OC-0377: Targeting a Novel Function for SAMHD1 in DNA Repair for Radiation Therapy and PARP Inhibition

Abstract BACKGROUND Central nervous system (CNS) tumors are the second most common childhood cancer. Despite innovations in surgery and chemo-/radiotherapy, CNS tumors remain the major cause of cancer-related death in children. Previous sequencing analyses in a pediatric cancer cohort identified BRCA and DSB repair signatures as potentially targetable events. Based on these findings, we propose the use of PARP inhibitors (PARPi) for aggressive CNS tumor subtypes, including high-grade glioma (HGG), medulloblastoma (MB) and ependymoma (EPN). METHODS We tested multiple PARPi in tumor cell lines (n=8) as well as primary patient-derived models (n=11) of pediatric HGG, MB, EPN and atypical teratoid/rhabdoid tumors (ATRTs). Based on PARPi sensitivity, selected models were further exposed to a combination of PARPi and DNA-damaging/modifying agents. The mode of action was investigated using Western blot and flow cytometry. RESULTS We show that a fraction of pediatric MB, EPN and ATRT demonstrate sensitivity towards PARP inhibition, which is paralleled by susceptibility to the DNA damaging drugs cisplatin and irinotecan. Interestingly, talazoparib, the most potent PARPi, showed synergistic cytotoxicity with DNA-damaging/modifying drugs. In addition, cell cycle blockade and increased DNA damage combined with reduced DNA repair signaling, such as activation of the ATR/Chk1 pathway were observed. Corroboratively, talazoparib exhibited a synergistic anti-cancer effect in combination with inhibitors of ATR, a major regulator of DNA damage response. CONCLUSION/OUTLOOK To sum up, we demonstrate that PARP inhibition synergizes with DNA damaging anti-cancer compounds or DNA repair inhibitors and, thus, represents a promising therapeutic strategy for a defined subgroup of pediatric high-risk CNS tumors patients. More in depth characterization of the underlying molecular events will most likely allow the identification of predictive biomarkers for most efficient implementation of this strategy into clinical application.

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Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.633344 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jessica Buck ◽

Patrick J. C. Dyer ◽

Hilary Hii ◽

Brooke Carline ◽

Mani Kuchibhotla ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Combination Therapy ◽

Cellular Response ◽

Molecular Subtype ◽

Parp Inhibitor ◽

Single Agent ◽

Parp Inhibition ◽

Preclinical Model ◽

Radiation Induced

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

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TR-04 * NANOPARTICLE siRNA DELIVERY VEHICLES INHIBIT DNA REPAIR AND SENSITIZE PEDIATRIC BRAIN TUMOR CELLS TO RADIATION THERAPY

Neuro-Oncology ◽

10.1093/neuonc/nov061.149 ◽

2015 ◽

Vol 17 (suppl 3) ◽

pp. iii37-iii37

Author(s):

F. Kievit ◽

Z. Stephen ◽

K. Wang ◽

C. Dayringer ◽

J. Silber ◽

...

Keyword(s):

Dna Repair ◽

Radiation Therapy ◽

Brain Tumor ◽

Tumor Cells ◽

Sirna Delivery ◽

Pediatric Brain Tumor ◽

Brain Tumor Cells ◽

Delivery Vehicles ◽

Pediatric Brain

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Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

Nature Communications ◽

10.1038/s41467-020-16142-7 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 6

Author(s):

Neha Chopra ◽

Holly Tovey ◽

Alex Pearson ◽

Ros Cutts ◽

Christy Toms ◽

...

Keyword(s):

Breast Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Parp Inhibition ◽

Inhibition Activity ◽

Repair Deficiency ◽

Dna Repair Deficiency

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Combining PARP inhibition, radiation, and immunotherapy: A possible strategy to improve the treatment of cancer?

International Journal of Molecular Sciences ◽

10.3390/ijms19123793 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3793 ◽

Cited By ~ 20

Author(s):

Mathieu Césaire ◽

Juliette Thariat ◽

Serge M. Candéias ◽

Dinu Stefan ◽

Yannick Saintigny ◽

...

Keyword(s):

Immune Response ◽

Radiation Therapy ◽

T Lymphocytes ◽

Ionizing Radiation ◽

Cytotoxic T Lymphocytes ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

Antitumor Immune Response ◽

Parp Inhibition

Immunotherapy has revolutionized the practice of oncology, improving survival in certain groups of patients with cancer. Immunotherapy can synergize with radiation therapy, increase locoregional control, and have abscopal effects. Combining it with other treatments, such as targeted therapies, is a promising means of improving the efficacy of immunotherapy. Because the value of immunotherapy is amplified with the expression of tumor antigens, coupling poly(ADP-ribose) polymerase (PARP) inhibitors and immunotherapy might be a promising treatment for cancer. Further, PARP inhibitors (PARPis) are being combined with radiation therapy to inhibit DNA repair functions, thus enhancing the effects of radiation; this association might interact with the antitumor immune response. Cytotoxic T lymphocytes are central to the antitumor immune response. PARP inhibitors and ionizing radiation can enhance the infiltration of cytotoxic T lymphocytes into the tumor bed, but they can also enhance PD-1/PDL-1 expression. Thus, the addition of immune checkpoint inhibitors with PARP inhibitors and/or ionizing radiation could counterbalance such immunosuppressive effects. With the present review article, we proposed to evaluate some of these associated therapies, and we explored the biological mechanisms and medical benefits of the potential combination of radiation therapy, immunotherapy, and PARP inhibitors.

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Efficacy of PARP Inhibition in Metastatic Castration-resistant Prostate Cancer is Very Different with Non-BRCA DNA Repair Alterations: Reconstructing Prespecified Endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib

European Urology ◽

10.1016/j.eururo.2020.09.024 ◽

2020 ◽

Author(s):

Konrad H. Stopsack

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Parp Inhibition ◽

Castration Resistant Prostate Cancer ◽

Phase 3 ◽

Castration Resistant

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Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

Scientific Reports ◽

10.1038/s41598-020-76975-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Daniel R. Principe ◽

Matthew Narbutis ◽

Regina Koch ◽

Ajay Rana

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Synthetic Lethality ◽

Parp Inhibitors ◽

The Cancer Genome Atlas ◽

Parp Inhibition ◽

Repair Pathway ◽

Wide Range ◽

Recombination Pathway ◽

Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

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