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Potential Reuse of Oncology
Drugs in the Treatment of Rare Diseases

Zhichao Liu,* Hong Fang, William Slikker, and Weida Tong,*

National Center for Toxicological Research
US Food and Drug Administration
Jefferson, AR 72079
USA

*Correspondence:
Zhichao.liu@fda.hhs.gov (Z. Liu) and weida.tong@fda.hhs.gov (W. Tong).

Cancer research has made remarkable progress with the help of advancing genomics techniques, resulting in more precise clinical application and many new anticancer drugs on the market. By contrast, very few treatment options are available for rare diseases that are often progressive, severe, and life-threatening. In this opinion we elaborate on the possible association between cancers and rare diseases across three different levels including clinical observation, crosstalk between germline mutation and somatic mutation, and shared biological pathways. Consequently, by utilizing systematic drug-repositioning approaches, and taking safety issues into consideration, we suggest that oncology drugs have great potential for reuse in the treatment of rare diseases.

CellPress Trends in Pharmacological Science, October 2016, Vol. 37, Issue 10, p843-857.  Link to abstract here

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Paternal Uniparental Disomy with Segmental Loss of Heterozygosity of Chromosome 11 are Hallmark Characteristics of Syndromic and Sporadic Embryonal Rhabdomyosarcoma

Abstract: Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS. We characterized eleven ERMS tumors from eight unrelated CS patients, carrying paternally derived HRAS c.34G>A (p.Gly12Ser; 6) or c.35G>C (p.Gly12Ala; 2) mutations. Loss of heterozygosity (LOH) was evaluated in all CS ERMS by microarray and/or short tandem repeat (STR) markers spanning the entire chromosome 11. Eight CS ERMS tumors displayed complete paternal uniparental disomy of chromosome 11 (pUPD11), whereas two displayed UPD only at 11p and a second primary ERMS tumor showed UPD limited to 11p15.5, the classical hallmark for ERMS. Three sporadic ERMS cell lines (RD, Rh36, Rh18) and eight formalin fixed paraffin embedded (FFPE) ERMS tumors were also analyzed for RAS mutations and LOH status. We found a higher than anticipated frequency of RAS mutations (HRAS or NRAS; 50%) in sporadic ERMS cell lines/tumors. Unexpectedly, complete uniparental disomy (UPD11) was observed in five specimens, while the other six showed LOH extending across the p and q arms of chromosome 11. In this study, we are able to clearly demonstrate complete UPD11 in both syndromic and sporadic ERMS.
Am J Med Genet A. Author manuscript; available in PMC 2016 Dec 1.
Published in final edited form as:
PMCID: PMC5130350
NIHMSID: NIHMS831094

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

Granton A. Jindal, Yogesh Goyal, Kei Yamaya, Alan S. Futran, Iason Kountouridis, Courtney A. Balgobin, Trudi Schüpbach, Rebecca D. Burdine, Stanislav Y. Shvartsman

http://www.pnas.org/content/early/2017/01/01/1615651114.abstract

Abstract: 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.

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Can a cancer drug treat a rare cardiac disease?

Yale News
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Newsweek article 12/5/16
TRACKING DOWN ONE OF CANCER’S DEADLIEST CULPRITS, THE RAS FAMILY OF GENES*
BY JESSICA WAPNER ON 12/5/16 AT 10:30 AM
[*emphasis RASopathiesNet]

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NEW PUBLICATIONS SEARCH ENGINE FORMAT: https://www.gopubmed.org

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[With thanks to Beth Stronach for sharing this]

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Gelb 2016
~ Dr. Bruce Gelb ~

Stem cell breakthrough unlocks mysteries associated with inherited heart condition
Date: August 30, 2016
Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Summary:
Using advanced stem cell technology, scientists have created a model of a heart condition called hypertrophic cardiomyopathy (HCM) — an excessive thickening of the heart that is associated with a number of rare and common illnesses, some of which have a strong genetic component.
http://www.sciencedaily.com/releases/2016/08/160830212133.htm

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Human Molecular Genetics Advance Access Publication Date: July 2016, Vol. 25, No. R2 R123–R132

Pathogenesis of the RASopathies

William E. Tidyman (1,3) and Katherine A. Rauen (2,3)*

1 Division of Behavioral and Developmental Pediatrics, Department of Pediatrics, 2 Department of Pediatrics, Division of Genomic Medicine, University of California Davis, Sacramento, CA, USA and 3 UC Davis MIND Institute, Sacramento, CA 95817, USA

*To whom correspondence should be addressed at: UC Davis MIND Institute, 2825 50th Street, Room 2284, Sacramento, CA 95817, USA. Tel: 916 7030204; Fax: 916 7030243; Email: rauen@ucdavis.edu

Abstract
The RASopathies are defined as a group of medical genetics syndromes that are caused by germ-line mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. Taken together, the RASopathies represent one of the most prevalent groups of malformation syndromes affecting greater than 1 in 1,000 individuals. The Ras/MAPK pathway has been well studied in the context of cancer as it plays essential roles in growth, differentiation, cell cycle, senescence and apoptosis, all of which are also critical to normal development. The consequence of germ-line dysregulation leads to phenotypic alterations of development. RASopathies can be caused by several pathogenetic mechanisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. These pathogenetic mechanisms can include functional alteration of GTPases, Ras GTPase-activating proteins, Ras guanine exchange factors, kinases, scaffolding or adaptor proteins, ubiquitin ligases, phosphatases and pathway inhibitors. Although these mechanisms are diverse, the common underlying biochemical phenotype shared by all the RASopathies is Ras/MAPK pathway activation. This results in the overlapping phenotypic features among these syndromes.

doi: 10.1093/hmg/ddw191

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PLoS Genet. 2016 May 19;12(5):e1006039. doi: 10.1371/journal.pgen.1006039. eCollection 2016.

The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer.

Hartung AM1, Swensen J2,3,4, Uriz IE1, Lapin M1, Kristjansdottir K1, Petersen US1, Bang JM1, Guerra B1, Andersen HS1, Dobrowolski SF3, Carey JC5, Yu P4,Vaughn C4, Calhoun A6, Larsen MR1, Dyrskjøt L7, Stevenson DA8, Andresen BS1.

Abstract

Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3′ splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.

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J Pediatr Hematol Oncol. 2016 Jun 1. [Epub ahead of print]

Childhood Rhabdomyosarcoma in Association With a RASopathy Clinical Phenotype and Mosaic Germline SOS1 Duplication.

Salem B1, Hofherr S, Turner J, Doros L, Smpokou P.

http://www.ncbi.nlm.nih.gov/pubmed/27258033

Abstract

Childhood rhabdomyosarcoma (RMS) accounts for approximately 3.5% of cancer cases among children 0 to 14 years of age. Genetic conditions associated with high risk of childhood RMS include Li-Fraumeni syndrome, pleuropulmonary blastoma, Beckwith-Wiedemann syndrome, and some RASopathies, such as neurofibromatosis type 1, Costello syndrome (CS), and Noonan syndrome (NS). Here, we report the rare case of a 4-year-old girl with clinical features of NS who developed an embryonal RMS of the chest and needed emergent treatment. Molecular genetic testing identified a de novo, large, mosaic duplication of chromosome 2 encompassing the SOS1 gene, presumably caused by a mosaic, unbalanced translocation between chromosomes 2 and 17 found on routine cytogenetic analysis. Sequence analysis of all known genes causing Noonan spectrum disorders was negative. RMS has been reported in a few patients with NS, associated in very few with germline SOS1 mutations, but none with copy number abnormalities. This is the first report to our knowledge of early-onset RMS developing in a child with features of NS and a mosaic RAS pathway gene aberration, a large SOS1 duplication. We hypothesize that the inciting event for tumor development in this case is due to the germline mosaic duplication of SOS1, which was duplicated in all cells of the tumor, and the ultimate development of the tumor was further driven by multiple chromosomal aberrations in the tumor itself, all described as somatic events in isolated RMS tumors.

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Recent advances in RASopathies

Yoko Aoki1, Tetsuya Niihori1, Shin-ichi Inoue1 and Yoichi Matsubara2

  1. 1Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
  2. 2National Research Institute for Child Health and Development, Tokyo, Japan

Received 6 May 2015; Revised 9 August 2015; Accepted 24 August 2015

Advance online publication 8 October 2015

http://www.nature.com/jhg/journal/v61/n1/full/jhg2015114a.html

RASopathies or RAS/mitogen-activated protein kinase (MAPK) syndromes are a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS/MAPK signaling pathway. These disorders include neurofibromatosis type I, Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome), Costello syndrome, cardiofaciocutaneous (CFC) syndrome, Noonan-like syndrome, hereditary gingival fibromatosis and capillary malformation–arteriovenous malformation. Recently, novel gene variants, including RIT1, RRAS, RASA2, A2ML1, SOS2 and LZTR1, have been shown to be associated with RASopathies, further expanding the disease entity. Although further analysis will be needed, these findings will help to better elucidate an understanding of the pathogenesis of these disorders and will aid in the development of potential therapeutic approaches. In this review, we summarize the novel genes that have been reported to be associated with RASopathies and highlight the cardiovascular abnormalities that may arise in affected individuals.