Breaking News
October 23, 2018 - Adverse Childhood Experiences Tied to Burnout in BSN Students
October 23, 2018 - High levels of oral disease among elite athletes affecting performance
October 23, 2018 - Study examines effect of immediate vs delayed pushing during labor on delivery outcomes
October 23, 2018 - LU-RRTC to spearhead capacity-building efforts for racial and ethnic populations
October 23, 2018 - Maintenance therapy with olaparib improves progression-free survival in advanced ovarian cancer patients
October 23, 2018 - Organic food may protect against cancers finds study
October 23, 2018 - Interweaving anxiety disorder associated with stuttering remains unrecognized
October 23, 2018 - Knowledge of sex differences in lower urinary tract may help stimulate breakthroughs in diagnosis, management
October 23, 2018 - Common antibodies associated with myocardial infarction
October 23, 2018 - Study reveals new treatment option for women with advanced breast cancer resistant to hormone therapy
October 23, 2018 - Brain’s ‘Self-Control’ Center May Be Key to Weight-Loss Success
October 23, 2018 - Prosthetic valve mismatches common in transcatheter valve replacement, ups risk of death
October 23, 2018 - Can virtual reality help people become more compassionate?
October 23, 2018 - Screen time eclipsed outdoor time for most students, shows study
October 23, 2018 - SLU researcher seeks to find solutions for ‘chemo brain’ symptoms and side effects of opioids
October 23, 2018 - Plastics now commonly found in human stools
October 23, 2018 - Zoledronic acid increases disease-free survival in premenopausal women with HR+ early breast cancer
October 23, 2018 - Cancer survivors at risk for heart failure during, after pregnancy
October 23, 2018 - Stanford project brings health education videos to mothers in South Africa
October 23, 2018 - HIV-infected Hispanics at higher risk of developing HPV-related cancers, finds study
October 23, 2018 - Politicians hop aboard ‘Medicare-for-all’ train, destination unknown
October 23, 2018 - Study suggests rising childhood obesity rates as cause for serious hip disease in adolescents
October 23, 2018 - Study highlights existence of barriers to early clinical trial access for adolescents and young adults
October 23, 2018 - Protein sequencing technique could revolutionize biomedical research
October 23, 2018 - Canon Medical to showcase world’s first Ultra-High Resolution CT system at ASTRO 2018
October 23, 2018 - Spectrum Pharmaceuticals Announces Release of Updated Poziotinib Data From MD Anderson Phase 2 Study in Non-Small Cell Lung Cancer Patients
October 23, 2018 - Cancer stem cells use ‘normal’ genes in abnormal ways
October 23, 2018 - Bad Blood: A conversation with investigative reporter John Carreyrou | News Center
October 23, 2018 - As U.S. fertility rates collapse, finger-pointing and blame follow
October 23, 2018 - Researchers develop promising targeted strategy to treat chemo-resistant blood cancer
October 23, 2018 - Pilot clinical trial shows effectiveness of bioelectronic medicine device for lupus
October 23, 2018 - Genentech’s combination therapy improves outcome in patients with non-squamous non-small cell lung cancer
October 23, 2018 - 11th World Stroke Congress examines high stroke impact in low- and middle-income countries
October 22, 2018 - Breast cancer survival could be extended with two new drug combinations
October 22, 2018 - Researchers discover how acne-causing bacteria resist treatment
October 22, 2018 - Cancer trial shows treating the prostate with radiotherapy improves survival
October 22, 2018 - New hope for a drug to treat lymphedema symptoms
October 22, 2018 - Immune-Based Treatment Helps Fight Aggressive Breast Cancer, Study Finds
October 22, 2018 - Takeda announces positive Phase 3 ALTA-1L data in first-line therapy for advanced ALK+ NSCLC
October 22, 2018 - Paternal exercise has significant impact on child’s lifelong metabolic health
October 22, 2018 - Targeting specific genomic mutation in breast cancer improves survival
October 22, 2018 - Loss of tumor protein p53 helps cancer cells grow in hostile environment
October 22, 2018 - IDT to demonstrate CRISPR expertise at European-focused events
October 22, 2018 - Breathing through the nose improves memory consolidation
October 22, 2018 - Recreational Marijuana Now Legal in Canada
October 22, 2018 - Scientists reveal drumming helps schoolchildren diagnosed with autism
October 22, 2018 - A stage IV cancer patient discusses what it means to live well with serious illness
October 22, 2018 - In Kids with Autism, Short Questionnaire May Detect GI Disorders
October 22, 2018 - Innovative strategy opens up new avenue of treatment for anthrax infections
October 22, 2018 - Merck presents MK-1454 Phase 1 data for treatment of advanced solid tumors or lymphomas
October 22, 2018 - Aspirin may be effective in preventing blood clots after knee replacement
October 22, 2018 - Drug cocktail that increases lifespan discovered
October 22, 2018 - Gilead Sciences presents Phase 3 results of filgotinib in biologic-experienced rheumatoid arthritis at 2018 ACR/ARHP Annual Meeting
October 22, 2018 - Study shows potential positive impact of group prenatal care on birth outcomes
October 22, 2018 - Immunotherapy with pembrolizumab extends survival in metastatic or recurrent head and neck cancer
October 22, 2018 - Health Tip: Keep Ticks Away
October 22, 2018 - Obsessive-compulsive disorder – Genetics Home Reference
October 22, 2018 - Researchers find disrupted functional connectivity in cerebellum of adults with HF-ASD
October 22, 2018 - Deciphera presents Phase 1 clinical results of DCC-2618 in patients with gastrointestinal stromal tumors
October 22, 2018 - Combination of Opdivo and Yervoy shows four-year survival benefits in patients with advanced melanoma
October 22, 2018 - Overcoming bottlenecks in early drug discovery with the power of sound
October 22, 2018 - Scientists discover genes that contribute to ADHD development
October 22, 2018 - Incyte announces Phase 2 FIGHT-202 trial data in patients with cholangiocarcinoma
October 22, 2018 - FDA approves update to Rituxan label to include information on treatment of rare forms of vasculitis
October 22, 2018 - At-home biofeedback therapy effective in relieving difficult-to-treat constipation
October 22, 2018 - Merck presents KEYNOTE-057 trial results for patients with high-risk non-muscle invasive bladder cancer
October 22, 2018 - People with periodontal disease less likely to reach healthy blood pressure ranges
October 22, 2018 - Phase III LONSURF study shows progression-free survival in patients with refractory metastatic gastric cancer
October 22, 2018 - Primary care doctors ‘not doing enough’ to curb STDs
October 22, 2018 - Pfizer announces PALOMA-3 trial results in patients with HR+, HER2- metastatic breast cancer
October 22, 2018 - ImmunoGen announces study results of platinum-resistant ovarian cancer therapy at ESMO 2018 Congress
October 22, 2018 - Study findings could set new standard of care for advanced anal cancer
October 22, 2018 - Erlotinib improves progression-free survival in EGFR mutated NSCLC
October 22, 2018 - Pain, insomnia, and depression often drive osteoarthritis patients to seek medical care
October 22, 2018 - The International Society of Refractive Surgery honors Vivior Chairman with Casebeer Award
October 22, 2018 - Multi-strain probiotic helps reduce chemotherapy-induced diarrhea in cancer patients
October 22, 2018 - Study shows potential of avelumab plus axitinib as new treatment option for patients with advanced RCC
October 22, 2018 - Vertex gets European CHMP positive opinion for KALYDECO to treat patients with cystic fibrosis
October 22, 2018 - Phase III trial reports positive results with HDAC inhibitor in advanced breast cancer patients
October 22, 2018 - Prostate radiotherapy improves survival in men with low burden of metastatic disease
Novel approach induces cell death via dual targeting of DNA repair mechanism

Novel approach induces cell death via dual targeting of DNA repair mechanism

image_pdfDownload PDFimage_print

Proteins commonly known as BRCA – short for BReast CAncer susceptibility gene- serve a critical role in cellular DNA repair, but when mutated they allow genetic errors to replicate, facilitating cancer development. If the BRCA repair system is disabled in cancer cells, the cells simply turn to backup repair mechanisms and adapt to alternative repair pathways, a survival mode that also underlies their ability to evade targeted drug therapies.

Now, new research by scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) shows that it is possible to eliminate at least two backup repair mechanisms at the same time using two targeted therapies. The strategy effectively narrows down the number of secondary repair pathways available, helping to ensure cancer cell eradication.

The novel approach, described June 12 in a paper published in Cell Reports, is named dual synthetic lethality, so-called because cancer cell death is induced by two drugs targeting distinct DNA repair pathways at the same time. “Cancers cells have multiple ways of protecting themselves from death,” explained senior investigator Tomasz Skorski, MD, PhD, Professor of Microbiology and Immunology and Associate Professor at the Fels Institute for Cancer Research and Molecular Biology at LKSOM.

Tumor cells that carry BRCA-deficiency mutations frequently rely on DNA repair mediated by a protein known as PARP1. Clinically, PARP1 inhibition can significantly improve progression-free survival in patients with cancers involving hereditary BRCA mutations.

Over time, however, the effectiveness of PARP1 inhibition declines, and cancer relapses. According to Dr. Skorski, this happens because targeting one pathway is not enough. “The tumor cells eventually escape PARP1 inhibition by activating another backup to the BRCA-mediated repair pathway,” he said. “Our previous work had suggested that RAD52-dependent pathways are a likely escape route, which led us to see whether simultaneous inhibition of both PARP1 and RAD52 could trigger more effective lethality.”

Dr. Skorski’s team first tested their idea in a series of experiments in BRCA-deficient solid tumor and leukemia cell lines in vitro. Using an experimental RAD52 inhibitor, they were able to show that RAD52 blockade enhanced synthetic lethal effects in cells treated with the PARP inhibitor olaparib, a drug approved by the Food and Drug Administration. For all tumor types, the dual treatment completely eradicated BRCA-deficient tumor cells.

The simultaneous targeting strategy was then tested against BRCA-deficient tumors in mice, in which the researchers recapitulated the effects of BRCA deficiency in breast cancer and in acute and chronic myelogenous leukemia. They found that dual inhibition exerted strong effects against tumors in vivo, showing greater activity than either agent alone.

Importantly, the teams’ experiments showed, both in vitro and in vivo, that normal cells, with normal BRCA activity, are unaffected by the dual treatment. “Normal cells continue to use BRCA-mediated repair as their primary DNA repair pathway and do not rely heavily on PARP1 or RAD52,” explained Katherine Sullivan-Reed, a graduate student in Dr. Skorski’s research laboratory and first author on the new paper. Leaving normal cells relatively unharmed helps limit the severity of side effects patients may experience with targeted cancer therapy.

The new research provides a foundation for pursuing the development of a clinically viable drug to inhibit RAD52, as well as the development of a screening test specifically for patients who carry tumors displaying BRCA-deficiency.

In the near-term, Dr. Skorski’s team also plans to continue investigating alternative DNA repair pathways, which are essential for tumor cells but expendable in normal cells. “One of our primary goals is to find additional targets to kill cancer cells, without increasing toxicity,” he added.

Source:

https://www.templehealth.org/News/TempleScientistsEradicateCancerCellsThroughDualTargetingofDNARepairMechanisms?showBack=true

Tagged with:

About author

Related Articles