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https://www.readbyqxmd.com/read/27542767/a-phase-i-study-of-the-cyclin-dependent-kinase-4-6-inhibitor-ribociclib-lee011-in-patients-with-advanced-solid-tumors-and-lymphomas
#1
Jeffrey R Infante, Philippe A Cassier, John F Gerecitano, Petronella O Witteveen, Rashmi Chugh, Vincent Ribrag, Abhijit Chakraborty, Alessandro Matano, Jason R Dobson, Adam S Crystal, Sudha Parasuraman, Geoffrey I Shapiro
PURPOSE: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb(+)). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb(+) advanced solid tumors or lymphomas. EXPERIMENTAL DESIGN: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous)...
December 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27493615/clinical-development-of-the-cdk4-6-inhibitors-ribociclib-and-abemaciclib-in-breast-cancer
#2
REVIEW
Romualdo Barroso-Sousa, Geoffrey I Shapiro, Sara M Tolaney
Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development...
June 2016: Breast Care
https://www.readbyqxmd.com/read/27336726/ribociclib-plus-letrozole-in-early-breast-cancer-a-presurgical-window-of-opportunity-study
#3
G Curigliano, P Gómez Pardo, F Meric-Bernstam, P Conte, M P Lolkema, J T Beck, A Bardia, M Martínez García, F Penault-Llorca, S Dhuria, Z Tang, N Solovieff, M Miller, E Di Tomaso, S A Hurvitz
OBJECTIVES: 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). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2...
August 2016: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/27267837/bez235-pik3-mtor-inhibitor-overcomes-pazopanib-resistance-in-patient-derived-refractory-soft-tissue-sarcoma-cells
#4
Hee Kyung Kim, Sun Young Kim, Su Jin Lee, Mihyeon Kang, Seung Tae Kim, Jiryeon Jang, Oliver Rath, Julia Schueler, Dong Woo Lee, Woong Yang Park, Sung Joo Kim, Se Hoon Park, Jeeyun Lee
BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients...
June 2016: Translational Oncology
https://www.readbyqxmd.com/read/27017286/targeting-cdk4-6-in-patients-with-cancer
#5
REVIEW
Erika Hamilton, Jeffrey R Infante
The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components...
April 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/26995305/cyclin-dependent-protein-kinase-inhibitors-including-palbociclib-as-anticancer-drugs
#6
REVIEW
Robert Roskoski
Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1 phase of the cell cycle produce cyclins of the D type that activate CDK4/6...
May 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/26642065/cyclin-dependent-kinase-pathways-as-targets-for-women-s-cancer-treatment
#7
REVIEW
Gottfried E Konecny
PURPOSE OF REVIEW: In this article, we not only review the preclinical and clinical studies of cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer, liposarcoma, mantel cell lymphoma, melanoma and germ cell tumors, but also examine promising preclinical data in glioblastoma, renal and ovarian cancer models that may provide directions for future development. RECENT FINDINGS: Targeting CDKs has been the focus of considerable basic science and clinical research...
February 2016: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/26390342/chemoproteomics-reveals-novel-protein-and-lipid-kinase-targets-of-clinical-cdk4-6-inhibitors-in-lung-cancer
#8
Natalia J Sumi, Brent M Kuenzi, Claire E Knezevic, Lily L Remsing Rix, Uwe Rix
Several selective CDK4/6 inhibitors are in clinical trials for non-small cell lung cancer (NSCLC). Palbociclib (PD0332991) is included in the phase II/III Lung-MAP trial for squamous cell lung carcinoma (LUSQ). We noted differential cellular activity between palbociclib and the structurally related ribociclib (LEE011) in LUSQ cells. Applying an unbiased mass spectrometry-based chemoproteomics approach in H157 cells and primary tumor samples, we here report distinct proteome-wide target profiles of these two drug candidates in LUSQ, which encompass novel protein and, for palbociclib only, lipid kinases...
December 18, 2015: ACS Chemical Biology
https://www.readbyqxmd.com/read/26303211/cyclin-dependent-kinase-4-6-inhibitors-for-the-treatment-of-breast-cancer-a-review-of-preclinical-and-clinical-data
#9
REVIEW
Neelima Vidula, Hope S Rugo
For millions of women, breast cancer remains a potentially life-endangering diagnosis. With advances in research, new therapies targeted to tumor biology are emerging to treat the most common form of this disease. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of therapeutic agents that have the potential to improve the outcomes of patients with hormone receptor-positive (HR(+)) breast cancer. Three CDK 4/6 inhibitors have been investigated for the treatment of HR(+) breast cancer, including palbociclib (PD 0332991), ribociclib (LEE011), and abemaciclib (LY2835219)...
February 2016: Clinical Breast Cancer
https://www.readbyqxmd.com/read/25914884/targeting-cell-cycle-regulators-in-hematologic-malignancies
#10
REVIEW
Eiman Aleem, Robert J Arceci
Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair...
2015: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/25876993/the-role-of-cdk4-6-inhibition-in-breast-cancer
#11
REVIEW
Conleth G Murphy, Maura N Dickler
Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib)...
May 2015: Oncologist
https://www.readbyqxmd.com/read/25852058/cdkn2a-p16-loss-implicates-cdk4-as-a-therapeutic-target-in-imatinib-resistant-dermatofibrosarcoma-protuberans
#12
Grant Eilers, Jeffrey T Czaplinski, Mark Mayeda, Nacef Bahri, Derrick Tao, Meijun Zhu, Jason L Hornick, Neal I Lindeman, Ewa Sicinska, Andrew J Wagner, Jonathan A Fletcher, Adrian Mariño-Enriquez
Dermatofibrosarcoma protuberans (DFSP) is an aggressive PDGFB-dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences. Some DFSP progress to a higher-grade fibrosarcomatous form, with rapid growth and increased risk of metastasis. Imatinib provides clinical benefit in approximately 50% of patients with unresectable or metastatic DFSP. However, efficacious medical therapies have not been developed for imatinib-resistant DFSP. We established a model of imatinib-resistant DFSP and evaluated CDK4/6 inhibition as a genomically credentialed targeted therapy...
June 2015: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/25848011/mitigation-of-acute-kidney-injury-by-cell-cycle-inhibitors-that-suppress-both-cdk4-6-and-oct2-functions
#13
Navjotsingh Pabla, Alice A Gibson, Mike Buege, Su Sien Ong, Lie Li, Shuiying Hu, Guoqing Du, Jason A Sprowl, Aksana Vasilyeva, Laura J Janke, Eberhard Schlatter, Taosheng Chen, Giuliano Ciarimboli, Alex Sparreboom
Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage...
April 21, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25810375/cdk4-amplification-reduces-sensitivity-to-cdk4-6-inhibition-in-fusion-positive-rhabdomyosarcoma
#14
Mary E Olanich, Wenyue Sun, Stephen M Hewitt, Zied Abdullaev, Svetlana D Pack, Frederic G Barr
PURPOSE: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3- or PAX7-FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13-q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS. EXPERIMENTAL DESIGN: We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts...
November 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25716100/targeting-breast-cancer-with-cdk-inhibitors
#15
REVIEW
Erica L Mayer
Dysregulation of the cell cycle is a classic hallmark of cancer growth and metastatic potential. Re-establishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy. Three oral agents selectively targeting CDK4/6 have been developed: palbociclib, abemaciclib, and LEE011. Preclinical models show optimal activity in hormone receptor positive breast cancer, which may display biologic features suggesting particular dependence on the CDK4/cyclin D1/Rb interaction...
2015: Current Oncology Reports
https://www.readbyqxmd.com/read/25092757/drug-combo-shows-promise-in-nras-mutant-melanoma
#16
(no author information available yet)
No abstract text is available yet for this article.
August 2014: Cancer Discovery
https://www.readbyqxmd.com/read/25028469/antiproliferative-effects-of-cdk4-6-inhibition-in-cdk4-amplified-human-liposarcoma-in-vitro-and-in-vivo
#17
Yi-Xiang Zhang, Ewa Sicinska, Jeffrey T Czaplinski, Stephen P Remillard, Samuel Moss, Yuchuan Wang, Christopher Brain, Alice Loo, Eric L Snyder, George D Demetri, Sunkyu Kim, Andrew L Kung, Andrew J Wagner
Well-differentiated/dedifferentiated liposarcomas (WD/DDLPS) are among the most common subtypes of soft tissue sarcomas. Conventional systemic chemotherapy has limited efficacy and novel therapeutic strategies are needed to achieve better outcomes for patients. The cyclin-dependent kinase 4 (CDK4) gene is highly amplified in more than 95% of WD/DDLPS. In this study, we explored the role of CDK4 and the effects of NVP-LEE011 (LEE011), a novel selective inhibitor of CDK4/CDK6, on a panel of human liposarcoma cell lines and primary tumor xenografts...
September 2014: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/24795392/molecular-pathways-cdk4-inhibitors-for-cancer-therapy
#18
REVIEW
Mark A Dickson
Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G1-S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16-CDK4-cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy...
July 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/24045179/dual-cdk4-cdk6-inhibition-induces-cell-cycle-arrest-and-senescence-in-neuroblastoma
#19
Julieann Rader, Mike R Russell, Lori S Hart, Michael S Nakazawa, Lili T Belcastro, Daniel Martinez, Yimei Li, Erica L Carpenter, Edward F Attiyeh, Sharon J Diskin, Sunkyu Kim, Sudha Parasuraman, Giordano Caponigro, Robert W Schnepp, Andrew C Wood, Bruce Pawel, Kristina A Cole, John M Maris
PURPOSE: Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell-cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes. EXPERIMENTAL PROCEDURES: We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011 (Novartis Oncology), a highly specific CDK4/6 inhibitor...
November 15, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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