6 results on '"Grillot K"'
Search Results
2. Novel selective estrogen receptors degraders regress tumors in pre-clinical models of endocrine-resistant breast cancer.
- Author
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Hager, J. H., Darimont, B., Joseph, J., Govek, S., Grillot, K., Aparicio, A., Bischoff, E., Kahraman, M., Kaufman, J., Lai, A., Lee, K.-J., Lu, N., Nagasawa, J., Prudente, R., Qian, J., Sensintaffar, J., Shao, G., Heyman, R., Rix, P., and Smith, N. D.
- Subjects
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ESTROGEN receptors , *BREAST cancer research , *HORMONE synthesis , *TUMORS , *CELL lines - Abstract
80% of all breast cancers express the estrogen receptor alpha (ERκ) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to depend on ERκ for growth and survival. The emerging evidence that ERa can signal in both a ligand-dependent and ligand-independent manner supports the development of agents that are not only competitive ERκ antagonists but also reduce steady state levels of the receptor and thus limit both modes of signaling. We have identified novel, non-steroidal ERa antagonists that induce degradation of ERa in breast cancer cell lines at picomolar concentrations resulting in significant reduction in steady state ERa protein levels. Using peptide-based conformational profiling, we show that these Selective Estrogen Receptor Degraders (SERDs) induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating a unique mechanism of action. This unique biological profile coupled with good oral pharmacokinetics produces tumor regressions in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Recent pre-clinical and clinical data indicate that PI3K pathway signaling can contribute to the endocrine resistant state. In a preclinical model of tamoxifen resistant breast cancer in which SERD monotherapy only produces tumor growth inhibition, SERD therapy in combination with torc1/2 inhibition results in frank tumor regressions. These orally bioavailable SERDs hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
3. Correction: The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.
- Author
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Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z, Kategaya L, Govek SP, Lai AG, Kahraman M, Brigham D, Sensintaffar J, Lu N, Shao G, Qian J, Grillot K, Moon M, Prudente R, Bischoff E, Lee KJ, Bonnefous C, Douglas KL, Julien JD, Nagasawa JY, Aparicio A, Kaufman J, Haley B, Giltnane JM, Wertz IE, Lackner MR, Nannini MA, Sampath D, Schwarz L, Manning HC, Tantawy MN, Arteaga CL, Heyman RA, Rix PJ, Friedman L, Smith ND, Metcalfe C, and Hager JH
- Published
- 2019
- Full Text
- View/download PDF
4. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.
- Author
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Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z, Kategaya L, Govek SP, Lai AG, Kahraman M, Brigham D, Sensintaffar J, Lu N, Shao G, Qian J, Grillot K, Moon M, Prudente R, Bischoff E, Lee KJ, Bonnefous C, Douglas KL, Julien JD, Nagasawa JY, Aparicio A, Kaufman J, Haley B, Giltnane JM, Wertz IE, Lackner MR, Nannini MA, Sampath D, Schwarz L, Manning HC, Tantawy MN, Arteaga CL, Heyman RA, Rix PJ, Friedman L, Smith ND, Metcalfe C, and Hager JH
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- Animals, Cell Line, Tumor, Disease Models, Animal, Heterografts, Humans, Mice, Prospective Studies, Rats, Treatment Outcome, Antineoplastic Agents administration & dosage, Breast Neoplasms drug therapy, Cinnamates administration & dosage, Indazoles administration & dosage, Receptors, Estrogen administration & dosage
- Abstract
ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
- Published
- 2016
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5. Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
- Author
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Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, and Smith ND
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- Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Breast drug effects, Breast metabolism, Breast pathology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Dogs, Drug Discovery, Drug Resistance, Neoplasm drug effects, Female, Heterografts, Humans, Mice, Rats, Small Molecule Libraries administration & dosage, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacokinetics, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Estrogen Receptor alpha metabolism, Proteolysis drug effects, Selective Estrogen Receptor Modulators pharmacology, Small Molecule Libraries therapeutic use, Tamoxifen pharmacology
- Abstract
Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
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- 2015
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6. ARN-509: a novel antiandrogen for prostate cancer treatment.
- Author
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Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, and Hager JH
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- Androgen Antagonists pharmacokinetics, Anilides pharmacokinetics, Anilides therapeutic use, Animals, Antineoplastic Agents, Hormonal blood, Antineoplastic Agents, Hormonal pharmacokinetics, Benzamides, Cell Line, Tumor, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Nitriles pharmacokinetics, Nitriles therapeutic use, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin blood, Phenylthiohydantoin pharmacokinetics, Phenylthiohydantoin therapeutic use, Rats, Receptors, Androgen drug effects, Thiohydantoins blood, Thiohydantoins chemical synthesis, Thiohydantoins pharmacokinetics, Tosyl Compounds pharmacokinetics, Tosyl Compounds therapeutic use, Xenograft Model Antitumor Assays, Androgen Antagonists therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Prostatic Neoplasms drug therapy, Thiohydantoins therapeutic use
- Abstract
Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
- Published
- 2012
- Full Text
- View/download PDF
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