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Ribociclib

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https://www.readbyqxmd.com/read/28620137/biological-specificity-of-cdk4-6-inhibitors-dose-response-relationship-in-vivo-signaling-and-composite-response-signature
#1
Erik S Knudsen, Jack Hutcheson, Paris Vail, Agnieszka K Witkiewicz
Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose-limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has diarrhea and fatigue as dose-limiting toxicities. In preclinical models, palbociclib has been extensively studied and induces cell cycle inhibition in an RB-dependent manner...
June 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28618307/meta-analysis-of-selected-toxicity-endpoints-of-cdk4-6-inhibitors-palbociclib-and-ribociclib
#2
REVIEW
R Costa, R B Costa, Sarah M Talamantes, Irene Helenowski, Jonna Peterson, Jason Kaplan, B A Carneiro, Francis J Giles, W J Gradishar
PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib and ribociclib are associated with distinct adverse effects (AEs) compared to other targeted therapies. This meta-analysis of clinical trials summarizes these agents' toxicity profile. METHODS: A librarian-guided literature search was conducted in March of 2017. The trials needed to have at least one of the study arms consisting of palbociclib or ribociclib monotherapy at currently FDA approved dose regimens...
June 12, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28580868/cell-cycle-therapeutics-come-of-age
#3
Matthew Ingham, Gary K Schwartz
The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy...
June 3, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28579722/pharmaceutical-approval-update
#4
Mary Choy
Ribociclib (Kisqali) for HR+/HER2- advanced or metastatic breast cancer in postmenopausal women; safinamide (Xadago) as adjunctive treatment for patients with Parkinson's disease; and avelumab (Bavencio) for metastatic Merkel cell carcinoma.
June 2017: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/28521250/development-and-validation-of-lc-ms-ms-methods-for-the-measurement-of-ribociclib-a-cdk4-6-inhibitor-in-mouse-plasma-and-ringer-s-solution-and-its-application-to-a-cerebral-microdialysis-study
#5
Ashish Kala, Yogesh T Patel, Abigail Davis, Clinton F Stewart
LC-MS/MS methods to measure ribociclib in mouse plasma and Ringer's solution were successfully developed and validated. Reverse phase chromatography was performed with gradient elution using C18 (100A, 50×4.6mm, 3μ) and C8-A (50×2.0mm, 5μ) columns for plasma and Ringer's samples, respectively. Mouse plasma samples were extracted using solid phase extraction method, whereas no extraction was required for the Ringer's solution samples. Analytes were detected using positive ion MRM mode. The precursor to product ions (Q1→Q3) selected for ribociclib and d6-ribociclib were (m/z) 435...
July 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28515242/new-approaches-to-endocrine-therapy-for-breast-cancer
#6
William J Gradishar
The management of advanced hormone receptor-positive disease has evolved with the emergence of CDK4/6 inhibitors. Improvements in progression-free survival of approximately 10 months were noted in pivotal trials of palbociclib. Strong efficacy was also seen with ribociclib, which was recently approved by the FDA. In the adjuvant treatment setting of hormone receptor-positive disease, an important issue for consideration is the duration of endocrine therapy.
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28453226/palbociclib-induces-activation-of-ampk-and-inhibits-hepatocellular-carcinoma-in-a-cdk4-6-independent-manner
#7
Feng-Shu Hsieh, Yao-Li Chen, Man-Hsin Hung, Pei-Yi Chu, Ming-Hsien Tsai, Li-Ju Chen, Yung-Jen Hsiao, Chih-Ting Shih, Mao-Ju Chang, Tzu-I Chao, Chung-Wai Shiau, Kuen-Feng Chen
Palbociclib, a CDK4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma (HCC), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC. We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5' AMP-activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition...
April 28, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28438180/recent-advances-of-highly-selective-cdk4-6-inhibitors-in-breast-cancer
#8
REVIEW
Hanxiao Xu, Shengnan Yu, Qian Liu, Xun Yuan, Sridhar Mani, Richard G Pestell, Kongming Wu
Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219)...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28432176/a-phase-i-study-of-the-cdk4-6-inhibitor-ribociclib-lee011-in-pediatric-patients-with-malignant-rhabdoid-tumors-neuroblastoma-and-other-solid-tumors
#9
Birgit Geoerger, Franck Bourdeaut, Steven G DuBois, Matthias Fischer, James I Geller, Nicholas G Gottardo, Aurélien Marabelle, Andrew D J Pearson, Shakeel Modak, Thomas Cash, Giles W Robinson, Marlyane Motta, Alessandro Matano, Suraj G Bhansali, Jason R Dobson, Sudha Parasuraman, Susan N Chi
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off)...
April 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28417244/ribociclib-first-global-approval
#10
Yahiya Y Syed
Ribociclib is an oral, small-molecule inhibitor of cyclin-dependent kinase (CDK) 4 and 6 that is under development by Novartis for the treatment of cancer. CDKs play an important role in cell cycle progression and cellular proliferation, and inhibition of these kinases with ribociclib results in G1 phase cell-cycle arrest. Ribociclib, in combination with an aromatase inhibitor, was recently approved in the USA for the first-line treatment of advanced breast cancer and has been submitted for approval in the EU for this indication...
May 2017: Drugs
https://www.readbyqxmd.com/read/28395543/pharmacokinetic-drug-evaluation-of-ribociclib-for-the-treatment-of-metastatic-hormone-positive-breast-cancer
#11
REVIEW
Giuseppe Curigliano, Carmen Criscitiello, Angela Esposito, Mattia Intra, Saverio Minucci
Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub-micromolar concentrations in a variety of pRb-positive cancer cells in vitro. Ribociclib is a new standard of care for metastatic HR+/HER2 negative metastatic breast cancer. Area covered: In this article, we review the preclinical and clinical development of ribociclib as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer...
May 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28382802/major-clinical-research-advances-in-gynecologic-cancer-in-2016-10-year-special-edition
#12
REVIEW
Dong Hoon Suh, Miseon Kim, Kidong Kim, Hak Jae Kim, Kyung Hun Lee, Jae Weon Kim
In 2016, 13 topics were selected as major research advances in gynecologic oncology. For ovarian cancer, study results supporting previous ones regarding surgical preventive strategies were reported. There were several targeted agents that showed comparable responses in phase III trials, including niraparib, cediranib, and nintedanib. On the contrary to our expectations, dose-dense weekly chemotherapy regimen failed to prove superior survival outcomes compared with conventional triweekly regimen. Single-agent non-platinum treatment to prolong platinum-free-interval in patients with recurrent, partially platinum-sensitive ovarian cancer did not improve and even worsened overall survival (OS)...
May 2017: Journal of Gynecologic Oncology
https://www.readbyqxmd.com/read/28359238/hr-her2-advanced-breast-cancer-and-cdk4-6-inhibitors-mode-of-action-clinical-activity-and-safety-profiles
#13
Sarah L Sammons, Donna L Topping, Kimberly L Blackwell
Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapies have shown great promise in improving clinical outcomes for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Addition of a CDK4/6 inhibitor to endocrine therapy increases efficacy and delays disease progression. Successful use of CDK4/6 inhibitor-based therapies in the clinic requires insight into the unique side-effect profiles of this class of agents and effective patient monitoring...
March 30, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28356261/ribociclib-approved-for-advanced-breast-cancer
#14
(no author information available yet)
The FDA has approved ribociclib combined with aromatase inhibitor therapy for women with metastatic HR-positive, HER2-negative breast cancer. It is the second CDK 4/6 inhibitor approved for these patients, behind palbociclib; a third is under investigation.
May 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28351928/ribociclib-lee011-mechanism-of-action-and-clinical-impact-of-this-selective-cyclin-dependent-kinase-4-6-inhibitor-in-various-solid-tumors
#15
Debu Tripathy, Aditya Bardia, William R Sellers
The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which was granted priority review by the US Food and Drug Administration in November 2016, and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib...
March 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28249908/kinome-wide-rna-interference-screen-reveals-a-role-for-pdk1-in-acquired-resistance-to-cdk4-6-inhibition-in-er-positive-breast-cancer
#16
Valerie M Jansen, Neil E Bhola, Joshua A Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E Hutchinson, Agnieszka K Witkiewicz, Preston D Moore, Mónica Valéria Estrada, Violeta Sánchez, Paula G Ericsson, Melinda E Sanders, Paula R Pohlmann, Michael J Pishvaian, David A Riddle, Teresa C Dugger, Wenyi Wei, Erik S Knudsen, Carlos L Arteaga
Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor-positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines...
May 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28226315/the-novel-cyclin-dependent-kinase-4-6-inhibitor-ribociclib-lee011-alone-and-in-dual-targeting-approaches-demonstrates-antitumoral-efficacy-in-neuroendocrine-tumors-in-vitro
#17
Elke Tatjana Aristizabal Prada, Svenja Noelting, Gerald Spoettl, Julian Maurer, Christoph Joseph Auernhammer
No abstract text is available yet for this article.
February 23, 2017: Neuroendocrinology
https://www.readbyqxmd.com/read/28197838/the-growing-role-of-cdk4-6-inhibitors-in-treating-hormone-receptor-positive-advanced-breast-cancer
#18
REVIEW
Ami N Shah, Massimo Cristofanilli
Single-agent endocrine therapy has been the standard therapeutic choice for the management of hormone receptor (HR)-positive, Her2-negative advanced breast cancer (ABC) for decades. However, the rapidly accumulating data regarding the biological role and safety of CDK4/6 inhibitors and the first-in-class approval of palbociclib have made these novel agents an essential component of treatment for HR-positive ABC. In the frontline setting, palbociclib in combination with endocrine therapy showed an improvement in progression-free survival (PFS) by 10 months to nearly 25 months when compared with endocrine therapy alone and a clinical benefit rate (CBR = stable disease >24 weeks + partial response + complete response) of 85%...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28126188/-cell-cycle-inhibitors-in-endocrine-receptor-positive-breast-cancer
#19
Marie-Paule Sablin, Francesco Ricci, Delphine Loirat, Aude Jobard, Clémence Basse, Emanuela Romano, Christophe Le Tourneau, Véronique Dieras
Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4 and 6 revived interest in this therapeutic class after the failure of pan-inhibitors. Palbociclib, ribociclib, and abemaciclib are the 3 drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation...
February 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/27986745/dual-alk-and-cdk4-6-inhibition-demonstrates-synergy-against-neuroblastoma
#20
Andrew C Wood, Kateryna Krytska, Hannah T Ryles, Nicole R Infarinato, Renata Sano, Theodore D Hansel, Lori S Hart, Frederick J King, Timothy R Smith, Edward Ainscow, Kathryn B Grandinetti, Tove Tuntland, Sunkyu Kim, Giordano Caponigro, You Qun He, Shiva Krupa, Nanxin Li, Jennifer L Harris, Yaël P Mossé
Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine whether drug combinations could enhance antitumor efficacy.Experimental Design: We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status...
June 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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