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CDk4/6 and Breast

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https://www.readbyqxmd.com/read/28418845/preclinical-development-of-g1t38-a-novel-potent-and-selective-inhibitor-of-cyclin-dependent-kinases-4-6-for-use-as-an-oral-antineoplastic-in-patients-with-cdk4-6-sensitive-tumors
#1
John E Bisi, Jessica A Sorrentino, Jamie L Jordan, David D Darr, Patrick J Roberts, Francis X Tavares, Jay C Strum
Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28403773/progress-of-cdk4-6-inhibitor-palbociclib-in-the-treatment-of-cancer
#2
Fengquan Chen, Jian Zhang, Wenfang Xu, Yingjie Zhang
The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. These kinases are closely related to oncogenesis and have been proved to be attractive targets for designing novel anticancer agents. The CDK inhibitors can effectively suppress the excessive proliferation of tumor cells by inducing cell cycle arrest. In recent years, a large number of CDK inhibitors have entered pre-clinical and/or clinical trials. Among these compounds, the selective CDK4/6 inhibitor Palbociclib has been approved by FDA for breast cancer treatment...
April 12, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28395543/pharmacokinetic-drug-evaluation-of-ribociclib-for-the-treatment-of-metastatic-hormone-positive-breast-cancer
#3
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...
April 11, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28370734/apoptosis-and-cell-cycle-regulatory-effects-of-adenosine-by-modulation-of-gli-1-and-erk1-2-pathways-in-cd44-and-cd24-breast-cancer-stem-cells
#4
S M Jafari, H R Joshaghani, M Panjehpour, M Aghaei, N Zargar Balajam
OBJECTIVES: Breast cancer stem cells (CSCs) are a small population of tumour cells with the ability of self-renewal and resistance to chemotherapy. Targeting CSCs is a promising strategy for treatment of cancer. A recent study demonstrated that adenosine receptor agonists inhibit glioblastoma CSCs proliferation. At present, the effect of adenosine on breast CSCs has not been reported. Therefore, this study was designed to evaluate the effect of adenosine and its signalling pathways in breast CSCs...
March 29, 2017: Cell Proliferation
https://www.readbyqxmd.com/read/28359238/hr-her2-advanced-breast-cancer-and-cdk4-6-inhibitors-mode-of-action-clinical-activity-and-safety-profiles
#5
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/28349562/palbociclib-has-anti-tumor-effects-on-pten-deficient-endometrial-neoplasias
#6
Maria Alba Dosil, Cristina Mirantes, Núria Eritja, Isidre Felip, Raúl Navaridas, Sònia Gatius, Maria Santacana, Eva Colàs, Cristian Moiola, Joan Antoni Schoenenberger, Mario Encinas, Eloi Garí, Xavier Matias-Guiu, Xavier Dolcet
PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to a dysregulation of cell division and promotes the accumulation of cell cycle complexes such as Cyclin D1-CDK4/6, which is an important feature of the tumor phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs...
March 27, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28325261/cdk4-6-inhibitors-in-her2-positive-breast-cancer
#7
REVIEW
Silvia Paola Corona, Andrea Ravelli, Daniele Cretella, Maria Rosa Cappelletti, Laura Zanotti, Martina Dester, Angela Gobbi, Pier Giorgio Petronini, Daniele Generali
Notwithstanding the continuous progress made in cancer treatment in the last 20 years, and the availability of new targeted therapies, metastatic Breast Cancer (BC) is still incurable. Targeting the cell cycle machinery has emerged as an attractive strategy to tackle cancer progression, showing very promising results in the preclinical and clinical settings. The first selective inhibitors of CDK4/6 received breakthrough status and FDA approval in combination with letrozole (February 2015) and fulvestrant (February 2016) as first-line therapy in ER-positive advanced and metastatic BC...
April 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28281842/opportunities-and-challenges-of-long-term-anti-estrogenic-adjuvant-therapy-treatment-forever-or-intermittently
#8
Poulomi Bhattacharya, Balkees Abderrahman, V Craig Jordan
Extended adjuvant (5-10 years) therapy targeted to the estrogen receptor (ER) has significantly decreased mortality from breast cancer (BC). Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops. Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy...
April 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28270497/neopalana-neoadjuvant-palbociclib-a-cyclin-dependent-kinase-4-6-inhibitor-and-anastrozole-for-clinical-stage-2-or-3-estrogen-receptor-positive-breast-cancer
#9
Cynthia X Ma, Feng Gao, Jingqin Luo, Donald W Northfelt, Matthew P Goetz, Andres Forero, Jeremy Hoog, Michael J Naughton, Foluso Ademuyiwa, Rama Suresh, Karen S Anderson, Julie Margenthaler, Rebecca Aft, Timothy J Hobday, Timothy Moynihan, William Gillanders, Amy Cyr, Timothy J Eberlein, Tina Hieken, Helen Krontiras, Zhanfang Guo, Michelle Lee, Nicholas C Spies, Zachary L Skidmore, Obi L Griffith, Malachi Griffith, Shana Thomas, Caroline Bumb, Kiran Vij, Cynthia Huang Bartlett, Maria Koehler, Hussam Al-Kateb, Souzan Sanati, Matthew J Ellis
PURPOSE: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the anti-proliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. EXPERIMENTAL DESIGN: Eligible patients with clinical stage II/III ER+/HER2- breast cancer received anastrozole 1mg daily for 4 weeks (cycle 0) (with goserelin if premenopausal), followed by adding palbociclib (125mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67>10%, in which case patients went off study due to inadequately response...
March 7, 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
#10
Valerie M Jansen, Neil E Bhola, Joshua A Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E Hutchinson, Agnieszka K Witkiewicz, Preston D Moore, Monica Valeria Estrada, Violeta Sanchez, Paula G Ericsson, Melinda Sanders, Paula R Pohlmann, Michael J Pishvaian, David A Riddle, Wenyi Wei, Teresa C Dugger, Erik Knudsen, Carlos L Arteaga
To discover mechanisms of resistance to CDK4/6 inhibitors, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, promote sensitivity to ribociclib. We identified 3-phosphoinositide dependent protein kinase 1 (PDK1) as the top siRNA that sensitized ER+ MCF-7 cells to ribociclib. Pharmacological inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, synergistically inhibited proliferation and increased apoptosis in a panel of ER+ breast cancer cell lines. Ribociclib-resistant MCF-7, T47D and HCC1428 cells, selected after chronic drug exposure, displayed increased levels of PDK1, P-RSK2, P-AKT and P-S6 compared to parental drug-sensitive cells...
March 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28203301/progress-with-palbociclib-in-breast-cancer-latest-evidence-and-clinical-considerations
#11
REVIEW
Andrea Rocca, Alessio Schirone, Roberta Maltoni, Sara Bravaccini, Lorenzo Cecconetto, Alberto Farolfi, Giuseppe Bronte, Daniele Andreis
Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated...
February 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28197838/the-growing-role-of-cdk4-6-inhibitors-in-treating-hormone-receptor-positive-advanced-breast-cancer
#12
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/28174091/inhibitors-of-cyclin-dependent-kinases-as-cancer-therapeutics
#13
REVIEW
Steven R Whittaker, Aurélie Mallinger, Paul Workman, Paul A Clarke
Over the past two decades there has been a great deal of interest in the development of inhibitors of the cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that different CDK isoforms have key roles in cancer cell proliferation through loss of regulation of the cell cycle, a hallmark feature of cancer. CDKs have now been shown to regulate other processes, particularly various aspects of transcription. The early non-selective CDK inhibitors exhibited considerable toxicity and proved to be insufficiently active in most cancers...
February 5, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28168755/palbociclib-can-overcome-mutations-in-cyclin-dependent-kinase-6-that-break-hydrogen-bonds-between-the-drug-and-the-protein
#14
Stella Hernandez Maganhi, Patrizia Jensen, Ignez Caracelli, Julio Zukerman Schpector, Stefan Fröhling, Ran Friedman
Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)-rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilized the drug in its binding site and that were not observed in the crystal structure of the protein-drug complex...
April 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28067227/cdk4-6-dependent-activation-of-dub3-regulates-cancer-metastasis-through-snail1
#15
Tongzheng Liu, Jia Yu, Min Deng, Yujiao Yin, Haoxing Zhang, Kuntian Luo, Bo Qin, Yunhui Li, Chenming Wu, Tao Ren, Yang Han, Peng Yin, JungJin Kim, SeungBaek Lee, Jing Lin, Lizhi Zhang, Jun Zhang, Somaira Nowsheen, Liewei Wang, Judy Boughey, Matthew P Goetz, Jian Yuan, Zhenkun Lou
Tumour metastasis, the spread of cancer cells from the original tumour site followed by growth of secondary tumours at distant organs, is the primary cause of cancer-related deaths and remains poorly understood. Here we demonstrate that inhibition of CDK4/6 blocks breast tumour metastasis in the triple-negative breast cancer model, without affecting tumour growth. Mechanistically, we identify a deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a key factor promoting epithelial-mesenchymal transition and breast cancer metastasis...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28050067/palbociclib-a-breakthrough-in-breast-carcinoma-in-women
#16
REVIEW
Ajay Kumar Gupta, Sushil Sharma, Navdeep Dahiya, D B S Brashier
Breast cancer (BC) is the most common cancer and leading cause of death in women worldwide. Cellular proliferation, growth, and division are tightly controlled by the cell-cycle regulatory machinery. An important pathway is cyclin-dependent kinases (CDKs) which regulate cell cycle and thus control transcriptional processes. In human cancer, multiple CDK family members are commonly deregulated. The cyclin D-CDK4/6-retinoblastoma (RB) protein-INK4 axis is particularly affected in many solid tumors which leads to cancer cell proliferation...
December 2016: Medical Journal, Armed Forces India
https://www.readbyqxmd.com/read/28042706/do-cdk4-6-inhibitors-have-potential-as-targeted-therapeutics-for-squamous-cell-cancers
#17
REVIEW
Nene N Kalu, Faye M Johnson
Introduction Dysregulation of cell cycle progression has an established link to neoplasia and cancer progression. Components of the cyclin D-CDK4/6-INK4-Rb pathway are frequently altered in squamous cell carcinomas (SCCs) by diverse mechanisms, including viral oncogene-induced degradation, mutation, deletion, and amplification. Activation of the CDK4/6 pathway may predict response to CDK4/6 inhibitors and provide clinical biomarkers. Recently, the CDK4/6 inhibitor palbociclib showed clinical efficacy in combination with cetuximab in HNSCC patients...
February 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28039467/targeting-cancer-stem-cell-propagation-with-palbociclib-a-cdk4-6-inhibitor-telomerase-drives-tumor-cell-heterogeneity
#18
Gloria Bonuccelli, Maria Peiris-Pages, Bela Ozsvari, Ubaldo E Martinez-Outschoorn, Federica Sotgia, Michael P Lisanti
In this report, we systematically examined the role of telomerase activity in lung and ovarian cancer stem cell (CSC) propagation. For this purpose, we indirectly gauged telomerase activity, by linking the hTERT-promoter to eGFP. Using lung (A549) and ovarian (SKOV3) cancer cells, transduced with the hTERT-GFP reporter, we then employed GFP-expression levels to fractionate these cell lines into GFP-high and GFP-low populations. We functionally compared the phenotype of these GFP-high and GFP-low populations...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/27986713/abemaciclib-shows-promise-for-early-breast-cancer
#19
(no author information available yet)
Treatment with the CDK4/6 inhibitor abemaciclib, alone or in combination with endocrine therapy, significantly lowered expression of the protein Ki67-a key marker of cell proliferation-in women with hormone receptor-positive, HER2-negative breast cancer. The findings from the phase II neoMONARCH trial suggest that CDK4/6 inhibition may be effective for neoadjuvant treatment of early breast cancer.
December 16, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27959954/protein-bound-polysaccharide-from-corbicula-fluminea-inhibits-cell-growth-in-mcf-7-and-mda-mb-231-human-breast-cancer-cells
#20
Ningbo Liao, Jianjun Zhong, Ronghua Zhang, Xingqian Ye, Yanjun Zhang, Wenjun Wang, Yuexia Wang, Shiguo Chen, Donghong Liu, Ruihai Liu
A novel protein-bound polysaccharide, CFPS-1, isolated from Corbicula fluminea, is composed predominantly of mannose (Man) and glucose (Glc) in a molar ratio of 3.1:12.7. The polysaccharide, with an average molecular weight of about 283 kDa, also contains 10.8% protein. Atomic force microscopy, high-performance liquid chromatography, Fourier transform infrared spectroscopy, gas chromatography/mass spectrometry, and nuclear magnetic resonance spectroscopy analyses revealed that CFPS-1 has a backbone of 1,6-linked and 1,4,6-linked-α-D-Glc, which is terminated with a 1-linked-α-D-Man residue at the O-4 position of 1,4,6-linked-α-D-Glc, in a molar ratio of 3:1:1...
2016: PloS One
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