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Can cancer meds treat a group of genetic disorders?

RASopathies are common genetic disorders identified by distinct facial features, developmental delays, cognitive impairments and heart problems. There are no treatments. Now two studies suggest that personalized therapies might someday help.

Not widely known, RASopathies are among the most common genetic disorders, affecting approximately one child out of 1,000. They are caused by mutations within the RAS pathway, a biochemical system cells use to transmit information from their exterior to their interior.

"Human development is very complex and it's amazing that it goes right so often. However, there are certain cases where it does not, as with RASopathies. Our new studies are helping to explain the mechanisms underlying these disorders."

Granton Jindal, graduate student, Department of Chemical and Biological Engineering, and the Lewis-Sigler Institute (LSI) for Integrative Genomics, Department of Molecular Biology, Princeton University, Princeton, NJ, USA.

Jindal is doing thesis research in the lab of Stanislav Shvartsman, Professor, Chemical and Biological Engineering and LSI and co-lead author of two studies. Each published this year, first in the Proceedings of the National Academy of Sciences (PNAS) (1) and second in Nature Genetics (2) online.

Due to the evolutionary similarities in the RAS pathway across diverse species, changes are expected to be similar and apply to humans as well. The researchers made their discoveries in zebrafish and fruit flies — animals commonly used as simplified models of human genetics. Further research is needed to confirm human crossover effects.

The PNAS paper presented a way to rank the severity of different mutations involved in RASopathies. Researchers introduced 16 mutations, one at a time, into developing zebrafish embryos. In each organism, clear differences in embryo shape became evident, according to the strength of the mutation.
Using the same mutant proteins in fruit flies produced similar defects.

Some of the mutations were already known to exist from human cancers. Researchers noted that cancer-related mutations caused more severe embryo deformation. Using an experimental cancer-fighting drug as a possible way to treat RASopathies, they saw the amount of medication needed to correct developmental defects in zebrafish embryos corresponded with mutation severity — increased severe mutations required higher dosage.

This observation aligns with ongoing medical efforts to adapt anti-cancer compounds to treat RASopathies.

"Until now, there was no systematic way of comparing different mutation severities for RASopathies effectively."

Yogesh Goyal, Department of Chemical and Biological Engineering, and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.

The PNAS paper observed an unexpected twist in treatment approach. All cellular pathways, RAS's included, are a series of molecular interactions which change intracellular conditions. Conventional wisdom was that RASopathies are triggered by overactive RAS molecular interactions, or "excessive signaling." 

However, the PNAS study found some RASopathies result from insufficient signaling in certain regions of zebrafish. This suggests drugs intended to "quiet signaling" in RASopathies might worsen defects.

The Nature Genetics study also found RAS pathway mutations cause defects in the timing of stages of embryo development. For example, in normal fruit fly cells, RAS pathways only turn on after receiving certain cues from outside the cell. However, in mutant fly embryo cells, RAS pathways abnormally activate before these cues are received. Early activation disturbed delicate embryonic development. Similar behavior was also found in zebrafish cells.

"At this time, most of the issues that arise from RASopathies are either addressed symptomatically or not addressed. The work [these researchers] are undertaking could lead to true therapies."

Bruce Gelb MD, Pediatric Cardiology, Director, Mindich Child Health and Development Institute, Mount Sinai School of Medicine, New York, USA

(1) In vivo severity ranking of Ras pathway mutations associated with developmental disorders

RASopathies are developmental disorders caused by germ-line mutations in Ras/MAPK pathway components. Hundreds of such mutations have been reported using patient-specific sequencing projects. However, a systematic framework to translate individual mutations into patient-specific phenotypic severity is missing. Here, we develop such a framework by focusing on mutations in MEK1, a MAPK kinase. We report that the aspect ratio of early zebrafish embryos can be used as a metric to efficiently rank these mutations. Furthermore, this rank is conserved in other zebrafish- and Drosophila-specific assays and is predictive of drug dose needed to reverse the aspect ratio. Our results suggest that a systematic mutation-based comparative analysis of human phenotypes is crucial for efficient diagnosis and potential treatment

Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale. Using this assay, we assessed 16 mutations reported in MEK1, a MAPK kinase, and provide a robust ranking of these mutations. We find that mutations found in cancer are more severe than those found in both RASopathies and cancer, which, in turn, are generally more severe than those found only in RASopathies. Moreover, this rank is conserved in other zebrafish embryonic assays and Drosophila-specific embryonic and adult assays, suggesting that our ranking reflects the intrinsic property of the mutant molecule. Furthermore, this rank is predictive of the drug dose needed to correct the defects. This assay can be readily used to test the strengths of existing and newly found mutations in MEK1 and other pathway components, providing the first step in the development of rational guidelines for patient-specific diagnostics and treatment of RASopathies.

Search terms: MEK1 zebrafish Drosophila RASopathies MEK inhibitor

Authors: Granton A. Jindala, Yogesh Goyala, Kei Yamayab, Alan S. Futrana, Iason Kountouridisb, Courtney A. Balgobinc, Trudi Schüpbachc, Rebecca D. Burdinec, and Stanislav Y. Shvartsmana.

The authors declare no conflict of interest.


(2)Divergent effects of intrinsically active MEK variants on developmental Ras signaling

Germline mutations in Ras pathway components are associated with a large class of human developmental abnormalities, known as RASopathies, that are characterized by a range of structural and functional phenotypes, including cardiac defects and neurocognitive delays1, 2. Although it is generally believed that RASopathies are caused by altered levels of pathway activation, the signaling changes in developing tissues remain largely unknown3, 4. We used assays with spatiotemporal resolution in Drosophila melanogaster (fruit fly) and Danio rerio (zebrafish) to quantify signaling changes caused by mutations in MAP2K1 (encoding MEK), a core component of the Ras pathway that is mutated in both RASopathies and cancers in humans5, 6. Surprisingly, we discovered that intrinsically active MEK variants can both increase and reduce the levels of pathway activation in vivo. The sign of the effect depends on cellular context, implying that some of the emerging phenotypes in RASopathies may be caused by increased, as well as attenuated, levels of Ras signaling.

Subject terms: Diseases Embryogenesis Pattern formation

Authors: Yogesh Goyal, Granton A Jindal, José L Pelliccia, Kei Yamaya, Eyan Yeung, Alan S Futran, Rebecca D Burdine, Trudi Schüpbach & Stanislav Y Shvartsman

The research for both papers was supported in part by the National Institutes of Health and the National Science Foundation.
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Feb 17, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

RASopathies affect approximately one child out of 1,000.
Fruit-fly embryos (ABOVE) show how signals at the early stage of development (RED - TOP)
activate genes (PURPLE - MIDDLE) and pattern structures (BOTTOM) in fly larva.
In zebrafish and fruit fly embryos, researchers saw how cancer-related mutations in the
RAS pathway, a biochemical system which transmits information from cell exterior to
cell interior — cause severe deformations.
Image Credit: Stanislav Shvartsman, Princeton University



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