We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
LGC Clinical Diagnostics

Download Mobile App




Anticancer Duo Kills Tumors While Preventing Relapse

By LabMedica International staff writers
Posted on 28 Jun 2018
Print article
Image: A mixed surface–ribbon representation of the catalytic domain of human poly (ADP-ribose) polymerase 1 (PARP1) binding the small-molecule inhibitor olaparib (shown as a space-filling model) (Photo courtesy of Wikimedia Commons).
Image: A mixed surface–ribbon representation of the catalytic domain of human poly (ADP-ribose) polymerase 1 (PARP1) binding the small-molecule inhibitor olaparib (shown as a space-filling model) (Photo courtesy of Wikimedia Commons).
A suggested new therapeutic approach for killing tumor cells simultaneously blocks both the PARP and RAD52 DNA repair pathways.

Previous studies have shown that BRCA (BReast CAncer susceptibility gene) deficient breast carcinoma cells and leukemia cells could not be completely eradicated by inhibitors of the enzyme Poly (ADP-ribose) polymerase (PARP). The main role of PARP is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signaling the enzymatic machinery involved in the SSB repair.

The ability of cancer cells to recover from treatment with PARP inhibitors (PARPis) indicates that more robust and rapid elimination of BRCA-deficient tumor cells is required to prevent time-dependent emergence of PARPi-resistant or refractory clones.

Investigators at Temple University (Philadelphia, PA, USA) hypothesized that RAD52-mediated DNA repair remained active in PARPi-treated BRCA-deficient tumor cells, and that targeting RAD52 should enhance the synthetic lethal effect of PARPi.

In studies described in the June 12, 2018, issue in the journal Cell Reports, cancer cells were treated with the drug olaparib. Initially this drug acts as a PARP inhibitor. BRCA1/2 mutations may be genetically predisposed to development of some forms of cancer, and may be resistant to other forms of cancer treatment. However, these cancers sometimes have a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs that selectively inhibit PARP may be of benefit if the cancers are susceptible to this treatment. However, over time cancer cells turn to backup repair mechanisms and adapt to alternative repair pathways, a survival mode that also underlies their ability to evade targeted drug therapies.

The investigators reported that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells. PARPi+RAD52i exerted synergistic activity against BRCA1-deficient tumors in immunodeficient mice with minimal toxicity to normal cells and tissues.

While the PARP inhibitor olaparib has been approved by the [U.S.] Food and Drug Administration for clinical use, no RAD52 inhibitors have yet been approved.

“Cancers cells have multiple ways of protecting themselves from death,” said senior author Dr. Tomasz Skorski, professor of microbiology and immunology at Temple University. “The tumor cells eventually escape PARP1 inhibition by activating another backup to the BRCA-mediated repair pathway. 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.”

Related Links:
Temple University

Platinum Member
COVID-19 Rapid Test
OSOM COVID-19 Antigen Rapid Test
One Step HbA1c Measuring System
GREENCARE A1c
POCT Fluorescent Immunoassay Analyzer
FIA Go
Gold Member
ADAMTS-13 Protease Activity Test
ATS-13 Activity Assay

Print article

Channels

Clinical Chemistry

view channel
Image: Reaching speeds up to 6,000 RPM, this centrifuge forms the basis for a new type of inexpensive, POC biomedical test (Photo courtesy of Duke University)

POC Biomedical Test Spins Water Droplet Using Sound Waves for Cancer Detection

Exosomes, tiny cellular bioparticles carrying a specific set of proteins, lipids, and genetic materials, play a crucial role in cell communication and hold promise for non-invasive diagnostics.... Read more

Molecular Diagnostics

view channel
Image: MOF materials efficiently enrich cfDNA and cfRNA in blood through simple operational process (Photo courtesy of Science China Press)

Blood Circulating Nucleic Acid Enrichment Technique Enables Non-Invasive Liver Cancer Diagnosis

The ability to diagnose diseases early can significantly enhance the effectiveness of clinical treatments and improve survival rates. One promising approach for non-invasive early diagnosis is the use... Read more

Hematology

view channel
Image: The low-cost portable device rapidly identifies chemotherapy patients at risk of sepsis (Photo courtesy of 52North Health)

POC Finger-Prick Blood Test Determines Risk of Neutropenic Sepsis in Patients Undergoing Chemotherapy

Neutropenia, a decrease in neutrophils (a type of white blood cell crucial for fighting infections), is a frequent side effect of certain cancer treatments. This condition elevates the risk of infections,... Read more

Pathology

view channel
Image: The OvaCis Rapid Test discriminates benign from malignant epithelial ovarian cysts (Photo courtesy of INEX)

Intra-Operative POC Device Distinguishes Between Benign and Malignant Ovarian Cysts within 15 Minutes

Ovarian cysts represent a significant health issue for women globally, with up to 10% experiencing this condition at some point in their lives. These cysts form when fluid collects within a thin membrane... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.