Publications by authors named "L A Parsels"
PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)-mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy.
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- Radiotherapy is the main treatment for a deadly type of brain cancer in kids called diffuse midline glioma (DMG), which has a special genetic mutation (H3K27M).
- Researchers found that this mutation makes the tumors weaker against radiation when combined with a medicine called PARP inhibitor (like olaparib), which can help fight the cancer.
- The study showed that using PARP inhibitors with radiotherapy also boosts the immune system, allowing it to attack the cancer cells better, which could be an important new treatment for kids with DMG.
Article Synopsis
- Radiotherapy can trigger a type I interferon-mediated immune response, which may be strengthened by a new ATM inhibitor, enhancing the body's antitumoral efforts against pancreatic cancer.
- Experiments with the ATM inhibitors AZD1390 and AZD0156 revealed that they boost radiation-induced type I interferon expression through specific immune signaling pathways.
- In mouse models, the combination of ATM inhibitors and radiotherapy improved immune responses, leading to better tumor control, increased CD8+ T cell activity, and the potential for effective systemic treatments against other tumors outside the radiation zone.
Diffuse intrinsic pontine glioma (DIPG) is a rare but highly lethal pediatric and adolescent tumor located in the pons of the brainstem. DIPGs harbor unique and specific pathological and molecular alterations, such as the hallmark lysine 27-to-methionine (H3K27M) mutation in histone H3, which lead to global changes in the epigenetic landscape and drive tumorigenesis. While fractionated radiotherapy, the current standard of care, improves symptoms and delays tumor progression, DIPGs inevitably recur, and despite extensive efforts chemotherapy-driven radiosensitization strategies have failed to improve survival.
View Article and Find Full Text PDFUnlabelled: Targeting the DNA damage response in combination with radiation enhances type I interferon (T1IFN)-driven innate immune signaling. It is not understood, however, whether DNA-dependent protein kinase (DNA-PK), the kinase critical for repairing the majority of radiation-induced DNA double-strand breaks in cancer cells, is immunomodulatory. We show that combining radiation with DNA-PK inhibition increases cytosolic double-stranded DNA and tumoral T1IFN signaling in a cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-independent, but an RNA polymerase III (POL III), retinoic acid-inducible gene I (RIG-I), and antiviral-signaling protein (MAVS)-dependent manner.
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