Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current treatment of metastatic breast cancer (MBC) aims at achieving meaningful clinical responses, improved quality of life, long-term remissions, prolonged survival, and dares to hope for a cure in a small percentage of cases. This article will discuss both consensus and controversies in the management of MBC in the context of the new evolving breast cancer molecular classification. Hormonal therapy remains the mainstay of management of MBC Luminal A and B. Data is emerging on management of ErbB2-positive HR-positive MBC by combining hormonal manipulation and targeted anti-ErbB2 therapy and has recently received regulatory approval in Europe and USA. The optimal use and duration of single agent or combination chemotherapy is discussed. Data and controversies surrounding the use of newer agents such as nab-paclitaxel, ixabepilone, eribulin, and PARP inhibitors as well as trastuzumab is reviewed. Better understanding of pathophysiology has paved the way for the introduction of newer anti-ErbB2 agents such as lapatinib, pertuzumab, T-DM1 and neratinib. Controversies regarding bevacizumab and anti-angiogenesis are discussed. Bisphosphonates have significantly reduced skeletal related events and made significant improvements in the quality of life of patients with MBC. Newer anti-RANK Ligand antibodies show promising results. Significant advances in the understanding of molecular biology of breast cancer have been made and should lead to an improvement in the outcome of MBC. More possibilities of cure can become an attainable goal in the near future.
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PMID:Treatment of metastatic breast cancer: state-of-the-art, subtypes and perspectives. 2133 Jan 48

When DNA damage is detected, checkpoint signal networks are activated to stop the cell cycle, and DNA repair processes begin. Inhibitory compounds targeting components of DNA damage response pathways have been identified and are being used in clinical trials, in combination with chemotherapeutic agents, to enhance cancer therapy. Inhibitors of checkpoint kinases, Chk1 and Chk2, have been shown to sensitize tumor cells to DNA damaging agents, and treatment of BRCA1/2-deficient tumor cells, as well as triple negative breast cancers, with poly(ADP-ribose) polymerase (PARP) inhibitors has shown promise. But systematic studies to determine which tumor subtypes are likely to respond to these specific inhibitors have not been reported. The current study was designed to test sensitivity of specific breast cancer subtype-derived cells to two classes of these new inhibitory drugs, PARP and Chk1 inhibitors. Luminal, HER2 overexpressing, and triple negative breast cancer-derived cells were tested for sensitivity to killing by PARP inhibitors, ABT-888 and BSI-201, and Chk1 inhibitor, PF-00477736, alone or in combination with gemcitabine or carboplatin. Each of the triple negative breast cancer cell lines showed strong sensitivity to the Chk1 inhibitor, but only the BRCA1-deficient breast cancer cell lines showed sensitivity to the PARP inhibitors, suggesting that in vitro testing of cancer cell lines of specific subtypes, with panels of the different PARP and Chk1 inhibitors, will contribute to stratification of patients for clinical trials using these classes of inhibitors.
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PMID:Response of subtype-specific human breast cancer-derived cells to poly(ADP-ribose) polymerase and checkpoint kinase 1 inhibition. 2170 65

Proteomics allows for better understanding of the function and regulation of cancer cells mediated by intra- and extracellular signaling networks. Integrating such information with clinicopathological characteristics of the tumor may lead to either detection of disease biomarkers useful to differentiate high-from low-risk patients, or to identification of new drug targets. Adjuvant chemotherapy is currently a personalized treatment strategy, especially for breast cancer (BC) patients, and the risk assessment of each patient influences its use because the benefit strictly correlates with the level of risk. Luminal A BCs are endocrine therapy (ET)-sensitive but exhibit low sensitivity to chemotherapy, while luminal B cancers, according to the Ki-67 proliferation rate may require for chemotherapy in addition to ET, and HER2-positive tumors derive benefit from adjuvant chemotherapy containing an anthracycline, a taxane and trastuzumab for one year. Triple-negative BCs have a high degree of genomic instability exhibiting a more aggressive clinical course with respect to other types of BC, and the anthracycline-taxane regimen constitutes the standard approach. Studies considering the use of targeted approaches (drugs), including poly (ADP-ribose) polymerase (PARP-1), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) inhibitors, or EFGR and HER2 blockers, are still under evaluation. In the genomic era, promising new targeted-therapies are worthy of further investigation, and mTOR inhibitors have been used for patients with high-risk ER-positive and HER2-negative tumors. In the near future, genetic and molecular profiling of BC will help to better-categorize patients, determine the choice of chemotherapy in low-risk, or intensify the treatment in high-risk cancer patients, eventually revealing new targeted agents.
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PMID:Proteomics as a Guide for Personalized Adjuvant Chemotherapy in Patients with Early Breast Cancer. 2654 84

Following the discovery that the prognostic impact of preoperative chemotherapy depends on the primary breast cancer subtype, the treatment strategy for primary breast cancer changed. Pathologic complete response(pCR)with preoperative chemotherapy is predictive of a favorable prognosis in patients with HER2 type or triple-negative type breast cancer, but not in patients with ER-positive/HER2-negative, the so-called Luminal type, breast cancer. However, the role of preoperative chemotherapy in patients with Luminal-B type breast cancer who may need chemotherapy should be further assessed. Recent studies have reported severalsubtypes of triple-negative breast cancer, distinguishable by gene expression analysis, which may respond differently to treatment. Furthermore, novel agents, including pertuzumab or T-DM1 for HER2 type breast cancer, bevacizumab or PARP inhibitors for triple negative-breast cancer, or combination regimens with these novelagents, are expected to achieve higher pCR rates and improve patient prognosis. The tumor microenvironment may also play an important role in predicting treatment response or prognosis. It is important that tailor-made treatment strategies for patients with primary breast cancer, especially for patients who will not respond favorably to current standard therapies, consider both the treatment effects and the medicaleconomic effects.
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PMID:[The Role of Preoperative Chemotherapy Depending on Breast Cancer Subtype]. 2776 Sep 31

Over the last 15 years, we have seen a huge expansion of the development of drugs directed against biomolecular targets within breast cancer cells. The over-expression of certain receptors (ER, PgR, HER-2, VEGF-R), as well as alteration of several intracellular signal transduction pathways (the PI3K-AKT-mTOR pathway, MEK-MAPK pathway, loss of PTEN, etc ...) has a great impact on the likelihood of recurrence and progression of the disease, influencing the natural history of breast cancer. The recent biomolecular classification of breast cancer (Luminal A / B, HER2- driven, Basal Like) allowed finally to identify specific treatments against molecular target to associate or not to traditional chemotherapy, and to use in relation to the prognosis of the disease. In the following paragraphs, we will set out the major targeted drug that have received indications in breast cancer, both in the localized and in advanced disease, referring to the specific target (hormonal receptors, HER2, VEGF, m-TOR, PARP etc ...).
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PMID:The Real Impact of Target Therapy in Breast Cancer Patients: Between Hope and Reality. 2818 51

The non-receptor tyrosine kinase, PTK6/BRK, is highly expressed in multiple tumor types, including prostate, ovarian, and breast cancers, and regulates oncogenic phenotypes such as proliferation, migration, and survival. PTK6 inhibition also overcomes targeted therapy resistance of HER2+ breast cancer. Although PTK6 is highly expressed in ER+ Luminal breast cancers, the role of PTK6 in this subtype has not been elucidated. In this study, we investigated the functions of PTK6 in ER+ Luminal breast cancer cells, including those that are relatively resistant to estrogen deprivation or targeted endocrine therapies used in the treatment of ER+ cancers. Enhanced expression of PTK6 in ER+ breast cancer cells enhances growth of ER+ breast cancer cells, including tamoxifen-treated cells. Downregulation of PTK6 in ER+ breast cancer cells, including those resistant to tamoxifen, fulvestrant, and estrogen deprivation, induces apoptosis, as evidenced by increased levels of cleaved PARP, and an increase in the AnnexinV+ population. PTK6 downregulation impairs growth of these cells in 3D Matrigel^TM cultures, and virtually abrogates primary tumor growth of both tamoxifen-sensitive and resistant MCF-7 xenografts. Finally, we show that p38 MAPK activation is critical for PTK6 downregulation-induced apoptosis, a mechanism that we previously reported for survival of HER2+ breast cancer cells, highlighting conserved mechanisms of survival regulation by PTK6 across breast cancer subtypes. In conclusion, our studies elucidate critical functions of PTK6 in ER+ Luminal breast cancers and support PTK6 as an attractive therapeutic target for ER+ breast cancers.
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PMID:PTK6 regulates growth and survival of endocrine therapy-resistant ER+ breast cancer cells. 2916 21

The genomics-based molecular classifications aim at identifying more homogeneous classes than immunohistochemistry, associated with a more uniform clinical outcome. We conducted an in silico analysis on a meta-dataset including gene expression data from 5342 clinically defined ER+/HER2- breast cancers (BC) and DNA copy number/mutational and proteomic data. We show that the Basal (16%) versus Luminal (74%) subtypes as defined using the 80-gene signature differ in terms of response/vulnerability to systemic therapies of BC. The Basal subtype is associated with better chemosensitivity, lesser benefit from adjuvant hormone therapy, and likely better sensitivity to PARP inhibitors, platinum salts and immune therapy, and other targeted therapies under development such as FGFR inhibitors. The Luminal subtype displays potential better sensitivity to CDK4/6 inhibitors and vulnerability to targeted therapies such as PIK3CA, AR and Bcl-2 inhibitors. Expression profiles are very different, showing an intermediate position of the ER+/HER2- Basal subtype between the ER+/HER2- Luminal and ER- Basal subtypes, and let suggest a different cell-of-origin. Our data suggest that the ER+/HER2- Basal and Luminal subtypes should not be assimilated and treated as a homogeneous group.
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PMID:The therapeutic response of ER+/HER2- breast cancers differs according to the molecular Basal or Luminal subtype. 3219 31

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