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Palbociclib

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https://www.readbyqxmd.com/read/28637687/inhibition-of-cdk4-6-by-palbociclib-significantly-extends-survival-in-medulloblastoma-patient-derived-xenograft-mouse-models
#1
Michelle L Cook Sangar, Laura A Genovesi, Madison W Nakamoto, Melissa J Davis, Sue E Knoblaugh, Pengxiang Ji, Amanda Millar, Brandon Wainwright, James M Olson
  <p>Bioinformatics analysis followed by in vivo studies in patient-derived xenograft models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly Group 3 MYC-amplified tumors which have the worst clinical prognosis.</p> <br />Experimental Design: <p>A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets.  The top hit from this analysis was validated in vivo using patient-derived xenograft models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice...
June 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28629371/combined-targeting-of-mdm2-and-cdk4-is-synergistic-in-dedifferentiated-liposarcomas
#2
Audrey Laroche-Clary, Vanessa Chaire, Marie-Paule Algeo, Marie-Alix Derieppe, François L Loarer, Antoine Italiano
PURPOSE: MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. EXPERIMENTAL DESIGN: DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting...
June 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28620137/biological-specificity-of-cdk4-6-inhibitors-dose-response-relationship-in-vivo-signaling-and-composite-response-signature
#3
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/28619757/cdk4-6-inhibitors-sensitize-rb-positive-sarcoma-cells-to-wee1-kinase-inhibition-through-reversible-cell-cycle-arrest
#4
Ashleigh M Francis, Angela Alexander, Yanna Liu, Smruthi Vijayaraghavan, Kwang Hui Low, Dong Yang, Tuyen Bui, Neeta Somaiah, Vinod Ravi, Khandan Keyomarsi, Kelly K Hunt
Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28618307/meta-analysis-of-selected-toxicity-endpoints-of-cdk4-6-inhibitors-palbociclib-and-ribociclib
#5
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/28606920/single-cell-dynamics-determines-response-to-cdk4-6-inhibition-in-triple-negative-breast-cancer
#6
Uzma Asghar, Alexis R Barr, Ros Cutts, Matthew Beaney, Irina S Babina, Deepak Sampath, Jennifer Giltnane, Jennifer A Lacap, Lisa Crocker, Amy Young, Alex Pearson, Maria Teresa Herrera-Abreu, Chris Bakal, Nicholas C Turner
Purpose: Triple negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes, and investigated mechanisms of sensitivity. <p>Experimental design: A panel of cell lines representative of TNBC were tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single cell analysis in conjunction with time-lapse imaging.</p> <p>Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro [p<0...
June 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28585619/-palbociclib-combinations-as-new-therapeutic-strategies-in-the-treatment-of-hr-her2-advanced-breast-cancer
#7
Katalin Boér
Until recently, the only endocrine agents used to treat HR+/HER2- advanced breast cancers were tamoxifen, aromatase inhibitors and fulvestrant, although a substantial proportion of patients relapse on these standard therapies. Intensive research has been conducted to develop new strategies to overcome endocrine resistance and to enhance the efficacy of endocrine treatments by combining hormone therapy with other targeted treatment approaches. The development of selective CDK4/6 inhibitors and the introduction of palbociclib, the first molecule in this class in clinical practice, represent an important step in the treatment of HR+ advanced breast cancer...
June 6, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28580868/cell-cycle-therapeutics-come-of-age
#8
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/28566433/mtorc1-inhibition-induces-resistance-to-methotrexate-and-6-mercaptopurine-in-ph-and-ph-like-b-all
#9
Thanh-Trang T Vo, Jong-Hoon S Lee, Duc Nguyen, Brandon Lui, William Pandori, Andrew Khaw, Sharmila Mallya, Mengrou Lu, Markus Müschen, Marina Konopleva, David A Fruman
Elevated activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph(+) and Ph-like B-ALL models...
May 31, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28566333/cdk4-phosphorylation-status-and-a-linked-gene-expression-profile-predict-sensitivity-to-palbociclib
#10
Eric Raspé, Katia Coulonval, Jaime M Pita, Sabine Paternot, Françoise Rothé, Laure Twyffels, Sylvain Brohée, Ligia Craciun, Denis Larsimont, Véronique Kruys, Flavienne Sandras, Isabelle Salmon, Steven Van Laere, Martine Piccart, Michail Ignatiadis, Christos Sotiriou, Pierre P Roger
Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4...
May 31, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28525384/secretome-analysis-of-breast-cancer-associated-adipose-tissue-to-identify-paracrine-regulators-of-breast-cancer-growth
#11
Lore Lapeire, An Hendrix, Evelyne Lecoutere, Mieke Van Bockstal, Jo Vandesompele, Dawn Maynard, Geert Braems, Rudy Van Den Broecke, Cathérine Müller, Marc Bracke, Véronique Cocquyt, Hannelore Denys, Olivier De Wever
Adipose tissue secretes a plethora of adipokines as evidenced by characterization of subcutaneous and visceral adipose tissue secretomes. However, adipose tissue composition and secretion pattern is depot and disease dependent, influencing the adipose tissue secretome. We investigated the secretome of cancer-associated adipose tissue (CAAT) explants from breast cancer patients and explored its role in breast cancer proliferation. CAAT proteins were identified by LC-MS/MS and human protein antibody arrays and stimulated proliferation of three breast cancer cell lines...
May 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28515242/new-approaches-to-endocrine-therapy-for-breast-cancer
#12
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/28506556/pfizer-to-make-palbociclib-temporarily-free-on-nhs
#13
Talha Khan Burki
No abstract text is available yet for this article.
June 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28488183/palbociclib-a-review-in-hr-positive-her2-negative-advanced-or-metastatic-breast-cancer
#14
REVIEW
Esther S Kim, Lesley J Scott
Oral palbociclib (Ibrance®) is a first-in-class, highly selective inhibitor of cyclin-dependent kinases 4 and 6 (i.e. a CDK4/6 inhibitor). It is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant (with or without a luteinizing hormone-releasing hormone agonist) in those previously treated with endocrine therapy. In clinical trials, palbociclib in combination with letrozole as initial endocrine-based therapy in postmenopausal women (PALOMA-1 and PALOMA-2), or in combination with fulvestrant in pre-, peri-, or postmenopausal women with disease progression after endocrine therapy (PALOMA-3), significantly prolonged progression-free survival (PFS) and improved clinical benefit response (CBR) rates...
May 9, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28486050/the-cdk4-6-inhibitor-palbociclib-synergizes-with-irinotecan-to-promote-colorectal-cancer-cell-death-under-hypoxia
#15
Jun Zhang, Lanlan Zhou, Shuai Zhao, David T Dicker, Wafik S El-Deiry
Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1α regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3β. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia...
May 9, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28473534/elacestrant-rad1901-a-selective-estrogen-receptor-degrader-serd-has-anti-tumor-activity-in-multiple-er-breast-cancer-patient-derived-xenograft-models
#16
Teeru Bihani, Hitisha K Patel, Heike Arlt, Nianjun Tao, Hai Jiang, Jeff Brown, Dinesh M Purandare, Gary Hattersley, Fiona Garner
PURPOSE: Estrogen receptor-positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of anti-estrogen therapy. Selective estrogen receptor degraders (SERDs) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer...
May 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28472324/cost-effectiveness-of-palbociclib-in-hormone-receptor-positive-advanced-breast-cancer
#17
H Mamiya, R K Tahara, S M Tolaney, N Choudhry, M Najafzadeh
BACKGROUND: Palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6 for the treatment of advanced breast cancer, has demonstrated significant efficacy in prolonging progression-free survival when added to existing therapies. Considering the high cost of palbociclib, we assessed cost-effectiveness of adding palbociclib to usual care in treatment of advanced breast cancer. METHODS: We developed a discrete event simulation model to simulate time to cancer progression and to compare life time clinical benefit and cost of alternative treatment strategies for patients with metastatic disease from societal perspective...
May 2, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28472136/the-efficacy-of-the-cyclin-dependent-kinase-4-6-inhibitor-in-endometrial-cancer
#18
Tomohito Tanaka, Yoshito Terai, Keisuke Ashihara, Satoe Fujiwara, Yoshimichi Tanaka, Hiroshi Sasaki, Satoshi Tsunetoh, Masahide Ohmichi
BACKGROUND: PD-0332991, the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, causes cell cycle arrest by inhibiting phosphorylation of retinoblastoma (Rb) protein. The aim of this study was to evaluate the therapeutic potential of PD-0332991 in endometrial cancer. METHODS AND FINDINGS: Four human endometrial cancer cell lines, ECC, HEC1A, HEC108 and TEN, were treated with PD-0332991 and their function was evaluated. In vivo, the therapeutic efficacy was evaluated in a model of subcutaneous endometrial cancer...
2017: PloS One
https://www.readbyqxmd.com/read/28467408/modelling-of-the-cancer-cell-cycle-as-a-tool-for-rational-drug-development-a-systems-pharmacology-approach-to-cyclotherapy
#19
Robert C Jackson, Giovanni Y Di Veroli, Siang-Boon Koh, Ian Goldlust, Frances M Richards, Duncan I Jodrell
The dynamic of cancer is intimately linked to a dysregulation of the cell cycle and signalling pathways. It has been argued that selectivity of treatments could exploit loss of checkpoint function in cancer cells, a concept termed "cyclotherapy". Quantitative approaches that describe these dysregulations can provide guidance in the design of novel or existing cancer therapies. We describe and illustrate this strategy via a mathematical model of the cell cycle that includes descriptions of the G1-S checkpoint and the spindle assembly checkpoint (SAC), the EGF signalling pathway and apoptosis...
May 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28463012/comparison-of-palbociclib-in-combination-with-letrozole-or-fulvestrant-with-endocrine-therapies-for-advanced-metastatic-breast-cancer-network-meta-analysis
#20
Costel Chirila, Debanjali Mitra, Ann Colosia, Caroline Ling, Dawn Odom, Shrividya Iyer, James A Kaye
BACKGROUND: Palbociclib is the first cyclin-dependent kinase 4/6 inhibitor approved in the United States for HR+/HER2- advanced/metastatic breast cancer, in combination with letrozole as initial endocrine-based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy. We compared progression-free survival (PFS) and discontinuations due to adverse events for palbociclib combinations against other endocrine therapies using a mixed-treatment comparison meta-analysis of randomized, controlled trials...
May 16, 2017: Current Medical Research and Opinion
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