scholarly journals PARP inhibitors as precision medicine for cancer treatment

2017 ◽  
Vol 4 (4) ◽  
pp. 576-592 ◽  
Author(s):  
Yi Du ◽  
Hirohito Yamaguchi ◽  
Jennifer L. Hsu ◽  
Mien-Chie Hung
Keyword(s):  
Cancer Treatment ◽  
Precision Medicine ◽  
Underlying Mechanism ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Brca Genes ◽  
Potential Marker ◽  
Dna Double Strand Break ◽  
Future Direction ◽  
Traditional Approaches

AbstractPersonalized or precision medicine is an emerging treatment approach tailored to individuals or certain groups of patients based on their unique characteristics. These types of therapies guided by biomarkers tend to be more effective than traditional approaches, especially in cancer. The inhibitor against poly (ADP-ribose) polymerase (PARP), olaparib (Lynparza, AstraZeneca), which was approved by the US Food and Drug Administration (FDA) in 2014, demonstrated efficacy specifically for ovarian cancer patients harboring mutations in BRCA genes, which encode proteins in DNA double-strand break repairs. However, the response to PARP inhibitors has been less encouraging in other cancer types that also carry defects in the BRCA genes. Thus, furthering our understanding of the underlying mechanism of PARP inhibitors and resistance is critical to improve their efficacy. In this review, we summarize the results of preclinical studies and the clinical application of PARP inhibitors, and discuss the future direction of PARP inhibitors as a potential marker-guided personalized medicine for cancer treatment.

scholarly journals A synergistic interaction between HDAC- and PARP inhibitors in childhood tumors with chromothripsis

2021 ◽  
Author(s):  
Umar Khalid ◽  
Milena Simovic ◽  
Murat Iskar ◽  
John KL Wong ◽  
Rithu Kumar ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Synergistic Interaction ◽  
Parp Inhibition ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Double Strand Break

ABSTRACTChromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses, and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.

scholarly journals Homologous Recombination Deficiency Testing for BRCA-Like Tumors: The Road to Clinical Validation

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1004
Author(s):  
Marjolijn M. Ladan ◽  
Dik C. van Gent ◽  
Agnes Jager
Keyword(s):  
Homologous Recombination ◽  
Brca Mutation ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Clinical Validation ◽  
Brca Mutations ◽  
Homologous Recombination Deficiency ◽  
The Road ◽  
Dna Double Strand Break ◽  
The Status

Germline BRCA mutations result in homologous recombination deficiency (HRD) in hereditary breast and ovarian cancer, as well as several types of sporadic tumors. The HRD phenotype makes these tumors sensitive to DNA double strand break-inducing agents, including poly-(ADP-ribose)-polymerase (PARP) inhibitors. Interestingly, a subgroup of cancers without a BRCA mutation also shows an HRD phenotype. Various methods for selecting patients with HRD tumors beyond BRCA-mutations have been explored. These methods are mainly based on DNA sequencing or functional characteristics of the tumor. We here discuss the various tests and the status of their clinical validation.

scholarly journals Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair

2021 ◽  
Author(s):  
Gianluca Sigismondo ◽  
Lavinia Arseni ◽  
Thomas G Hofmann ◽  
Martina Seiffert ◽  
Jeroen Krijgsveld
Keyword(s):  
Genome Stability ◽  
Parp Inhibitor ◽  
Strand Break ◽  
Parp Inhibitors ◽  
High Temporal Resolution ◽  
End Joining ◽  
Post Translational Modifications ◽  
Dna Double Strand Break ◽  
Associated Proteins ◽  
Non Homologous End Joining

The DNA damage response (DDR) is essential to maintain genome stability, and its deregulation predisposes to carcinogenesis while encompassing attractive targets for cancer therapy. Chromatin governs the DDR via interplay among all chromatin layers including DNA, histones post-translational modifications (hPTMs), and chromatin-associated proteins. Here we employ multi-layered proteomics to characterize chromatin-mediated interactions of repair proteins, signatures of hPTMs, and the DNA-bound proteome during DNA double-strand break repair at high temporal resolution. We functionally attribute novel chromatin-associated proteins to repair by non-homologous end-joining or homologous recombination (HR) revealing histone reader ATAD2, microtubule organizer TPX2 and histone methyltransferase G9A as regulators of HR and PARP inhibitor sensitivity. Furthermore, we dynamically profile numerous hPTMs at γH2AX-mononucleosomes during the DDR. Integration of these complementary data implicated G9A-mediated monomethylation of H3K56 in HR. Collectively, we provide a dynamic chromatin-centered view of DDR, while representing a valuable resource for the use of PARP inhibitors in cancer.

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