Author Interviews, Cancer Research, Genetic Research, Personalized Medicine, Technology / 06.01.2016
canSAR Database Analysis Speeds Identification of New Cancer Targets
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Dr. Bissan Al-Lazikini[/caption]
MedicalResearch.com Interview with:
Dr Bissan Al-Lazikani
Team leader in computational biology
The Institute of Cancer Research
London
Medical Research: What is the background for the canSAR database? What are the main uses for the tool?
Dr. Al-Lazikani: Drug discovery is a difficult, time consuming and expensive venture that frequently ends in late stage drug failures - especially in oncology.
As with any complex venture, decisions throughout the drug discovery pipeline can be empowered by having access to the right information at the right time. But for drug discovery this means bringing together billions of experimental data from very diverse areas of science spanning genomics, proteomics, chemistry and more.
We developed canSAR to help guide our own drug discovery efforts by integrating these huge, diverse data and by analysing the data and deriving hidden links and knowledge from them. This means that we can answer questions in minutes that would have taken weeks using previously available public resources. But, more importantly, canSAR analyses and links these data in a way that allows us to derive knowledge that was hidden before. For example, one of the main ways canSAR is used is to help select the best druggable targets for drug discovery. Using canSAR we were able to uncover many druggable cancer proteins that were previously overlooked, and we are delighted to see that several of these proteins are now the subjects of drug discovery and development projects both by us and by others.
We took the decision to make canSAR publicly and freely available because we believe that cancer drug discovery is a vast challenge that requires openness and data sharing worldwide. It has been embraced by the community is being used by tens of thousands of cancer scientists worldwide, both in academia and industry, to generate hypotheses for experiments and select targets for drug discovery.
Dr. Bissan Al-Lazikini[/caption]
MedicalResearch.com Interview with:
Dr Bissan Al-Lazikani
Team leader in computational biology
The Institute of Cancer Research
London
Medical Research: What is the background for the canSAR database? What are the main uses for the tool?
Dr. Al-Lazikani: Drug discovery is a difficult, time consuming and expensive venture that frequently ends in late stage drug failures - especially in oncology.
As with any complex venture, decisions throughout the drug discovery pipeline can be empowered by having access to the right information at the right time. But for drug discovery this means bringing together billions of experimental data from very diverse areas of science spanning genomics, proteomics, chemistry and more.
We developed canSAR to help guide our own drug discovery efforts by integrating these huge, diverse data and by analysing the data and deriving hidden links and knowledge from them. This means that we can answer questions in minutes that would have taken weeks using previously available public resources. But, more importantly, canSAR analyses and links these data in a way that allows us to derive knowledge that was hidden before. For example, one of the main ways canSAR is used is to help select the best druggable targets for drug discovery. Using canSAR we were able to uncover many druggable cancer proteins that were previously overlooked, and we are delighted to see that several of these proteins are now the subjects of drug discovery and development projects both by us and by others.
We took the decision to make canSAR publicly and freely available because we believe that cancer drug discovery is a vast challenge that requires openness and data sharing worldwide. It has been embraced by the community is being used by tens of thousands of cancer scientists worldwide, both in academia and industry, to generate hypotheses for experiments and select targets for drug discovery.
Dr. Schmidt[/caption]
MedicalResearch.com Interview with:
Dr. Marjanka Schmidt PhD
Group Leader, Molecular Pathology
Netherlands Cancer Institute
Medical Research: What is the background for this study? What are the main findings?
Dr. Schmidt: BRCA1/2 mutation carriers who developed a primary breast cancer are thought to be at high risk to develop a contralateral breast cancer (breast cancer in the opposite breast). Our study is one of the first to provide unbiased risk estimates for young breast cancer patients with a pathogenic BRCA1/2 mutation. We also showed that age of onset of the first breast cancer is a predictor for the development of contralateral breast cancer in BRCA1/2 mutation carriers, but not in non-carriers.
Dr. Li Ding[/caption]
MedicalResearch.com Interview with:
Dr. Li Ding PhD
Director, Medical Genomics group
McDonnell Genome Institute
Department of Medicine
Washington University in St. Louis
St. Louis, Missouri
Medical Research: What is the background for this study? What are the main findings?
Dr. Li Ding: Next-generation sequencing technologies have provided unprecedented opportunities for building a comprehensive catalog of point mutations, simple insertion and deletion mutations (indels) and structural variants in human cancers. Although significant progress has been made for documenting these common events through studies from individual research labs and large consortiums, there has been little progress in the discovery of complex indels after the transition from Sanger sequencing to NGS technologies. It is well known in the scientific community that indel detection using short next generation sequencing reads is a challenging problem. Our study, for the first time, directly addresses complex indel detection that has been barely touched in the cancer field. More importantly, our analysis discovered 285 complex indels in cancer genes such as PIK3R1, GATA3, and TP53, revealing an unexpected high prevalence of these events in human cancers.
Dr. Camron Bryant[/caption]
MedicalResearch.com Interview with:
Camron D. Bryant, Ph.D.
Assistant Professor
Laboratory of Addiction Genetics
Department of Pharmacology and Experimental Therapeutics & Psychiatry
Boston University School of Medicine
Boston, MA 02118
Medical Research: What is the background for this study? What are the main findings?
Dr. Bryant: The addictions, including addiction to psychostimulants such as methamphetamine and cocaine, are heritable neuropsychiatric disorders. However, the genetic factors underlying these disorders are almost completely unknown. We used an unbiased, discovery-based genetic approach to fine map a novel candidate genetic factor influencing the acute stimulant response to methamphetamine in mice. We then directly validated the causal genetic factor using a gene editing approach. The gene - Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) - codes for an RNA binding protein that is involved in alternative splicing of hundreds of genes in the brain. Based on a genome-wide transcriptome analysis of differentially expressed genes within the striatum - a crucial brain region involved in the stimulant properties of amphetamines - we predict that Hnrnph1 is essential for proper neural development of the dopamine circuitry in the brain. These findings could have implications for understanding not only the addictions but also other neuropsychiatric disordersthat involve perturbations in the dopaminergic circuitry. (e.g., ADHD and schizophrenia) as well as neurodegenerative disorders such as Parkinson's disease.
Dr. Susana Puig[/caption]
MedicalResearch.com Interview with:
Susana Puig MD PhD
Chief Dermatology Service
Research Director
"Melanoma: Imaging, genetics and immunology" at IDIBAPS
Consultant & Assistant Professor
Melanoma Unit, Dermatology Department
Hospital Clinic, University of Barcelona
Barcelona Spain
Medical Research: What is the background for this study? What are the main findings?
Dr. Puig: CDKN2A is the main high-penetrance melanoma susceptibility gene. A rare functional variant in MITF, p.E318K (rs149617956), has been identified as a moderate risk allele in melanoma susceptibility and also predisposes to renal cell carcinoma.
In this study MITF p.E318K was associated with an increased melanoma risk (OR=3.3, p<0.01), especially in patients with multiple primary melanoma (OR=4.5, p<0.01) and high nevi count (>200 nevi) (OR=8.4, p<0.01). Interestingly, two fast growing melanomas were detected among two MITF p.E318K carriers during dermatologic digital follow-up. Furthermore, we have detected a similar prevalence of MITF p.E318K in CDKN2A wild-type and mutated individuals.
Dr. Jane Churpek[/caption]
MedicalResearch.com Interview with:
Dr. Jane E. Churpek, MD
Assistant Professor of Medicine
Co-Director, Comprehensive Cancer Risk and Prevention Program
The University of Chicago Medicine
Chicago, IL 6063
Medical Research: What is the background for this study? What are the main findings?
Dr. Churpek: We designed this study to try to understand whether damaging, inherited changes in genes known to cause an increased risk of breast cancer are common in those who develop leukemia after getting chemotherapy and/or radiation for treatment of breast cancer.
Leukemias that occur in this setting are called “therapy-related.” This means that chemotherapy or radiation, or both, may have been involved in causing the leukemia. This is an uncommon but serious complication of cancer treatment, and the factors that put women at risk for this complication are not well understood.
We looked at the clinical histories of 88 such women. We found that most of them have relatives who also had cancer, suggesting they may be cancer-prone to begin with. Because we did not have a group of women who had similar breast cancer treatment and who did not get a therapy-related leukemia, we cannot definitively prove that more women with therapy-related leukemia than expected had these mutations. However, this study gives us reason to further study the role of these genes in therapy-related leukemia.
Dr. Ida Donkin[/caption]
MedicalResearch.com Interview with:
Ida Donkin MD, PhD
Postdoc, Medical Doctor, PhD
University of Copenhagen
Faculty Of Health Sciences
Copenhagen, Denmark
Medical Research: What is the background for this study?
Dr. Donkin: We know that children of obese fathers are more prone to develop obesity themselves – regardless of the weight of the mother. We also know that obesity and diabetes are diseases with a very big inheritable components in their aetiology. If your parents are obese, you have a risk of about 75% percent of developing obesity yourself. But we do not know how the disease is inherited from one generation to the next. Despite exhaustive research trying to investigate genes potentially responsible for this, and more than 125 genetic mutations have been discovered to associate to the development of obesity, all the genetic mutations put together cannot explain more than about 10% of the actual inheritance. So how is obesity inherited from parents to children? One explanation could be the transfer of epigenetic information from one generation to the next. Epigenetic information is established in our body’s cells in response to our lifestyle and the environment around us. We discovered that the epigenetic factors of semen cells also responds to changes in our lifestyle, and we speculated whether these might be the key to understand how obesity in dads can lead to obesity in children.
Medical Research: What are the main findings?
Dr. Donkin: In this study we discovered that the information kept in our semen cells responds dynamically to changes in our lifestyle. If you are obese, your semen cells will contain a different epigenetic pattern than if you are lean. Weight loss induced by gastric bypass surgery will dynamically change these epigenetic patterns, meaning that by changing our lifestyle, we can actively change the epigenetic information we pass on to our children. Other research groups have created solid evidence showing us that most these epigenetic marks kept in the 
Dr. Kaltman[/caption]
MedicalResearch.com Interview with:
Jonathan Kaltman, MD
Chief, Heart Development and Structural Diseases Branch
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
Medical Research: What are the main findings?
Dr. Kaltman: Congenital heart disease (CHD) is the most common birth defect but the cause for most defects is unknown. Surgery and clinical care of patients with congenital heart disease has improved survival but now we are learning that many patients have neurodevelopmental abnormalities, including learning disability and attention/behavioral issues.
Medical Research: What are the main findings?
Dr. Azim[/caption]
MedicalResearch.com Interview with:
Hatem A. Azim MD PhD
Breast Cancer Translational Research Laboratory
Institut Jules Bordet
Université Libre de Bruxelles
Brussels, Belgium
Medical Research: What is the background for this study? What are the main findings?
Dr. Azim: As at breast cancer diagnosis is known to impact prognosis, with young patients having worse outcome. On the other hand, elderly patients are less studies in general and little is known on their tumor characteristics.
In this study, we aimed to define the pattern of genomic aberrations in different age groups. This can result in identifying if key potentially targetable genomic alterations are more specific to particular age groups and thus could open the door to design particular studies targeting these aberrations in these age groups. We found that age is associated with unique biological features at the DNA level, independent of tumor stage, histology and breast cancer molecular subtype.
Of particular mention, the higher prevalence of GATA3 mutation in younger patient, a known driver mutation associated with endocrine resistance. In addition, age at diagnosis appears to impact the tumor transcriptome confirming previous observations, but also highlighting novel findings, of particular relevance the higher expression of stem cell related genes in young patients.
Dr. Schulert[/caption]
MedicalResearch.com Interview
Grant S Schulert MD, PhD
Clinical Fellow, Division of Rheumatology
Cincinnati Childrens Hospital
Medical Research: What is the background for this study? What are the main findings?
Dr. Schulert: Influenza infection causes millions of illnesses annually, but most of those are relatively mild. In a subset of cases, patients can become critically ill, even if they are relatively young and healthy. Several previous reports had observed in these critically ill patients features of a hyperinflammatory syndrome known as HLH (hemophagocytic lymphohistiocytosis) or MAS (macrophage activation syndrome). This hyperinflammation can be triggered by other infections as well as in a subtype of juvenile arthritis, but there is also a familial form occurring in early childhood with known genetic causes. Our questions with this study were
1) how often are features consistent with HLH/MAS seen in fatal H1N1 influenza infections and
2) do patients with fatal H1N1 infection have genetic mutations associated with HLH/MAS?
Our collaborator Paul Harms, MD, and his team at the Michigan Center for Translational Pathology, University of Michigan Medical School identified 16 cases of fatal H1N1 influenza infection. Based on their clinical features, between 41-88% of these patients could be categorized as having a hyperinflammatory HLH/MAS. We then used processed tissue samples from the patients for whole exome genetic sequencing, which reads the entire genetic code of every gene in a person. Five patients carried mutations in genes which cause HLH, and several others carried mutations in genes linked to MAS. This suggests that there may be genetic risk factors for developing fatal hyperinflammatory syndromes in H1N1 infection.
Dr. Biglan[/caption]
MedicalResearch.com Interview with:
Kevin M. Biglan, M.D., M.P.H
Professor of Neurology and the Associate Chair for Clinical Research
Department of Neurology and the Center for Human Experimental Therapeutics
University of Rochester School of Medicine and Dentistry
Rochester, New York
Medical Research: What is the background for this study? What are the main findings?
Dr. Biglan: A therapeutic goal of research in Huntington Disease (HD) is the identification of treatments that delay the progression of disease and onset of illness in individuals at risk for developing manifest HD. Designing such efficacy trials is challenging. A major hurdle is the lack of practical primary outcome measures to assess the effect of an intervention on delaying disease onset. Use of the dichotomous endpoint of clinical diagnosis as the primary outcome requires large sample sizes and long duration of follow up in order to show a significant therapeutic effect on delaying disease onset. Continuous measures that can reliably distinguish cytosine-adenine-guanine (CAG) expanded individuals in the pre-manifest period may allow for the identification of potential disease modifying therapies using relatively smaller cohorts followed for shorter periods of time.
The Prospective Huntington At-Risk Observational Study (PHAROS) represents the largest observational study to clinically evaluate pre-manifest Huntington Disease wherein both research participants and investigators were unaware of 
Dr. Klempner[/caption]
MedicalResearch.com Interview with:
Samuel Klempner, M.D. Assistant Professor
Division of Hematology/Oncology
UC Irvine Health
Orange, CA 92868
Medical Research: What is the background for this study? What are the main findings?
Dr. Klempner: The background for our series is the concept that little is known about the genetic landscape of rare tumors such as acinic cell tumors, and that understanding genetic changes in tumors can identify treatment options. This paradigm can, and should, be extended beyond rare tumor types and many researchers are currently studying various tumor types. Another important background idea is that tumor genomic alterations may be more important than that anatomic site of origin. For example, I would argue that a breast cancer that harbors an 
Dr. Vonberg[/caption]
MedicalResearch.com Interview with:
Frederick W. Vonberg, MA, MBBS
Research Fellow in Neurocritical Care
Boston Children's Hospital and Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Response: An association between schizophrenia and epilepsy has long been suspected, ever since people noticed similarities in some aspects of the presentation of the two conditions, and in their epidemiology. For example, people with epilepsy are thought to be more at risk of developing schizophrenia. Furthermore, a psychosis resembling schizophrenia can characterize some forms of 
