scholarly journals BRCA1 as a Therapeutic Target in Sporadic Epithelial Ovarian Cancer

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Katherine V. Clark-Knowles ◽  
Anna M. O'Brien ◽  
Johanne I. Weberpals
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Chemotherapeutic Agents ◽  
Brca1 Protein ◽  
Critical Pathways ◽  
Promising Target ◽  
Increased Sensitivity ◽  
Preclinical And Clinical Studies

In sporadic epithelial ovarian cancer (EOC), the inactivation of BRCA1 through various mechanisms is a relatively common event. BRCA1 protein dysfunction results in the breakdown of various critical pathways in the cell, notably, the DNA damage response and repair pathway. Tumors from patients withBRCA1germline mutations have an increased sensitivity to DNA damaging chemotherapeutic agents, such as cisplatin, due to defective DNA repair. Thus, inhibiting BRCA1 in sporadic EOC using novel targeted therapies is an attractive strategy for the treatment of advanced or recurrent EOC. Several classes of small molecule inhibitors that affect BRCA1 have now been tested in preclinical and clinical studies suggesting that this is a rational therapeutic approach. The aim of this paper is to provide an understanding of how BRCA1 has evolved into a promising target for the treatment of sporadic disease and to outline the main potential small molecule inhibitors of BRCA1 in EOC.

scholarly journals Development of a High-Throughput Lysyl Hydroxylase (LH) Assay and Identification of Small-Molecule Inhibitors against LH2

2018 ◽  
Vol 24 (4) ◽  
pp. 484-491 ◽  
Author(s):  
Ashwini K. Devkota ◽  
John R. Veloria ◽  
Hou-Fu Guo ◽  
Jonathan M. Kurie ◽  
Eun Jeong Cho ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cancer Metastasis ◽  
Small Molecule Inhibitors ◽  
Lysyl Hydroxylase ◽  
Promising Target ◽  
Lysine Residues ◽  
Collagen Molecules ◽  
Cross Links

Lysyl hydroxylase-2 (LH2) catalyzes the hydroxylation of telopeptidyl lysine residues on collagen, leading to the formation of stable collagen cross-links that connect collagen molecules and stabilize the extracellular matrix. High levels of LH2 have been reported in the formation and stabilization of hydroxylysine aldehyde-derived collagen cross-links (HLCCs), leading to fibrosis and cancer metastasis in certain tissues. Identification of small-molecule inhibitors targeting LH2 activity requires a robust and suitable assay system, which is currently lacking. Thus, despite being a promising target for these diseases, small-molecule inhibitors for LH2 have yet to be reported. Therefore, we developed a luminescence-based strategy to monitor LH activity and validated its ability to identify new inhibitors in a screen of approximately 65,000 compounds against LH2. Primary hits were confirmed using the same LH assay against mimiviral L230. This newly developed LH assay is robust, suitable for high-throughput screening, and able to identify potent specific inhibitors of LH2.

Causes and Consequences of Cancer-Associated Thrombocytosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-33-SCI-33
Author(s):  
Anil Sood ◽  
Rebecca L. Stone ◽  
Vahid Afshar-Kharghan
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Epithelial Ovarian Cancer ◽  
Mouse Models ◽  
Interleukin 6 ◽  
Conflicts Of Interest ◽  
Chemotherapeutic Agents ◽  
Antibody Treatment ◽  
Platelet Counts ◽  
Tumor Bearing

Abstract Platelets represent one of the largest storage pools of angiogenic and oncogenic growth factors in the human body. The observation that thrombocytosis (platelet count >450,000/µL) occurs in patients with solid malignancies was made over 100 years ago. However, mechanisms of paraneoplastic thrombocytosis and the role that platelets play in abetting cancer growth are unclear. We have used clinical data coupled with sophisticated mouse models to identify the mechanisms and biological implications of paraneoplastic thrombocytosis. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti-interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an anti-platelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. Biologically, platelets were detected within the tumor microenvironment and affected tumor growth and response to chemotherapeutic agents. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. Blocking the stimulatory effects of platelets may have implications for new therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeted Therapies in Epithelial Ovarian Cancer

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Nicanor I. Barrena Medel ◽  
Jason D. Wright ◽  
Thomas J. Herzog
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Targeted Therapies ◽  
Late Presentation ◽  
Effective Prevention ◽  
Critical Pathways ◽  
Promising Strategy ◽  
Advanced Stages ◽  
Detection Strategies

Epithelial ovarian cancer remains a major women's health problem due to its high lethality. Despite great efforts to develop effective prevention and early detection strategies, most patients are still diagnosed at advanced stages of disease. This pattern of late presentation has resulted in significant challenges in terms of designing effective therapies to achieve long-term cure. One potential promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. This review examines three of the most provocative targeted therapies with current or future applicability in epithelial ovarian cancer.

scholarly journals Microtubule-Interfering Drugs: Current and Future Roles in Epithelial Ovarian Cancer Treatment

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6239
Author(s):  
Joan Tymon-Rosario ◽  
Naomi N. Adjei ◽  
Dana M. Roque ◽  
Alessandro D. Santin
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Data ◽  
Standard Of Care ◽  
Therapeutic Agents ◽  
Chemotherapeutic Agents ◽  
Front Line ◽  
Current Standard ◽  
The Past ◽  
Taxane Resistance

Taxanes and epothilones are chemotherapeutic agents that ultimately lead to cell death through inhibition of normal microtubular function. This review summarizes the literature demonstrating their current use and potential promise as therapeutic agents in the treatment of epithelial ovarian cancer (EOC), as well as putative mechanisms of resistance. Historically, taxanes have become the standard of care in the front-line and recurrent treatment of epithelial ovarian cancer. In the past few years, epothilones (i.e., ixabepilone) have become of interest as they may retain activity in taxane-treated patients since they harbor several features that may overcome mechanisms of taxane resistance. Clinical data now support the use of ixabepilone in the treatment of platinum-resistant or refractory ovarian cancer. Clinical data strongly support the use of microtubule-interfering drugs alone or in combination in the treatment of epithelial ovarian cancer. Ongoing clinical trials will shed further light into the potential of making these drugs part of current standard practice.

Chemotherapy for Patients withBRCA1andBRCA2–Mutated Ovarian Cancer: Same or Different?

2015 ◽  
pp. 114-121 ◽  
Author(s):  
David S.P. Tan ◽  
Stanley B. Kaye
Keyword(s):  
Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
The United States ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
First Line ◽  
Platinum Based Chemotherapy ◽  
Increased Sensitivity ◽  
Precise Relationship

Retrospective studies have shown an improved prognosis, higher response rates to platinum-containing regimens, and longer treatment-free intervals between relapses in patients with BRCA 1 and BRCA 2 ( BRCA1/2)–mutated ovarian cancer (BMOC) compared with patients who are not carriers of this mutation. These features of BMOC are attributed to homologous-recombination repair (HR) deficiency in the absence of BRCA1/2 function, which results in an impaired ability of tumor cells to repair platinum-induced double-strand breaks (DSBs), thereby conferring increased chemosensitivity and increased sensitivity to poly(ADP-ribose) polymerase (PARP) enzyme inhibition and other DNA-damaging chemotherapeutic agents such as pegylated liposomal doxorubicin (PLD). Therefore, the chemotherapeutic approach for patients with BMOC should focus on treatment with platinum-based chemotherapy at first-line and recurrent-disease settings and measures to increase the platinum-free interval following early platinum-resistant relapse (i.e., progression-free survival of less than 6 months from last platinum-based chemotherapy) by using nonplatinum cytotoxic agents, with the aim of reintroducing platinum again at a later date. The role of first-line intraperitoneal platinum-based therapy in the specific context of BMOC also merits further analysis. Other than platinum, alternative DNA-damaging agents (including PLD and trabectedin) also may have a therapeutic role in patients with recurrent BMOC. The recent approval of olaparib for clinical use in Europe and the United States will also affect chemotherapeutic strategies for these patients. Further work to clarify the precise relationship between BRCA1/2 mutation genotype and clinical phenotype is crucial to delineating the optimal therapeutic choices in the future for patients with BMOC.

Identification and Characterization of Novel Small-Molecule Inhibitors of the Replication Checkpoint.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 763-763
Author(s):  
James Bradner ◽  
Yong-Son Kim ◽  
Angela Koehler ◽  
Masaoki Kawasumi ◽  
Xiaodong Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Small Molecule ◽  
Mammalian Cells ◽  
Small Molecule Inhibitors ◽  
Chromatin Condensation ◽  
Replication Stress ◽  
Chemotherapeutic Agents ◽  
Replication Checkpoint ◽  
Chromosomal Fragility ◽  
Microarray Format

Abstract Background The replication (G2/M) checkpoint is principally mediated by the serine/threonine protein kinase ATR (ataxia telangiectasia mutated and Rad3-related). ATR is a large (350 kD) member of the phosphatidylinositol kinase related kinase family. After exposure to genotoxic or replication stress, ATR halts cell cycle progression, allowing DNA repair complexes time enough to restore the fidelity of the genome prior to cell division. Previous experiments have demonstrated that cancer cells with p53 mutation are critically dependent on ATR-mediated arrest of the cell cycle. Industrial approaches to identify ATR inhibitors have failed likely as a result of protein insolubility. Methods We have undertaken a novel chemical genetic approach employing small molecule microarrays (SMMs) to identify molecules with high binding specificity for ATR. Three diversity-oriented combinatorial chemical libraries of more than 15,000 entities were generated by split-pool synthesis in solid phase on polystyrene macrobead supports. Compounds were robotically printed in microarray format on glass slides. Four analogs of FK506 were printed as positive controls. Extracts were prepared from mammalian cells transfected with over-expression constructs of FLAG-tagged ATR, FKBP12 and GFP. A protocol was developed and optimized for screening employing a primary anti-FLAG mouse monoclonal antibody and Cy5-fluorophore labeled anti-mouse antibody. Data analysis for small molecule binders was performed with GenePix software on an Axon Scanner. Biological activity of these molecules was analyzed in the context of mitotic spread and chromosomal fragility assays. Results Protein expression and antibody fidelity was verified by Western blot. The lysate-based SMM screening approach was optimized and validated by recognition of an interaction between over-expressed, epitope-tagged FKBP12 and analogs of FK506. Six small molecule hits suggesting ATR binding were identified and verified by triplicate microarray assays. Positive compounds were structurally similar members of a dihydropyrancarboxamide library suggesting recognition of a common target. Mitotic spread analysis of cells treated with two of these molecules and hydroxyurea demonstrated the premature chromatin condensation phenotype characteristic of replication checkpoint inhibition. Chromosomal fragility was notably augmented by these molecules as well. Chemosensitivity following replication stress was witnessed in p53-negative cells relative to an otherwise identical wild-type cell line. Conclusions Classical approaches to drug discovery are often limited by challenges in protein biochemistry such as protein size, solubility, activity and yield. We present compelling data that the small molecule microarray format can effectively be tailored for use with cellular lysates over-expressing a protein target of biological interest. Furthermore, we have used an optimized protocol to identify two novel, active small molecule inhibitors of the replication checkpoint (SMIRC-1 and SMIRC-2). The enhanced chemosensitivity in p53-negative cell lines supports a plausible role for ATR inhibitors as potentially useful chemotherapeutic agents.

scholarly journals Small Molecule Inhibitors of HSF1-Activated Pathways as Potential Next-Generation Anticancer Therapeutics

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2757 ◽  
Author(s):  
Chiranjeev Sharma ◽  
Young Seo
Keyword(s):  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Chemotherapeutic Agents ◽  
Heat Shock Factor 1 ◽  
Next Generation ◽  
Anticancer Activities ◽  
Cancer Cell Growth ◽  
Survival Studies ◽  
New Chemotherapeutic Agents

Targeted therapy is an emerging paradigm in the development of next-generation anticancer drugs. Heat shock factor 1 (HSF1) has been identified as a promising drug target because it regulates several pathways responsible for cancer cell growth, metastasis, and survival. Studies have clearly demonstrated that HSF1 is an effective drug target. Herein, we provide a concise yet comprehensive and integrated overview of progress in developing small molecule inhibitors of HSF1 as next-generation anticancer chemotherapeutics while critically evaluating their potential and challenges. We believe that this review will provide a better understanding of important concepts helpful for outlining the strategy to develop new chemotherapeutic agents with promising anticancer activities by targeting HSF1.

scholarly journals Cooperation therapy between anti-growth by photodynamic-AIEgens and anti-metastasis by small molecule inhibitors in ovarian cancer

Theranostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 2385-2398 ◽  
Author(s):  
Jun Dai ◽  
Min Xu ◽  
Quan Wang ◽  
Juliang Yang ◽  
Jinjin Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitors

scholarly journals The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2150
Author(s):  
Nicole E. James ◽  
Morgan Woodman ◽  
Paul A. DiSilvestro ◽  
Jennifer R. Ribeiro
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Patient Survival ◽  
Gynecologic Malignancy ◽  
Comprehensive Description ◽  
Patient Response ◽  
Improve Patient Survival ◽  
Programmed Cell Death 1 ◽  
Preclinical And Clinical Studies ◽  
Improve Patient

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with an overall 5-year survival of only 47%. As the development of novel targeted therapies is drastically necessary in order to improve patient survival, current EOC clinical trials have heavily focused on immunotherapeutic approaches, centered upon programmed cell death 1 (PD-1) inhibitors. While PD-1 monotherapies have only exhibited modest responses for patients, it has been theorized that in order to enhance EOC patient response to immunotherapy, combinatorial regimens must be investigated. In this review, unique challenges to EOC PD-1 response will be discussed, along with a comprehensive description of both preclinical and clinical studies evaluating PD-1-based combinatorial therapies. Promising aspects of PD-1-based combinatorial approaches are highlighted, while also discussing specific preclinical and clinical areas of research that need to be addressed, in order to optimize EOC patient immunotherapy response.

Carboplatin and etoposide as first-line chemotherapy in advanced epithelial ovarian cancer

1995 ◽  
Vol 5 (6) ◽  
pp. 443-448 ◽  
Author(s):  
D. Z. Edelmann ◽  
T. Peretz ◽  
V. Barak ◽  
S. O. Anteby
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Performance Status ◽  
Survival Rates ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Chemotherapeutic Agents ◽  
Synergistic Activity ◽  
First Line ◽  
Advanced Epithelial Ovarian Cancer

Carboplatin and etoposide are chemotherapeutic agents active in ovarian cancer, previously proved to have a synergistic activity in animal models. The objective of this phase II study was to determine the feasibility and the efficacy of the combination of carboplatin and etoposide in previously untreated patients with advanced epithelial ovarian cancer.Carboplatin, 400 mg m−2 day 1, and etoposide, 100 mg m−2 days 1–3 every 4 weeks were administered to 28 patients with advanced stage (III–IV) ovarian cancer and a performance status 0–2 (ECOG scale), as a firstline chemotherapy.Twenty-three patients were evaluable for response; 15 (65%) (95% CI: 45–81%) responded, 10 (43%) (95% CI: 25–63%) with clinical complete response. Pathologic complete response demonstrated during postchemotherapy laparotomy was noted in 5/23 (22%) (95% CI: 9–42%) patients. The median progression-free interval was 8.5 months, and median survival was 19.5 months. Toxicity, mainly hematologic, was severe. Nine (32%) patients experienced at least one episode of leucopenic fever, which consequently led to toxic deaths in two (7%) patients.The relatively low response and survival rates with increased toxicity rate are disappointing.

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