Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Olaparib (AZD2281) is an orally active Poly(ADP-ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose-finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single-dose on day 1, followed by twice-daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400-mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose-limiting toxicities were not observed up to and including the 400-mg b.i.d. dose level. Following twice-daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single-dose pharmacokinetics. PARP-1 inhibition was observed from the 100-mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post-dose on day 1 during the multiple-dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400-mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400-mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed.
 ...
PMID:A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. 2214 84

Poly(ADP-ribose) polymerase (PARP) family has become a promising therapeutic target in various malignancies including breast cancer. When homologous recombination repair is deficient, as it is observed in BRCA1/2-mutated tumor models, inhibition of PARP was shown to induce massive and selective tumor cell death (the so-called "synthetic lethality"). In breast cancer, PARP inhibitors have been developed as single-agent in BRCA1/2-mutated tumors or in combination with chemotherapy. Recently, a randomized phase III clinical trial failed to demonstrate any survival improvement by combining the iPARP iniparib to chemotherapy in triple-negative metastatic breast cancer patients. This emphasizes the need for future development of this class of compounds to resolve critical issues such as optimal schedule of administration and association to other anticancer treatments, as well as identification of pertinent biomarkers predictive for efficacy.
 ...
PMID:[PARP inhibitors and breast cancer: update and perspectives]. 2245 Mar 59

Genomic instability can be observed at both chromosomal and chromatin levels. Instability at the macro level includes centrosome abnormalities (CA) resulting in numerical as well as structural chromosomal changes, whereas instability at the micro level is characterized by defects in DNA repair pathways resulting in microsatellite instability (MIN) or mutations. Genomic instability occurs during carcinogenesis without impairing survival and growth, though the precise mechanisms remain unclear. Solid tumors arising from most cells of epithelial origin are characterized by genomic instability which renders them resistant to chemotherapy and radiotherapy. This instability is also observed in 25% of myeloma patients and has been shown to be highly prognostic, independently of the international staging system (ISS). However, a biomarker of aberrant DNA repair and loss of heterozygosity (LOH), was only observed at a frequency of 5% in newly diagnosed patients. Several new molecules targeting the pathways involved in genomic instability are under development and some have already entered clinical trials. Poly(ADP-ribose) polymerase-1 (PARP) inhibitors have been FDA-approved for the treatment of breast cancer type 1 susceptibility protein (BRCA1)-mutated metastatic breast cancer, as well as ovarian and lung cancer. Topoisomerase inhibitors and epigenetic histone modification-targeting inhibitors, such as HDAC (Histone Deacetylase) inhibitors which are novel agents that can target genomic instability. Several of the small molecule inhibitors targeting chromosomal level instability such as PARP, Akt, Aurora kinase, cyclin dependent kinase or spindle kinase inhibitors have been tested in mouse models and early phase I/II trials. ATM, ATR kinase inhibitors and DNA helicase inhibitors are also promising novel agents. However, most of these drugs are not effective as single agents but appear to act synergistically with DNA damaging agents such as radiotherapy, platinum derivatives, immunomodulators, and proteasome inhibitors. In this review, new drugs targeting genomic instability and their mechanisms of action will be discussed.
 ...
PMID:Drug Targeting of Genomic Instability in Multiple Myeloma. 3237 51