF1 mutant and NF1 heterozygous cells provides an ideal therapeutic index for treatment of NF1 patients who carry mutations in one copy of NF1. Pharmacokinetic studies of three schweinfurthin A analogs have been initiated, and in vivo efficacy testing of one schweinfurthin analogue has been conducted. Furthermore, experiments are underway to identify potential schweinfurthin A targets in the cell.
Future Direction
Potential Commercial Applications
Strengths
Weaknesses
Patent Status
US Patent 8,686,016 Issued April 01, 2014
European and Australian PCT Application 2010242874 filed Apr 30, 2010
Relevant Publications
Lockett, S. et al., Cytometry A. 2014 Jun; 85(6): 512-21 (PMID: 24515854)
Turbyville, TJ. et al., Mol Cancer Ther. 2010 May; 9(5): 1234-43 (PMID: 20442305)
Inventor Bios
Karlyne M. Reilly, Ph.D.
Dr. Reilly received her Ph.D. in molecular and cellular biology from Harvard University in 1997 under Dr. Douglas Melton. She trained as a postdoctoral fellow in the laboratory of Dr. Tyler Jacks at the Center for Cancer Research of MIT, where she held fellowships from the Leukemia & Lymphoma Society, the AACR-Sidney Kimmel Foundation, and the American Cancer Society. In 2002, she established the Genetic Modifiers of Tumorigenesis Group at the Center for Cancer Research, NCI. Her laboratory focuses on mouse models of cancer to study the biology of tumorigenesis and the genetic basis of variable susceptibility to cancer.
John A. Beutler, Ph.D.
Dr. Beutler received his Ph.D. from Philadelphia College of Pharmacy and Science in 1980 and received postdoctoral training at Northeastern University and the University of Texas Medical Center. He is a renowned scientist in the discovery of natural products for treatment of cancer and HIV, working in the Molecular Targets Laboratory in the Center for Cancer Research, NCI. He has worked at many points in the drug discovery pipeline, from high throughput screening, discovery chemistry, and molecular pharmacology, to GMP production of drug candidates.
[1] Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A:327–32. [PubMed]
[2] http://www.nature.com/ejhg/journal/v15/n2/pdf/5201676a.pdf
[3] Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. Corpus callosum morphology and its relationship to cognitive function in neurofibromatosis type 1. J Child Neurol. 2010;25:834–41. [PubMed]
[4]http://www.hopkinsmedicine.org/neurology_neurosurgery/specialty_areas/neurofibromatosis/nf1/treatment-nf1.html
NIH Reference No.: E-183-2009
Executive Summary
- Invention Type: Diagnostic, Therapeutic
- Patent Status: US Patent Grant No. 8,686,016; European and Australian PCT Application No. 2010242874 - Patent issued in US in 2014, Application pending in EU and AU
- LINK: http://www.ott.nih.gov/technology/e-183-20090
- NIH Reference Number: E-183-2009
- NIH Institute or Center: National Cancer Institute (NCI)
- Disease Focus: Neurofibromatosis type 1 (NF1) and/or undesirable conditions associated with mutations of the NF1 gene or haploinsufficiency for NF1, such as sporadic gliomas
- Basis of Invention: Small molecule
- How it works: Schweinfurthin A (SA) disrupts F-actin cytoskeletal structures via inhibition of growth factor-induced Rho signaling specifically in NF1-deficient tumor cells.
- Lead Inventors: Karlyne Reilly, Ph.D. and John Beutler, Ph.D.
- Development Stage: In vitro and in vivo demonstrating that SA is specifically effective in cells that are null for NF1 gene
- Novelty: Natural product-based therapeutic which targets a signaling pathway different from the current drugs
- Clinical Application: Novel class of treatment for NF1 and malignant tumors carrying NF1 mutations such as sporadic gliomas
General Description
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant genetic disorder affecting one in 3000[1]-5000[2] people, and is clinically defined by a variety of lesions including the presence of six or more café-au-lait spots, two or more neurofibromas or one plexiform neurofibroma, or optic glioma. NF1 patients are at an increased risk of developing malignant peripheral nerve sheath tumors (MPNSTs), malignant astrocytomas, sporadic glioblastomas as well as tumors not associated with the nervous system, such as myeloid leukemia and pheochromocytoma.
The prognosis is difficult to predict and can manifest differently even among family members. In children, NF1 can progress rapidly and is associated with learning disabilities, low average IQ and behavioral problems[3]. Treatment options depend on the symptoms that a person exhibits[4]. Aside from surgical removal of cancer tumors, chemotherapy and radiation therapy, there are no effective treatments for NF1 patients. Thus, there remains a significant unmet need for therapies to treat NF1 and malignant tumors carrying NF1 mutations, Current drugs used in clinical trials target the RAS signaling pathway. In contrast, this invention may serve as a lead molecule in developing novel therapies targeting an alternative signaling pathway
Scientific Progress
The invention describes using schweinfurthin A and synthetic schweinfurthin analogs to inhibit growth of a range of NF1 mutant cells, specifically anaplastic astrocytoma cells and malignant peripheral nerve sheath tumor cells. It has been shown that NF1 inhibits RAS activity and that NF1 loss leads to accumulation of RAS and hyper-stimulation brought by many growth factors, which ultimately leads to tumor formation. However, the inventors discovered that schweinfurthin A does not inhibit growth of the A549 lung tumor cell line, which carries an activating mutation in RAS, suggesting schweinfurthin A, and its analogs may inhibit NF1 tumors through a distinct signal pathway. Furthermore, the inventors discovered that schweinfurthin A does not have appreciable activity against NF1 heterozygous primary astrocyte cells as reported in the patent. This differential activity in NF1 mutant and NF1 heterozygous cells provides an ideal therapeutic index for treatment of NF1 patients who carry mutations in one copy of NF1. Pharmacokinetic studies of three schweinfurthin A analogs have been initiated, and in vivo efficacy testing of one schweinfurthin analogue has been conducted. Furthermore, experiments are underway to identify potential schweinfurthin A targets in the cell.
Future Direction
- To determine whether schweinfurthin synthetic analogs maintain potency and specificity in appropriate in vivo.
- Investigation of BBB penetration ability for schweinfurthin A analogues
- Perform ADME/PK studies of candidate analogues
Potential Commercial Applications
- Therapies for tumors associated with NF1 (including brain and peripheral nervous system tumors)
- Therapies for leukemia
- Therapies for NF1 and associated conditions
Strengths
- Natural products are evolutionarily selected to play targeted roles in organisms
- Schweinfurthin A is highly potent and selective to cells with mutations of NF1
- Specificity of mode of action may reduce potential side-effects
- Novel mode of action may limit market competition
- Its mechanism of action is unique compare to other existing therapies for NF1
- Utilizes proven small-molecule technology
Weaknesses
- Need to confirm the BBB penetration if targeting glioblastoma
Patent Status
US Patent 8,686,016 Issued April 01, 2014
European and Australian PCT Application 2010242874 filed Apr 30, 2010
Relevant Publications
Lockett, S. et al., Cytometry A. 2014 Jun; 85(6): 512-21 (PMID: 24515854)
Turbyville, TJ. et al., Mol Cancer Ther. 2010 May; 9(5): 1234-43 (PMID: 20442305)
Inventor Bios
Karlyne M. Reilly, Ph.D.
Dr. Reilly received her Ph.D. in molecular and cellular biology from Harvard University in 1997 under Dr. Douglas Melton. She trained as a postdoctoral fellow in the laboratory of Dr. Tyler Jacks at the Center for Cancer Research of MIT, where she held fellowships from the Leukemia & Lymphoma Society, the AACR-Sidney Kimmel Foundation, and the American Cancer Society. In 2002, she established the Genetic Modifiers of Tumorigenesis Group at the Center for Cancer Research, NCI. Her laboratory focuses on mouse models of cancer to study the biology of tumorigenesis and the genetic basis of variable susceptibility to cancer.
John A. Beutler, Ph.D.
Dr. Beutler received his Ph.D. from Philadelphia College of Pharmacy and Science in 1980 and received postdoctoral training at Northeastern University and the University of Texas Medical Center. He is a renowned scientist in the discovery of natural products for treatment of cancer and HIV, working in the Molecular Targets Laboratory in the Center for Cancer Research, NCI. He has worked at many points in the drug discovery pipeline, from high throughput screening, discovery chemistry, and molecular pharmacology, to GMP production of drug candidates.
[1] Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A:327–32. [PubMed]
[2] http://www.nature.com/ejhg/journal/v15/n2/pdf/5201676a.pdf
[3] Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. Corpus callosum morphology and its relationship to cognitive function in neurofibromatosis type 1. J Child Neurol. 2010;25:834–41. [PubMed]
[4]http://www.hopkinsmedicine.org/neurology_neurosurgery/specialty_areas/neurofibromatosis/nf1/treatment-nf1.html
