Noonan syndrome, a developmental disorder characterized by congenital heart disease, dysmorphic facial and chest features, and mental retardation bears an increased risk of progressing to juvenile myelomonocytic leukemia (JMML), a fatal myeloproliferative neoplasm (MPN), and acute leukemias. This disease affects 1 in 1000 to 2500 children. There is an enormous unmet need for novel therapeutic interventions that specifically target disease-causing molecules for the prevention and treatment of leukemias in Noonan syndrome. Germline heterozygous mutations in the tyrosine phosphatase Ptpn11 (Shp2), a positive regulator of the Ras signaling pathway, are associated with 50% of individuals with Noonan syndrome. Moreover, somatic heterozygous mutations in Ptpn11 have been found in non-syndromic JMML (35%) and other childhood leukemias. These mutations disrupt the autoinhibitory structure of Shp2, resulting in greatly increased catalytic activity. Recent studies have demonstrated that a single Ptpn11 disease mutation, such as E76K or D61G/Y, is sufficient to drive the development of a Noonan syndrome-like developmental disorder and JMML-like MPN followed by progression to acute leukemias in mice, strongly suggesting a causal role for Ptpn11 activating mutations in these diseases. It is evident that the increased catalytic activity of mutated Shp2 leads to aberrant hematopoietic cell proliferation and differentiation. Shp2 might thus be an effective target of mechanism-based therapeutic intervention for Ptpn11-associated hematological malignancies. Through structure-based chemical database screening in combination with biochemical/biological experimentation, we have identified several small molecule compounds that selectively inhibit Shp2 (United States Patent 8,673,913 B2). Among these inhibitors is the natural product compound cryptotanshinone, one of the major active ingredients of the traditional medicinal herbal plant Salvia miltiorrhiza Bunge. Notably, disease related mutant Shp2 with the open conformation is more sensitive to this inhibitor than wildtype Shp2. More importantly, cryptotanshinone is already in clinical use in Asian countries to treat heart disease and stroke in adult patients (presumably through inhibition of Shp2 function in promoting platelet adhesion/aggregation). Given that this Shp2 inhibitor is a clinically-used drug with low toxicity, we plan to use this drug to determine in animal models whether Shp2 is an effective target of therapeutic intervention for the treatment of Ptpn11-associated non-syndromic leukemias and/or for the prevention of leukemic progression in Ptpn11 mutation positive Noonan syndrome. We will first test the inhibitor?s effects on Ptpn11E76K/+ mouse leukemic cells in vitro. After determining the most effective concentrations from these assays, dose finding experiments, and toxicity tests, we will then test the inhibitor in Ptpn11E76K/+ leukemic mice. Furthermore, we will determine the effectiveness of the inhibitor on Ptpn11 mutation-positive JMML patient cells.

Public Health Relevance

Genetic lesions in Ptpn11 (Shp2) that cause greatly increased activity of Shp2 are associated with the development of Noonan syndrome and various childhood leukemias. The project proposed in this application seeks to determine whether Shp2 is an effective target of therapeutic intervention for the prevention of leukemic progression in Noonan syndrome and/or for the treatment of Ptpn11-associated non-syndromic leukemias, with the natural product Shp2 inhibitor cryptotanshinone.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD087760-02
Application #
9394811
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Tsilou, Katerina
Project Start
2016-12-07
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322