The Experts below are selected from a list of 15765 Experts worldwide ranked by ideXlab platform
Ursula A Matulonis - One of the best experts on this subject based on the ideXlab platform.
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abstract ia01 PARP Inhibitors as single agents and in combinations for ovarian cancer what lies ahead
Clinical Cancer Research, 2018Co-Authors: Ursula A MatulonisAbstract:Poly (ADP ribose) polymerase (PARP) Inhibitors are an exciting and promising new class of anticancer drugs. Initial clinical trials of PARP Inhibitors began over a decade ago following the discovery that PARP Inhibitors in vitro had heightened anticancer activity in BRCA mutated cancer cells compared to BRCA wild-type cells. PARP inhibitor clinical development has taken several strategies, including single-agent and combination testing. Single-agent PARP Inhibitors have been used as either primary treatment of recurrent ovarian cancer or as maintenance treatment following anticancer response after platinum-based chemotherapy. Three PARP Inhibitors are now FDA approved for recurrent ovarian cancer, all as single agents: 1) olaparib for patients with recurrent germline BRCA mutated ovarian cancer who have received 3 or more prior lines of chemotherapy and also as maintenance therapy post-platinum therapy for patients with platinum sensitive recurrence who are in response to platinum-based chemotherapy and regardless of BRCA or tumor HR status; 2) rucaparib for patients with BRCA mutated ovarian cancer (either deleterious tumor or germline mutation) who have received at least 2 prior lines of chemotherapy; and 3) niraparib for platinum-sensitive recurrent ovarian cancer patients as maintenance therapy who are in response to platinum-based chemotherapy and regardless of BRCA or tumor HR status. Because of the myelosuppression observed with PARP Inhibitors, combining these agents with chemotherapy has been difficult and has required lowering the doses of either the PARP inhibitor and/or the chemotherapy agents and often abbreviating the treatment schedule; several negative phase III studies have been reported. Combining PARP Inhibitors with biologic agents is another strategy currently being tested in clinical trials and one that avoids overlapping toxicities. The combination of the PARP inhibitor olaparib and the antivascular endothelial growth factor receptor agent cediranib has shown promising phase II results against olaparib alone, especially in BRCA wild-type ovarian cancer. These results have led to phase III studies comparing the olaparib and cediranib combination to standard therapies (NCT02502266 and NCT02446600). Other studies are under way testing PARP Inhibitors with other biologic agents such as immunotherapy agents and other targeted agents such as ATR Inhibitors, PI3 kinase Inhibitors, and heat shock protein 90 Inhibitors. Citation Format: Ursula A. Matulonis. PARP Inhibitors as single agents and in combinations for ovarian cancer: What lies ahead? [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA01.
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PARP Inhibitors in ovarian cancer a trailblazing and transformative journey
Clinical Cancer Research, 2018Co-Authors: Panagiotis A Konstantinopoulos, Ursula A MatulonisAbstract:PARP Inhibitors have transformed treatment for ovarian cancer, a cancer notable for homologous recombination (HR) deficiencies and aberrant DNA repair, especially high grade serous subtype. PARP Inhibitors are now approved for recurrent ovarian cancer as maintenance following response to platinum chemotherapy and BRCA mutated (BRCAm) cancer treatment.
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PARP Inhibitors in ovarian cancer evidence experience and clinical potential
Therapeutic Advances in Medical Oncology, 2017Co-Authors: Tarra Evans, Ursula A MatulonisAbstract:Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP Inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP Inhibitors have been identified. As single agents, PARP Inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP Inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwis...
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PARP Inhibitors in ovarian cancer current status and future promise
Gynecologic Oncology, 2014Co-Authors: Panagiotis A Konstantinopoulos, Ursula A MatulonisAbstract:Abstract Clinical investigation of poly(ADP-ribose) polymerase (PARP) Inhibitors for ovarian cancer treatment has rapidly evolved from observations of single-agent in vitro activity of these agents in BRCA -deficient cancer cells in 2005 to the initiation of multiple phase III studies in 2013. With clinical trial design and treatment of ovarian cancer increasingly based on histological and molecular characteristics, PARP Inhibitors are on the horizon of becoming the first biologic agents to be used to treat ovarian cancer based upon pre-selection characteristics of the patient's cancer. PARP Inhibitors are most active in ovarian cancers that have defects or aberrations in DNA repair; use of these agents has been of particular interest in high grade serous cancers (HGSC), where studies have shown that ~50% of HGSC have abnormalities of DNA repair through BRCA germline and somatic mutation, post-translational changes of BRCA , and abnormalities of other DNA repair molecules. In addition, as aberrant DNA pathways in other histological subtypes of ovarian cancer are identified, and through the combination of PARP Inhibitors with other biologic agents, the pool of eligible patients who may benefit from PARP Inhibitors will likely expand. Pending review by the Food and Drug Administration (FDA) and the outcome of confirmatory phase III studies, PARP Inhibitors could become the first FDA-approved biologic agent for ovarian cancer and also the first new FDA-approval in ovarian cancer since carboplatin and gemcitabine were approved for platinum sensitive ovarian cancer in 2006. This review discusses the PARP Inhibitors that are currently in testing for ovarian cancer treatment and the future of this class of anti-cancer agents.
Alan Ashworth - One of the best experts on this subject based on the ideXlab platform.
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PARP Inhibitors synthetic lethality in the clinic
Science, 2017Co-Authors: Christopher J. Lord, Alan AshworthAbstract:PARP Inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP Inhibitors and potential ways to maximize their clinical effectiveness.
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Developing rational drug combination strategies for PARP Inhibitors.
Journal of Clinical Oncology, 2012Co-Authors: Farah L. Rehman, Richard Elliott, Rachel Brough, Jessica Frankum, Anan Ragab, Christopher J. Lord, Alan AshworthAbstract:3050 Background: The recent clinical development of Poly (ADP-ribose) polymerase (PARP) Inhibitors has provided formal proof-of-concept that synthetic lethal approaches can be used to treat cancer. The promise of PARP Inhibitors in BRCA mutant tumours is apparent but questions regarding their wider clinical use remain. To date, a number of clinical trials have been designed using PARP Inhibitors as single agents as well as in combination with current standards of care. However, there is a paucity of pre-clinical information about PARP inhibitor/drug combinations and empirical clinical trials of standard of care plus PARP Inhibitors may not represent the most effective approach to dissect this. We aim to identify effective drug combination strategies that could be used clinically in selected patient groups. Methods: Using a combination of high and medium throughput techniques and established methodologies for determining synergy, additivity and antagonism, we have characterised the effects of combining PARP Inhibitors with a diverse panel of over 3,000 compounds in a range of tumour cell models including isogenic matched cell line pairs to determine the impact of genetic background on drug combination efficacy. We have integrated this data with functional profiling data to identify genetic backgrounds where these combinations may be most effective. Results: Results to date suggest promising combinations of PARP Inhibitors with temozolomide, CHK1 Inhibitors, ATM Inhibitors and other agents. Some of these combinations show specificity for genetic backgrounds such as PTEN mutations. Conclusions: Screening of drug libraries has identified promising PARP inhibitor drug combinations and demonstrates how some drug combinations show specificity in particular genetic backgrounds. This raises the possibility of widening the therapeutic index in patients with these genetic backgrounds and treating a wider group of patients with PARP Inhibitors.
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making the best of PARP Inhibitors in ovarian cancer
Nature Reviews Clinical Oncology, 2010Co-Authors: Susana Banerjee, Stan B. Kaye, Alan AshworthAbstract:Inhibitors of poly(ADP-ribose)polymerase (PARP) have shown promise as therapeutic agents for the treatment of ovarian cancers with mutations in BRCA1 or BRCA2. By exploiting the synthetic lethal interaction that exists between PARP inhibition and BRCA mutations, these agents specifically kill cancer cells by targeting their DNA repair system. The authors of this Review describe the importance of BRCA mutations for the efficacy of PARP Inhibitors. They also discuss the preclinical and clinical trial results of PARP Inhibitors, the challenges related to the use of these agents, and future directions.
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synthetic lethal targeting of pten mutant cells with PARP Inhibitors
Embo Molecular Medicine, 2009Co-Authors: Ana M Mendespereira, Rachel Brough, Christopher J. Lord, Sarah A Martin, Afshan Mccarthy, Jessica R Taylor, Todd Waldman, Alan AshworthAbstract:The tumour suppressor gene, phosphatase and tensin homolog (PTEN), is one of the most commonly mutated genes in human cancers. Recent evidence suggests that PTEN is important for the maintenance of genome stability. Here, we show that PTEN deficiency causes a homologous recombination (HR) defect in human tumour cells. The HR deficiency caused by PTEN deficiency, sensitizes tumour cells to potent Inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), both in vitro and in vivo. PARP Inhibitors are now showing considerable promise in the clinic, specifically in patients with mutations in either of the breast cancer susceptibility genes BRCA1 or BRCA2. The data we present here now suggests that the clinical assessment of PARP Inhibitors should be extended beyond those with BRCA mutations to a larger group of patients with PTEN mutant tumours.
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targeted therapy for cancer using PARP Inhibitors
Current Opinion in Pharmacology, 2008Co-Authors: Christopher J. Lord, Alan AshworthAbstract:Poly (ADP-ribose) Polymerase (PARP) has a well-established role in DNA repair processes, and small molecule Inhibitors of PARP have been developed as chemotherapy sensitisers for the treatment of cancer. The subsequent demonstration that PARP inhibition is selective for BRCA1 or BRCA2 deficiency suggests that PARP Inhibitors may be particularly useful for the treatment of cancer with BRCA mutations. This would represent one of the first clinically implemented examples of a synthetic lethal approach for cancer treatment. However, there are still unanswered questions surrounding PARP Inhibitors, namely the levels of specificity and potency that are required to elicit BRCA selectivity. The recent identification of mechanisms of cellular resistance to PARP Inhibitors may provide indications as to how these drugs may be best used in the clinic.
Johann S. Bono - One of the best experts on this subject based on the ideXlab platform.
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PARP Inhibitors
Drugs, 2012Co-Authors: Bristi Basu, Shahneen K. Sandhu, Johann S. BonoAbstract:The use of poly(ADP-ribose) polymerase (PARP) Inhibitors provided proof-of-concept for a synthetic lethal anticancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP Inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.
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poly adp ribose polymerase PARP Inhibitors exploiting a synthetic lethal strategy in the clinic
CA: A Cancer Journal for Clinicians, 2011Co-Authors: Shahneen Sandhu, Craig P Carden, Johann S. BonoAbstract:Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. The homologous recombination (HR) DNA repair pathway is critical for the repair of DNA double-strand breaks and HR deficiency leads to a dependency on error-prone DNA repair mechanisms, with consequent genomic instability and oncogenesis. Tumor-specific HR defects may be exploited through a synthetic lethal approach for the application of anticancer therapeutics, including PARP Inhibitors. This theory proposes that targeting genetically defective tumor cells with a specific molecular therapy that inhibits its synthetic lethal gene partner should result in selective tumor cell killing. The demonstration of single-agent antitumor activity and the wide therapeutic index of PARP Inhibitors in BRCA1 and BRCA2 mutation carriers with advanced cancers provide strong evidence for the clinical application of this approach. Emerging data also indicate that PARP Inhibitors may be effective in sporadic cancers bearing HR defects, supporting a substantially wider role for PARP Inhibitors. Drugs targeting this enzyme are now in pivotal clinical trials in patients with sporadic cancers. In this article, the evidence supporting this antitumor synthetic lethal strategy with PARP Inhibitors is reviewed, evolving resistance mechanisms and potential molecular predictive biomarker assays are discussed, and the future development of these agents is envisioned. CA Cancer J Clin 2011;61:31-49. (C) 2011 American Cancer Society.
Thomas Reiner - One of the best experts on this subject based on the ideXlab platform.
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poly adp ribose polymerase PARP Inhibitors and radiation therapy
Frontiers in Pharmacology, 2020Co-Authors: Stephen A Jannetti, Brian M Zeglis, Michael R Zalutsky, Thomas ReinerAbstract:Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells, with a structure and function that have attracted interest since its discovery. PARP Inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient. Several small molecule PARP Inhibitors have been approved by the FDA for multiple cancers bearing this deficiency These PARP Inhibitors also act as radiosensitizing agents by delaying single strand break (SSB) repair and causing subsequent double strand break (DSB) generation, a concept that has been leveraged in various preclinical models of combination therapy with PARP Inhibitors and ionizing radiation. Researchers have determined the efficacy of various PARP Inhibitors at sub-cytotoxic concentrations in radiosensitizing multiple human cancer cell lines to ionizing radiation. Furthermore, several groups have begun evaluating combination therapy strategies in mouse models of cancer, and a fluorescent imaging agent that allows for subcellular imaging in real time has been developed from a PARP inhibitor scaffold. Other PARP inhibitor scaffolds have been radiolabeled to create PET imaging agents, some of which have also entered clinical trials. Most recently, these highly targeted small molecules have been radiolabeled with therapeutic isotopes to create radiotherapeutics and radiotheranostics in cancers whose primary interventions are surgical resection and whole-body radiotherapy. In this review we discuss the utilization of these small molecules in combination therapies and in scaffolds for imaging agents, radiotherapeutics, and radiotheranostics. Development of these radiolabeled PARP Inhibitors has presented promising results for new interventions in the fight against some of the most intractable cancers.
Stephen A Jannetti - One of the best experts on this subject based on the ideXlab platform.
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poly adp ribose polymerase PARP Inhibitors and radiation therapy
Frontiers in Pharmacology, 2020Co-Authors: Stephen A Jannetti, Brian M Zeglis, Michael R Zalutsky, Thomas ReinerAbstract:Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells, with a structure and function that have attracted interest since its discovery. PARP Inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient. Several small molecule PARP Inhibitors have been approved by the FDA for multiple cancers bearing this deficiency These PARP Inhibitors also act as radiosensitizing agents by delaying single strand break (SSB) repair and causing subsequent double strand break (DSB) generation, a concept that has been leveraged in various preclinical models of combination therapy with PARP Inhibitors and ionizing radiation. Researchers have determined the efficacy of various PARP Inhibitors at sub-cytotoxic concentrations in radiosensitizing multiple human cancer cell lines to ionizing radiation. Furthermore, several groups have begun evaluating combination therapy strategies in mouse models of cancer, and a fluorescent imaging agent that allows for subcellular imaging in real time has been developed from a PARP inhibitor scaffold. Other PARP inhibitor scaffolds have been radiolabeled to create PET imaging agents, some of which have also entered clinical trials. Most recently, these highly targeted small molecules have been radiolabeled with therapeutic isotopes to create radiotherapeutics and radiotheranostics in cancers whose primary interventions are surgical resection and whole-body radiotherapy. In this review we discuss the utilization of these small molecules in combination therapies and in scaffolds for imaging agents, radiotherapeutics, and radiotheranostics. Development of these radiolabeled PARP Inhibitors has presented promising results for new interventions in the fight against some of the most intractable cancers.