The sixth international RASopathies symposium: Precision medicine—From promise to practice

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Abstract

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.

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Most cited references 25

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SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

Carmine Fedele, Hao Ran, Brian Diskin … (2018)

Adaptive resistance to MEK inhibitors (MEK-Is) typically occurs via induction of genes for different receptor tyrosine kinases (RTKs) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 ( PTPN11 ) is required for RAS/ERK pathway activation by most RTKs, and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEK-I inhibited the proliferation of multiple cancer cell lines in vitro . PTPN11 knockdown/MEK-I treatment had similar effects, while expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS -mutant pancreas, lung, and ovarian cancer and in wild type RAS-expressing triple negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEK-Is and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEK-I combinations could have therapeutic utility in multiple malignancies.

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Incorporating the patient's perspective into drug development and communication: an ad hoc task force report of the Patient-Reported Outcomes (PRO) Harmonization Group meeting at the Food and Drug Administration, February 16, 2001.

Catherine Acquadro, Rick Berzon, Dominique Dubois … (2003)

The extent to which patient-based outcomes can be used to evaluate and communicate the effect of new drugs and devices is a subject of much debate. Criteria for evaluating the scientific quality of data to support health-related quality of life (HRQL) and other patient-based labeling and promotional claims in the United States and Europe have been proposed by various scientists and organizations. Since March 2000, a working group composed of members of the International Society for Quality of Life Research (ISOQOL), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), the Pharmaceutical Manufacturer's Association Health Outcomes Committee (PhRMA-HOC), and the European Regulatory Issues on Quality of Life Assessment (ERIQA) met to discuss and coordinate the various recommendations by their respective groups and address the need to harmonize outcomes review criteria within and across United States and European regulatory agencies. Over time, the discussion expanded from HRQL outcomes to include any outcome based on data provided by the patient or patient proxy, that is, patient-reported outcomes (PROs). The working group therefore became known as the PRO Harmonization Group. Working with a member of the US Food and Drug Administration (FDA), four key issues requiring clarification were identified: how PROs are defined and put into operation for research purposes; the added value of PROs in the drug review and evaluation process; selected questions related to the PRO measurement and research methodology; and the interest and demand for PRO information by decision makers. On February 15, 2001, all members of the PRO Harmonization Group attended a meeting in Rockville, Maryland, to discuss these four issues further, and on February 16, 2001, a formal presentation was made to representatives from various departments and reviewing divisions of the FDA. These presentations are summarized in this report. All participants agreed that PROs are important for understanding the impact of treatment on patient functioning and well-being. They also stressed the need to communicate PRO information to key decision makers, including regulatory agencies, clinicians, patients and their families, and payers. Finally, the meeting resulted in plans for continuing the dialogue on PRO measurement and interpretation. The February 16, 2001, meeting represented an important step in harmonizing efforts across various organizations and in opening a dialogue with the FDA around major issues related to methodologic standards for measuring and interpreting PROs in the drug evaluation process.

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Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation.

Benjamin G. Neel, L Pao, Toshiyuki Araki … (2004)

Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 (also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in approximately 50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome-associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11(D61G/+) embryos ( approximately 50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11(D61G/+) embryos ( approximately 50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage-dependent and pathway-selective manner.

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Author and article information

Journal

Title: American Journal of Medical Genetics Part A

Abbreviated Title: Am J Med Genet

Publisher: Wiley

ISSN (Print): 1552-4825

ISSN (Electronic): 1552-4833

Publication date Created: December 16 2019

Publication date Created: March 2020

Publication date (Electronic): December 11 2019

Publication date (Print): March 2020

Volume: 182

Issue: 3

Pages: 597-606

Affiliations

[1 ]Al duPont Hospital for Children Wilmington Delaware

[2 ]RASopathies Network USA Altadena California

[3 ]Yale University School of Medicine New Haven Connecticut

[4 ]Hospital for Sick Children Toronto Ontario Canada

[5 ]Noonan Syndrome Foundation Farmington Connecticut

[6 ]Princeton University Princeton New Jersey

[7 ]Manchester Centre for Genomic MedicineManchester University NHS Foundation Trust and University of Manchester Manchester UK

[8 ]UCSF, Helen Diller Family Comprehensive Cancer Center San Francisco California

[9 ]Baylor College of Medicine Houston Texas

[10 ]Bridge Group Consulting Morristown New Jersey

[11 ]CFC International Saint Petersburg Florida

[12 ]Neurofibromatosis Network Rochester Minnesota

[13 ]Department of Pediatrics, Mindich Child Health and Development InstituteIcahn School of Medicine at Mount Sinai New York New York

[14 ]Department of Genetics and Genomic Sciences, Mindich Child Health and Development InstituteIcahn School of Medicine at Mount Sinai New York New York

[15 ]Stanford University Stanford California

[16 ]National Cancer Institute Bethesda Maryland

[17 ]Memorial Sloan Kettering Cancer Center New York New York

[18 ]Tohoku University School of Medicine Sendai Miyagi Japan

[19 ]Johns Hopkins Hospital Baltimore Maryland

[20 ]Parent Project Muscular Dystrophy Hackensack New Jersey

[21 ]Parent Liaison, FDA Bethesda Maryland

[22 ]Masonic Medical Research Institute Utica New York

[23 ]Boehringer‐Ingelheim Regional Center Vienna Vienna Austria

[24 ]Perlmutter Cancer Center and NYU School of MedicineNYU Langone Health New York New York

[25 ]Cincinnati Children's Hospital Medical Center and University of CincinnatiSchool of Medicine Cincinnati Ohio

[26 ]Department of Pediatrics, Division of Genomic MedicineUniversity of California Davis Sacramento California

[27 ]Department of Cardiology, Division of GeneticsBoston Children's Hospital Boston Massachusetts

[28 ]Department of Pediatrics, Division of GeneticsBoston Children's Hospital Boston Massachusetts

[29 ]UCL Cancer Institute London UK

[30 ]The Scripps Research Institute Jupiter Florida

[31 ]VIB‐KU Leuven Center for Cancer Biology Leuven Belgium

[32 ]Hubrecht Institute—KNAW and University Medical Center Utrecht Utrecht The Netherlands

[33 ]Genetics and Rare Diseases Research DivisionOspedale Pediatrico Bambino Gesù—IRCCS Rome Italy

[34 ]Costello Syndrome Family Network Woodinville Washington

[35 ]McGovern Medical SchoolUniversity of Texas Health Science Center Houston Texas

[36 ]Children's National Hospital & The George Washington School of Medicine Washington District of Columbia

[37 ]Pediatric Oncology BranchNational Cancer Institute Bethesda Maryland

[38 ]University Hospital Magdeburg, Institute of Human Genetics Magdeburg Germany

Article

DOI: 10.1002/ajmg.a.61434

PMC ID: 7021559

PubMed ID: 31825160

SO-VID: af4e4ca0-f102-4c00-890a-c6312b343e3b

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http://doi.wiley.com/10.1002/tdm_license_1.1

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The sixth international RASopathies symposium: Precision medicine—From promise to practice

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Most cited references 25

SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

Incorporating the patient's perspective into drug development and communication: an ad hoc task force report of the Patient-Reported Outcomes (PRO) Harmonization Group meeting at the Food and Drug Administration, February 16, 2001.

Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation.

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