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https://www.readbyqxmd.com/read/29792845/current-frontline-endocrine-treatment-options-for-women-with-hormone-receptor-positive-human-epidermal-growth-factor-receptor-2-her2-negative-advanced-stage-breast-cancer
#1
REVIEW
Hikmat N Abdel-Razeq
Despite the recent advances in breast cancer early detection and awareness, a significant portion of patients present with an advanced-stage disease and more patients will progress to stage IV despite adequate treatment of their initial early-stage disease. Hormone receptor (HR)-positive, Human Epidermal Growth Factor Receptor-2 (HER2)-negative subtype is the commonest among all breast cancer subtypes. The management of the advanced-stage disease of this subtype has evolved significantly over the past few years...
May 19, 2018: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/29784737/nccn-guidelines-updates-breast-cancer
#2
Sharon H Giordano, Anthony D Elias, William J Gradishar
The emergence of CDK4/6 inhibitors has changed the treatment algorithm for advanced/metastatic estrogen receptor-positive breast cancer. In pivotal trials of palbociclib, ribociclib, and abemaciclib, doubling in progression-free survival has been seen. All 3 agents in this class are now included in the NCCN Guidelines for Breast Cancer, and clinicians should be incorporating these agents into their treatment algorithms. The other important issue in this breast cancer setting is extended duration of endocrine therapy...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29726787/role-of-cyclin-dependent-kinase-4-6-inhibitors-in-the-current-and-future-eras-of-cancer-treatment
#3
S Parylo, A Vennepureddy, V Dhar, P Patibandla, A Sokoloff
Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy...
January 1, 2018: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29725889/use-of-cyclin-dependent-kinase-cdk-4-6-inhibitors-for-hormone-receptor-positive-human-epidermal-growth-factor-receptor-2-negative-metastatic-breast-cancer-a-roundtable-discussion-by-the-breast-cancer-therapy-expert-group-bcteg
#4
REVIEW
Jame Abraham, Robert Coleman, Anthony Elias, Frankie Ann Holmes, Kevin Kalinsky, Muaiad Kittaneh, Elyse Lower, Reshma Mahtani, E Terry Mamounas, Mark Pegram, Charles Vogel
PURPOSE: To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community. METHODS: A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice...
May 4, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29716919/abemaciclib-a-selective-cdk4-6-inhibitor-enhances-the-radiosensitivity-of-non-small-cell-lung-cancer-in-vitro-and-in-vivo
#5
Sarwat Naz, Anastasia L Sowers, Rajani Choudhuri, Maria F Wissler, Janet Gamson, Askale Mathias, John A Cook, James B Mitchell
PURPOSE: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of CDK4/6 inhibitor, Abemaciclib in Non-Small Cell Lung Cancer cells (NSCLC) in vitro and in vivo Experimental Design: IR enhancement by Abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by γ-H2AX analysis. Global metabolic alterations by Abemaciclib and IR combination was evaluated by LC/MS mass spectrometry and YSI-Bioanalyzer...
May 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29700711/cyclin-dependent-kinase-4-6-inhibitors-in-hormone-receptor-positive-early-breast-cancer-preliminary-results-and-ongoing-studies
#6
REVIEW
Dorota Kwapisz
The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER-positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed...
April 26, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29539425/the-cdk4-6-inhibitor-abemaciclib-induces-a-t-cell-inflamed-tumor-microenvironment-and-enhances-the-efficacy-of-pd-l1-checkpoint-blockade
#7
David A Schaer, Richard P Beckmann, Jack A Dempsey, Lysiane Huber, Amelie Forest, Nelusha Amaladas, Yanxia Li, Ying Cindy Wang, Erik R Rasmussen, Darin Chin, Andrew Capen, Carmine Carpenito, Kirk A Staschke, Linda A Chung, Lacey M Litchfield, Farhana F Merzoug, Xueqian Gong, Philip W Iversen, Sean Buchanan, Alfonso de Dios, Ruslan D Novosiadly, Michael Kalos
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control...
March 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29527939/different-inhibitors-for-the-same-target-in-metastatic-luminal-breast-cancer-is-there-any-difference
#8
Elie El Rassy, Ziad Bakouny, Tarek Assi, Joseph Kattan
AIM: To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer. MATERIALS & METHODS: A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication...
April 2018: Future Oncology
https://www.readbyqxmd.com/read/29522364/abemaciclib-for-the-treatment-of-breast-cancer
#9
Takeshi Kotake, Masakazu Toi
There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms. Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer. Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy...
April 2018: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29497278/abemaciclib-a-cdk4-6-inhibitor-for-the-treatment-of-hr-her2-advanced-breast-cancer
#10
REVIEW
Silvia Paola Corona, Daniele Generali
Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29483214/preclinical-activity-of-abemaciclib-alone-or-in-combination-with-antimitotic-and-targeted-therapies-in-breast-cancer
#11
Neil O'Brien, Dylan Conklin, Richard Beckmann, Tong Luo, Kevin Chau, Josh Thomas, Ann Mc Nulty, Christophe Marchal, Ondrej Kalous, Erika von Euw, Sara Hurvitz, Colleen Mockbee, Dennis J Slamon
The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+ /HER2- and ER+ /HER2+ subtypes. However, a subset of triple-negative breast cancer (TNBC) cell lines with intact Rb signaling were also found to be responsive...
May 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29470723/cyclin-dependent-kinase-4-6-inhibitors-as-first-line-treatment-for-post-menopausal-metastatic-hormone-receptor-positive-breast-cancer-patients-a-systematic-review-and-meta-analysis-of-phase-iii-randomized-clinical-trials
#12
Allan Ramos-Esquivel, Hellen Hernández-Steller, Marie-France Savard, Denis Ulises Landaverde
BACKGROUND: To compare the efficacy and toxicity of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and nonsteroidal aromatase inhibitors (AI) versus AI alone as first-line therapy for patients with advanced hormone receptor-positive breast cancer. MATERIALS AND METHODS: Phase III randomized clinical trials (RCT) were identified after a systematic review of electronic databases. A random-effect model was used to determine the pooled hazard ratio (HR) for progression-free survival (PFS) using the inverse-variance method...
February 22, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29429832/design-and-synthesis-of-4-2-3-dihydro-1h-benzo-d-pyrrolo-1-2-a-imidazol-7-yl-n-5-piperazin-1-ylmethyl-pyridine-2-yl-pyrimidin-2-amine-as-a-highly-potent-and-selective-cyclin-dependent-kinases-4-and-6-inhibitors-and-the-discovery-of-structure-activity-relationships
#13
Yan Wang, Wen-Jian Liu, Lei Yin, Heng Li, Zhen-Hua Chen, Dian-Xi Zhu, Xiu-Qing Song, Zhen-Zhen Cheng, Peng Song, Zhan Wang, Zhi-Gang Li
Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50  = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219...
March 1, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29392622/clinical-development-of-cdk4-6-inhibitor-for-breast-cancer
#14
Hiroji Iwata
Endocrine therapy is the mainstay of treatment for patients with estrogen receptor positive (ER+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Many clinicians consider the sequential endocrine therapy is gold standard strategy because of better outcome and the maintenance of a better quality of life (QOL) for MBC patients. However, clinical practice shall be changed according to development of CDK4/6 inhibitor in current. CDK4/6 is key kinase which promote the cell cycle, and especially the expression of cyclin D1 and the activation of CDK4/6 to drive breast cancer proliferation...
February 1, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29374415/-inhibitors-of-cyclin-dependent-kinases-cdk-a-new-group-of-medicines-in-therapy-of-advanced-breast-cancer
#15
EDITORIAL
Tomasz Sarosiek
Cyclin-dependent kinases (CDKs) are a family of enzyme proteins present in cell nuclei that regulate the various stages of the cell cycle. They act as proto-oncogens, and increased expression of some of these proteins (CDK4 and CDK6) is observed in breast cancer cells and associated with decreased sensitivity to anti-estrogen therapy. CDK inhibitors are chemicals that inhibit the enzymatic activity of specific CDKs. Currently three drugs in this group are available on the market and are registered for the treatment of advanced HR-positive, HER2-negative breast cancer...
January 23, 2018: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
https://www.readbyqxmd.com/read/29247857/a-highly-potent-cdk4-6-inhibitor-was-rationally-designed-to-overcome-blood-brain-barrier-in-gliobastoma-therapy
#16
Lei Yin, Heng Li, Wenjian Liu, Zhenglin Yao, Zhenzhen Cheng, Huabei Zhang, Hui Zou
Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system...
January 20, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29245989/cdk4-6-dual-inhibitor-abemaciclib-demonstrates-compelling-preclinical-activity-against-esophageal-adenocarcinoma-a-novel-therapeutic-option-for-a-deadly-disease
#17
Juliann E Kosovec, Ali H Zaidi, Ashten N Omstead, Daisuke Matsui, Mark J Biedka, Erin J Cox, Patrick T Campbell, Robert W W Biederman, Ronan J Kelly, Blair A Jobe
Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro , apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo , esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29236235/potential-biomarkers-of-cdk4-6-inhibitors-in-hormone-receptor-positive-advanced-breast-cancer
#18
REVIEW
Hehui Fang, Doudou Huang, Fang Yang, Xiaoxiang Guan
PURPOSE: Cyclin D/cyclin-dependent kinase 4/6 (CDK4/6) complex inhibitors have recently been proven effective when combined with endocrine therapy in clinical trials. However, the clinical benefit from CDK4/6 inhibitor varied from different patients. In order to optimize the clinical application of CDK4/6 inhibitors, this review focuses on the potential biomarkers applicable to identify patients who will benefit the most from CDK4/6 inhibition. METHODS: We have summarized the clinical trials about addition of CDK4/6 inhibitors to endocrine therapy and reviewed literature currently available on the potential biomarkers in predicting efficacy of CDK4/6 inhibitors...
April 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29232554/genomic-aberrations-that-activate-d-type-cyclins-are-associated-with-enhanced-sensitivity-to-the-cdk4-and-cdk6-inhibitor-abemaciclib
#19
Xueqian Gong, Lacey M Litchfield, Yue Webster, Li-Chun Chio, Swee Seong Wong, Trent R Stewart, Michele Dowless, Jack Dempsey, Yi Zeng, Raquel Torres, Karsten Boehnke, Cecilia Mur, Carlos Marugán, Carmen Baquero, Chunping Yu, Steven M Bray, Isabella H Wulur, Chen Bi, Shaoyou Chu, Hui-Rong Qian, Philip W Iversen, Farhana F Merzoug, Xiang S Ye, Christoph Reinhard, Alfonso De Dios, Jian Du, Charles W Caldwell, María José Lallena, Richard P Beckmann, Sean G Buchanan
Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer...
December 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29232548/genomic-biomarkers-predicting-response-to-selective-cdk4-6-inhibition-progress-in-an-elusive-search
#20
Geoffrey I Shapiro
In this issue of Cancer Cell, Gong et al. have analyzed the sensitivity of 560 cell lines to the selective CDK4/6 inhibitor abemaciclib and have defined cancers with specific genomic "D-cyclin activating features (DCAF)" as particularly vulnerable. These findings will facilitate patient selection as development of this drug class continues.
December 11, 2017: Cancer Cell
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