Breaking News
December 11, 2018 - Antioxidants may prevent cognitive impairment in diabetes
December 11, 2018 - Oral cancer prognostic signature identified
December 11, 2018 - How Can I Find Out What Caused My Miscarriage?
December 11, 2018 - Novel personalized medicine tool for assessing inherited colorectal cancer syndrome risk developed
December 11, 2018 - Study uncovers 11 new genes associated with epilepsy
December 11, 2018 - Filling research gaps could help develop more disability-inclusive workplaces
December 11, 2018 - Cartilage tissue engineering brings good news for patients with cartilage defects
December 11, 2018 - Novel 3D printing workflow helps predict leaky heart valves
December 11, 2018 - Imagination can help overcome fear and anxiety-related disorders, shows study
December 11, 2018 - Are caries linked to political regime?
December 11, 2018 - Leader in Diabetes Clinical Trials Wins Naomi Berrie Award
December 11, 2018 - Scientists discover cellular mechanism that triggers pneumonia in humans
December 11, 2018 - Increasing mental health problems related to drug use in over 55’s
December 11, 2018 - High-intensity interval exercise could help combat cognitive dysfunction in obese people
December 11, 2018 - Annual flu shot can save lives of heart failure patients
December 11, 2018 - Researchers compare health outcomes for VA and non-VA hospitals
December 11, 2018 - Recommendations Developed for Psoriatic Arthritis Treatment
December 11, 2018 - Genetic analysis links obesity with diabetes, coronary artery disease
December 11, 2018 - Study shows that having genetic information can affect how the body responds
December 11, 2018 - UNAIDS Report: 9 Million Are Likely HIV Positive And Don't Know It
December 11, 2018 - Lund University researchers succeed in obtaining dendritic cells by direct reprogramming
December 11, 2018 - Breast tumors recruit bone marrow cells to boost their growth, study reveals
December 11, 2018 - Updated breast cancer screening guideline highlights importance of shared decision-making
December 11, 2018 - EHR-related stress associated with physician burnout
December 11, 2018 - AHA: 12-Year-Old Heart Defect Survivor Inspires NFL Player’s Foundation
December 11, 2018 - Breast cancer patients who take heart drug with trastuzumab have less heart damage
December 11, 2018 - Providing aid to those humans – and animals – affected by the California fires
December 11, 2018 - Even without proof, CBD is finding a niche as a cure-all
December 11, 2018 - Drawing leads to better memory than writing
December 11, 2018 - Researchers report novel findings on plant hormone
December 10, 2018 - A Tale of Two Labels
December 10, 2018 - Triple combination cancer immunotherapy improves outcomes in preclinical melanoma model
December 10, 2018 - A 14-year-old explains what it’s like to get a new heart
December 10, 2018 - Team Players Honored with 2018 Baton Awards
December 10, 2018 - Global report highlights how the changing world is affecting children’s physical activity levels
December 10, 2018 - Genes play a role in physical activity and sleep
December 10, 2018 - DDT in Alaskan fish shown to increase risk of cancer
December 10, 2018 - Laws to curb use of cell phones have greatly reduced fatalities for motorcyclists
December 10, 2018 - Argenx Provides Detailed Data from Phase 2 Clinical Trial of Efgartigimod in Immune Thrombocytopenia and Phase 1/2 Clinical Trial of Cusatuzumab in Acute Myeloid Leukemia
December 10, 2018 - University of Maryland doctors treat first breast cancer patients with GammaPod radiotherapy
December 10, 2018 - The heartbeat seat: Demoing new well-being technologies in a car
December 10, 2018 - Leading Cancer Researcher to Direct Herbert Irving Comprehensive Cancer Center
December 10, 2018 - Researchers explore how glial cells develop in the brain from neural precursor cells
December 10, 2018 - Study compares pain-related diagnoses in First Nations and non-First Nations children, youth
December 10, 2018 - Experts address sleep disorders following traumatic brain injury
December 10, 2018 - Scientists find answers to how cancer spreads
December 10, 2018 - Study explores why older people read more slowly
December 10, 2018 - Smart life-collar could save lives of young children
December 10, 2018 - Asbestos found in most NHS hospitals finds BBC inquiry
December 10, 2018 - Researchers use new technique to probe hydrogen bonds
December 10, 2018 - Music improves social communication in autistic children
December 10, 2018 - Some Brain Tumors May Respond to Immunotherapy, New Study Suggests
December 10, 2018 - Banning junk food ads to combat childhood obesity
December 10, 2018 - Skin Autofluorescence Predicts T2DM, Heart Disease, Mortality
December 10, 2018 - Largest autism sequencing study to date yields 102 genes associated with ASD
December 10, 2018 - Statins associated with low risk of side effects
December 10, 2018 - Episodic memory tests help in predicting brain atrophy and Alzheimer’s disease
December 10, 2018 - Study explores how schools address adolescent self-harming practices
December 10, 2018 - Pregnancy in adolescence linked to increased risks of complications in young mothers
December 10, 2018 - Risk Analysis publishes special issue on communicating about Zika virus
December 10, 2018 - Botox May Help Prevent Post-Op A-Fib
December 10, 2018 - African-American mothers rate boys higher for ADHD
December 10, 2018 - Graphic warning labels cancel out cigarettes’ appeal to young people
December 10, 2018 - Australian researchers to study gas inhalational anaesthetic and likelihood of cancer return
December 10, 2018 - Individual neurons located within the brain have implications for psychiatric diseases
December 10, 2018 - Researchers improve bariatric surgery scoring system to extend prediction time for diabetic remission
December 10, 2018 - HPV type 16 or 18 associated with cervical cancer risk in young women
December 10, 2018 - Cervical cancer risk is higher in women with positive HPV, but no cellular abnormalities
December 10, 2018 - Combo therapy not needed if low RA disease activity achieved
December 10, 2018 - Novel therapeutic targets based on biology of aging show promise for Alzheimer’s disease
December 10, 2018 - UC San Diego professor receives NCI Outstanding Investigator Award for cancer research
December 10, 2018 - Study evaluates placental mesenchymal stem cell sheets for myocardial repair and regeneration
December 10, 2018 - Blueprint Medicines Announces Updated Results from Ongoing EXPLORER Clinical Trial of Avapritinib Demonstrating Broad Clinical Activity and Significant Symptom Reductions in Patients with Systemic Mastocytosis
December 10, 2018 - Study clarifies ApoE4’s role in dementia
December 10, 2018 - Eating disorders now a top priority with Australian Government
December 10, 2018 - Neuronal activity in the brain allows prediction of risky or safe decisions
December 10, 2018 - FDA Alerts Health Care Professionals and Patients Not to Use Drug Products Intended to be Sterile from Promise Pharmacy
December 10, 2018 - Improving dementia care and treatment saves thousands of pounds in care homes
December 10, 2018 - Heroin-assisted treatment can offer benefits, reduce harms
December 10, 2018 - People covered by Michigan’s expanded Medicaid program report improvements in health, finds study
Researchers suggest new treatment for rare inherited cancers

Researchers suggest new treatment for rare inherited cancers

image_pdfDownload PDFimage_print
Credit: CC0 Public Domain

Studying two rare inherited cancer syndromes, Yale Cancer Center (YCC) scientists have found the cancers are driven by a breakdown in how cells repair their DNA. The discovery, published today in Nature Genetics, suggests a promising strategy for treatment with drugs recently approved for other forms of cancer, said the researchers.

The two conditions—called Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Succinate Dehydrogenase-related Hereditary Paraganglioma and Pheochromocytoma (SDH PGL/PCC)—boost the risk of tumors that may be benign or cancerous. Oncologists aim to remove tumors by surgery, but treatments are largely ineffective if the tumors have become metastatic.

In both inherited cancer syndromes, cells produce abnormally high amounts of metabolites, which are part of the biochemical process that the body uses to turn carbohydrates, fats, and proteins into energy. This is due to inherited defects in the genes that encode for enzymes that normally process these metabolites. The Yale investigators discovered that these high levels of metabolites can degrade a process known as homologous recombination, by which cells mend DNA damage that occurs when they divide.

“Our finding identifies an Achilles heel for these tumors, which potentially can be treated using a new type of medication, called a PARP inhibitor,” said Peter Glazer, M.D., Ph.D., chair of the Department of Therapeutic Radiology at YCC, and co-corresponding author on the study.

PARP (poly ADP-ribose polymerase) inhibitors are designed to kill off cancer cells that already have lost some of their ability to repair their DNA via homologous recombination. The inhibitors aim to wipe out DNA repair completely, thus killing the cell. The Food and Drug Administration has approved three such drugs to treat breast, ovarian, and other types of cancers with mutations in BRCA genes that disrupt homologous recombination.

Scientists have struggled to find which clues, aside from BRCA status, can predict exactly which patients will benefit from the drugs. “Our research is identifying additional biomarkers for tumors that are sensitive to PARP inhibitors, which will be helpful to the field,” said Parker Sulkowski, a graduate student in Glazer’s lab and lead author on the paper.

Analysis of these sample tumors indicated defects in DNA repair. The investigators then performed experiments in multiple kinds of human cells that model the two inherited syndromes. These studies demonstrated that the two metabolites could suppress the homologous recombination pathway and leave the cells sensitive to PARP inhibitors.

Next, the investigators modeled the disease in a series of experiments in “xenografts,” in which human tumor cells were implanted within mice. As with the cell experiments, treatments with a PARP inhibitor consistently and significantly slowed tumor growth in the mice.

Given the strength of these pre-clinical findings, co-corresponding authors Brian Shuch, M.D., and Ranjit Bindra, M.D., plan to test PARP inhibitors in clinical trials for these inherited cancer syndromes. Meanwhile, Glazer’s lab will continue to probe the underlying biology of the syndromes, seeking a more detailed understanding of how the metabolites suppress DNA repair. The scientists also hope to shed light on related abnormalities in metabolism that might make other cancer indications vulnerable to PARP inhibitors or eventually to other targeted DNA repair inhibitors.

“Our finding of this unexpected link between metabolism and DNA repair in these cancers is opening up a whole area of research,” Glazer said, “and it gives another example of the importance of DNA repair in cancer formation and cancer therapy.”


Explore further:
Murine study finds potential boost for ovarian cancer drug Olaparib

More information:
Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair, Nature Genetics (2018). DOI: 10.1038/s41588-018-0170-4 , https://www.nature.com/articles/s41588-018-0170-4

Journal reference:
Nature Genetics

Provided by:
Yale University

Tagged with:

About author

Related Articles