olaparib/LYNPARZA / P53 Cancer Research Results

OL, olaparib/LYNPARZA: Click to Expand ⟱
Features: PARP inhibitor

Olaparib

Olaparib (brand name Lynparza; developmental name AZD2281) is an orally active poly(ADP-ribose) polymerase (PARP) inhibitor used as an anticancer pharmaceutical. It inhibits PARP-mediated DNA repair and produces the greatest cytotoxicity in tumour cells with deficient homologous recombination repair, particularly cells carrying deleterious BRCA1 or BRCA2 alterations.

Classification

Field Information
Product type Pharmaceutical; targeted anticancer agent
Drug class PARP inhibitor
Primary targets PARP1, PARP2 and PARP3
Mechanistic category DNA-damage response inhibitor; synthetic-lethality agent
Common brand name Lynparza
Developmental name AZD2281

Major Mechanisms and Targets

Target or Process Direction Effect
PARP1 Down Inhibits catalytic activity and promotes PARP1 trapping on damaged DNA.
PARP2 Down Inhibits PARP2-dependent detection and repair of DNA strand breaks.
PARP3 Down Inhibits an additional PARP-family enzyme involved in the DNA-damage response.
Poly(ADP-ribosyl)ation / PARylation Down Reduces PARP-dependent modification and recruitment of DNA-repair proteins.
PARP–DNA complexes / PARP trapping Up Stabilizes cytotoxic PARP–DNA complexes that obstruct replication-fork progression.
Single-strand DNA-break repair Down Prevents efficient repair of DNA single-strand lesions.
Replication-fork stalling and collapse Up Unrepaired lesions and trapped PARP complexes impede DNA replication.
DNA double-strand breaks Up Replication of unrepaired DNA lesions produces potentially lethal double-strand breaks.
DNA damage Up Causes progressive accumulation of genomic lesions in susceptible tumour cells.
γH2AX Up Increases a marker of DNA double-strand-break signalling.
Homologous recombination repair dependence Up Forces damaged cells to depend more strongly on BRCA-mediated homologous recombination.
Synthetic lethality Up Selectively kills cells that combine PARP inhibition with deficient homologous recombination repair.
BRCA1/BRCA2-deficient cell survival Down HR-deficient cells cannot adequately repair olaparib-induced double-strand DNA breaks.
Genomic instability Up Increases chromosome and replication-associated damage beyond tolerable levels.
Cell-cycle arrest Up Activates DNA-damage checkpoints and inhibits progression through the cell cycle.
Apoptosis Up Induces programmed cell death following irreparable DNA damage.
Tumour-cell proliferation Down Suppresses proliferation, particularly in BRCA-mutated or HR-deficient tumour cells.
Tumour growth Down Reduces tumour growth in responsive preclinical and clinical settings.
Platinum sensitivity Up / predictive association Tumours with homologous-recombination defects may be sensitive to both platinum agents and PARP inhibition.

Biomarkers Associated with Response

Biomarker Association
BRCA1 mutation or loss Generally associated with increased olaparib sensitivity.
BRCA2 mutation or loss Generally associated with increased olaparib sensitivity.
Homologous recombination deficiency (HRD) May identify tumours with impaired double-strand-break repair and greater benefit.
Genomic instability Can serve as an indirect measure of historical homologous-recombination deficiency.
Platinum sensitivity Often correlates with PARP-inhibitor responsiveness but is not a definitive biomarker.

Resistance Mechanisms

Resistance Mechanism Effect
BRCA1/BRCA2 reversion mutations Restore the reading frame and homologous-recombination repair capacity.
Restoration of homologous recombination Allows repair of olaparib-induced double-strand DNA breaks.
Replication-fork stabilization Protects stalled replication forks from degradation and collapse.
Reduced PARP1 expression or altered PARP1 Can reduce formation of cytotoxic trapped PARP–DNA complexes.
Drug-efflux transporters Increased ABC transporter activity may lower intracellular olaparib exposure.
Loss of 53BP1 pathway activity May partially restore DNA-end resection and homologous recombination in BRCA1-deficient cells.

Clinical Cancer Applications

Depending on jurisdiction, tumour biomarkers, disease stage and prior therapy, olaparib is used in selected ovarian, fallopian-tube, primary peritoneal, breast, pancreatic and prostate cancers. Some indications require a germline or somatic BRCA1/2 alteration, homologous-recombination deficiency, or another qualifying homologous-recombination-repair alteration.

Typical Pharmaceutical Dose

A commonly used adult tablet regimen is 300 mg orally twice daily. Dose reduction, temporary interruption or discontinuation may be required for toxicity, renal impairment or clinically significant drug interactions. Olaparib capsules and tablets are not milligram-for-milligram interchangeable.

Major Adverse Effects and Precautions

  • Anaemia, neutropenia, leukopenia and thrombocytopenia
  • Nausea, vomiting, diarrhoea, dyspepsia and reduced appetite
  • Fatigue or asthenia
  • Headache and dizziness
  • Elevated serum creatinine related partly to transporter inhibition
  • Rare but serious myelodysplastic syndrome or acute myeloid leukaemia
  • Rare pneumonitis
  • Embryo-fetal toxicity
  • Potential clinically significant CYP3A-mediated drug interactions

Summary

Olaparib inhibits PARP catalytic activity and traps PARP proteins on damaged DNA. This suppresses DNA strand-break repair, obstructs replication forks and increases double-strand DNA breaks. Tumour cells with defective BRCA-dependent homologous recombination cannot adequately repair this damage, producing synthetic lethality, cell-cycle arrest and apoptosis. Olaparib should therefore be classified primarily as a PARP1/PARP2 inhibitor, PARP-trapping agent, DNA-repair inhibitor and synthetic-lethality pharmaceutical.



P53, P53-Guardian of the Genome: Click to Expand ⟱
Source: TCGA
Type: Proapototic
TP53 is the most commonly mutated gene in human cancer. TP53 is a gene that encodes for the p53 tumor suppressor protein ; TP73 (Chr.1p36.33) and TP63 (Chr.3q28) genes that encode transcription factors p73 and p63, respectively, are TP53 homologous structures.
p53 is a crucial tumor suppressor protein that plays a significant role in regulating the cell cycle, maintaining genomic stability, and preventing tumor formation. It is often referred to as the "guardian of the genome" due to its role in protecting cells from DNA damage and stress.
TP53 gene, which encodes the p53 protein, is one of the most frequently mutated genes in human cancers.
Overexpression of MDM2, an inhibitor of p53, can lead to decreased p53 activity even in the presence of wild-type p53.
In some cancers, particularly those with mutant p53, there may be an overexpression of the p53 protein.
Cancers with overexpression: Breast, lung, colorectal, overian, head and neck, Esophageal, bladder, pancreatic, and liver.
Scientific Papers found: Click to Expand⟱
7033- GA,  OL,    Gallic Acid Enhances Olaparib-Induced Cell Death and Attenuates Olaparib Resistance in Human Osteosarcoma U2OS Cell Line
- in-vitro, OS, U2OS
tumCV↓, angioG↓, DNAdam↑, Apoptosis↑, cl‑PARP↓, Bcl-2↓, BAX↑, ROS↓, eff↑, TumCMig↓, VEGF↓, Casp9↑, P53↑, selectivity↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↓, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,   BAX↑, 1,   Bcl-2↓, 1,   Casp9↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

tumCV↓, 1,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 1,   P53↑, 1,   cl‑PARP↓, 1,  

Migration(tgid=13) ⓘ

TumCMig↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 1,   VEGF↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

eff↑, 1,   selectivity↑, 1,  
Total Targets: 14

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: P53, P53-Guardian of the Genome
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:426  Target#:236  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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