PARP Inhibitor

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PARP Inhibitor In healthy cells, DNA damage occurs and is repaired by Cancer cells also experience proteins, such as poly ADP-ribose polymerase (PARP), damage to their DNA, just like so the cell can continue to function. This damage can be healthy cells, and use proteins spontaneous or the result of environmental factors like such as PARP to repair the radiation or some chemicals.i damaged DNA.ii Mechanism of Action* Single Strand Break (SSB) SSB converts to Double Strand Break (DSB) PARP recruited; PARylation initiation PARP Ribosylation inhibition PARP1 PARP1 PARP1 Replication fork collapses HRD tumors (may be BRCAmut or BRCAwt) PARP inhibition Accumulation of DNA damage Accumulation of DNA damage Cell Cell Death Death DSB: Double strand break HRD: Homologous recombination deﬁciency Platinum causes DSB PARP: Poly ADP-ribose polymerase P PR: Partial response SSB: Single strand break PARP Replication forks collapse at additional inhibition sites of damage PARP inhibitors block the PARP protein. That means the damaged DNA can’t be PARP1 repaired in the cancer cell, so PARP1 the DNA accumulates more and more damage, turning PARP inhibition from single-strand breaks to causes more DSBs double strand breaks. This accumulation can lead to the death of the cancer cell.ii Cell Accumulation of DNA damage Death *As understood through pre-clinical evidence. References i Davar D, Beumer JH, Hamieh L, Tawbi H. Role of PARP inhibitors in cancer biology and therapy. Curr Med Chem. 2012;19(23):3907-3921. ii Jubin T, Kadam A, Jariwala M, et al. The PARP family: insights into functional aspects of poly(ADP-ribose) polymerase-1 in cell growth and survival. Cell Prolif. 2016;49(4):421-437. NP-GBL-NRP-OGM-200001 / March 2020.

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The Role of PARP1 in Monocyte and Macrophage
cells Review The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors Maciej Sobczak 1, Marharyta Zyma 2 and Agnieszka Robaszkiewicz 1,* 1 Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] 2 Department of Immunopathology, Medical University of Lodz, 7/9 Zeligowskiego, Bldg 2, Rm177, 90-752 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-6354449; Fax: +48-42-6354449 or +48-42-635-4473 Received: 4 August 2020; Accepted: 4 September 2020; Published: 6 September 2020 Abstract: Modulation of PARP1 expression, changes in its enzymatic activity, post-translational modifications, and inflammasome-dependent cleavage play an important role in the development of monocytes and numerous subtypes of highly specialized macrophages. Transcription of PARP1 is governed by the proliferation status of cells at each step of their development. Higher abundance of PARP1 in embryonic stem cells and in hematopoietic precursors supports their self-renewal and pluri-/multipotency, whereas a low level of the enzyme in monocytes determines the pattern of surface receptors and signal transducers that are functionally linked to the NFκB pathway. In macrophages, the involvement of PARP1 in regulation of transcription, signaling, inflammasome activity, metabolism, and redox balance supports macrophage polarization towards the pro-inflammatory phenotype (M1), which drives host defense against pathogens. On the other hand, it seems to limit the development of a variety of subsets of anti-inflammatory myeloid effectors (M2), which help to remove tissue debris and achieve healing.
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POTENTIAL CONFLICT OF INTEREST DISCLOSURES • Financial Relationships – SAB/Consultant: AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Medimmune, Nuevolution, Pfizer, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, Tarveda, – Stock/ Options/Financial: Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, Tarveda – Licensed Technology HRD assay to Myriad Genetics – Sponsored Research: Abbvie, Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Critical Outcomes Technology, Illumina, Ionis, Immunomet, Karus Therapeutics, Komen Research Foundation, Pfizer, Nanostring, Takeda/Millennium Pharmaceuticals, Tesaro I will discuss off label use and/or investigational use of drugs Dual mechanisms of action of PARPi Replication Fork Collapse PARP inhibitors Double strand breaks ADP ribosylation required for PARP to leave DNA Trapped PARP creates “toxic” double strand breaks Can PARP activity be extended beyond HRD PARP inhibitor responses are transient Ariel 2 Rucaparib Ian McNeish Lancet: LOH high is HRD assay performed by Foundation Med HRD BRCA mutant No detectable aberration Conclusion: Germline BRCA1/2 is strongest predictor of benefit HRD positivity identifies an additional population with significant benefit A population of patients without HRD show modest benefit Categorizing Predictive Biomarkers of Response for PARP inhibitors PARPness Deleterious gene variants or RNA/protein expression differences (e.g. SLFN11, E- Cadherin) not directly related to HRR deficiency that still engender PARP sensitivity. HRDness Increased genomic instability and reliance on error-prone DDR Loss of HRR efficiency Deleterious variants or post-translational loss of non-BRCA DDR genes (e.g. ATM), or select non-DDR genes (e.g. ARID1A); Hypoxia; Oncometabolites (e.g. 2-hydroxyglutarate). BRCAness Molecular phenocopy of tumors with BRCA1/2 deleterious mutations.
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