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CDK4/6 Inhibitors

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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/28627629/reducing-autophagy-and-inducing-g1-phase-arrest-by-aloperine-enhances-radio-sensitivity-in-lung-cancer-cells
#2
Zhijie Xu, Yuanliang Yan, Shuangshuang Zeng, Long Qian, Shuang Dai, Lingfang Xiao, Lin Wang, Xue Yang, Yi Xiao, Zhicheng Gong
Aloperine (ALO), an isolated alkaloid from the leaves of Sophora alopecuroides (S. alopecuroides), has been suggested to exhibit anti-inflammatory and antitumor properties, and has been traditionally used to treat various diseases, including cancers. However, little is known about the effects of ALO on the radio-sensitivity of lung cancer cells. In the present study, we confirmed that agent ALO inhibits cell growth, promotes cell aopotosis and induces G1 phase arrest and consequently enhanced the radio-sensitivity in radio-resistant lung cancer cells A549/IR...
June 19, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28626036/treating-er-breast-cancer-with-cdk4-6-inhibitors
#3
(no author information available yet)
Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment.
June 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28620137/biological-specificity-of-cdk4-6-inhibitors-dose-response-relationship-in-vivo-signaling-and-composite-response-signature
#4
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
#5
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
#6
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/28607489/the-metabolic-function-of-cyclin-d3-cdk6-kinase-in-cancer-cell-survival
#7
Haizhen Wang, Brandon N Nicolay, Joel M Chick, Xueliang Gao, Yan Geng, Hong Ren, Hui Gao, Guizhi Yang, Juliet A Williams, Jan M Suski, Mark A Keibler, Ewa Sicinska, Ulrike Gerdemann, W Nicholas Haining, Thomas M Roberts, Kornelia Polyak, Steven P Gygi, Nicholas J Dyson, Piotr Sicinski
D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2...
June 15, 2017: Nature
https://www.readbyqxmd.com/read/28606920/single-cell-dynamics-determines-response-to-cdk4-6-inhibition-in-triple-negative-breast-cancer
#8
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
#9
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
#10
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/28578693/cdk4-6-inhibitor-shr6390-exerts-potent-antitumor-activity-in-esophageal-squamous-cell-carcinoma-by-inhibiting-phosphorylated-rb-and-inducing-g1-cell-cycle-arrest
#11
Jiayuan Wang, Qingqing Li, Jiajia Yuan, Jingyuan Wang, Zuhua Chen, Zhentao Liu, Zhongwu Li, Yumei Lai, Jing Gao, Lin Shen
BACKGROUND: Cell cycle dysregulation is common in human malignancies, and CDK4/6 inhibitors targeting cell cycle have potential antitumor activity. SHR6390 is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway. However, the role of SHR6390 in esophageal squamous cell carcinoma (ESCC) remains unknown, which will be investigated in our study. METHODS: Eca 109, Eca 9706, and KYSE-510 ESCC cell lines were chosen for further analysis. The effect of SHR6390 on cell viability, cell cycle and cell apoptosis, the status of kinases in Cyclin D1-CDK4/6-Rb pathway were determined by MTS assay, flow cytometry, and western blotting, respectively...
June 2, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28566333/cdk4-phosphorylation-status-and-a-linked-gene-expression-profile-predict-sensitivity-to-palbociclib
#12
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/28560460/synthetic-lethal-interaction-of-cdk-inhibition-and-autophagy-inhibition-in-human-solid-cancer-cell-lines
#13
Yoshinari Okada, Shunsuke Kato, Yasuhiro Sakamoto, Takayuki Oishi, Chikashi Ishioka
Cell cycle control is a promising target in cancer treatments, and some small-molecule cyclin-dependent kinase (CDK) inhibitors have exhibited clinical effectiveness. However, no biomarkers predictive of efficacy have been developed. Recent studies have revealed that CDK inhibitor (CKI) proteins, such as p27 and p16, also induced cytoprotective autophagy in cancer cells. However, it is unclear whether small-molecule CKIs also induce autophagy in solid tumors, as induced autophagy promotes cancer cell survival...
May 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28559771/cdk4-6-inhibitors-in-the-treatment-of-metastatic-breast-cancer
#14
Johannes Ettl, Jens Huober, Diana Lüftner, Frederik Marmé, Rachel Würstlein
No abstract text is available yet for this article.
May 2017: Breast Care
https://www.readbyqxmd.com/read/28548702/p16-loss-and-e2f-cell-cycle-deregulation-in-infant-posterior-fossa-ependymoma
#15
Seth C Lummus, Andrew M Donson, Katherine Gowan, Kenneth L Jones, Rajeev Vibhakar, Nicholas K Foreman, B K Kleinschmidt-DeMasters
BACKGROUND: Posterior fossa (PF) ependymomas (EPNs) in infants less than 1 year of age (iEPN-PF) have a poorer clinical outcome than EPNs in older children. While radiation therapy is the standard of care for the latter, it is withheld in infants to avoid neurotoxicity to immature brain. It is unknown whether the adverse outcome in iEPN-PFs is due to treatment differences or aggressive biology. We examined this question using molecular profiling. METHODS: Six anaplastic iEPN-PFs were subjected to transcriptomic analysis and FISH for p16 loss and gains of 1q, and compared with anaplastic PF EPNs from older children...
May 26, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28537004/mek-inhibitors-in-the-treatment-of-metastatic-melanoma-and-solid-tumors
#16
REVIEW
Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella, Martina Strudel, Paolo A Ascierto
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines...
May 23, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28533223/monarch-1-a-phase-2-study-of-abemaciclib-a-cdk4-and-cdk6-inhibitor-as-a-single-agent-in-patients-with-refractory-hr-her2-metastatic-breast-cancer
#17
Maura N Dickler, Sara Tolaney, Hope S Rugo, Javier Cortés, Veronique Dieras, Debra A Patt, Hans Wildiers, Clifford A Hudis, Joyce A O'Shaughnessy, Esther Zamora, Denise Yardley, Martin Frenzel, Andrew G Koustenis, José Baselga
<br />The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC). <br /><br />Experimental Design: <br />MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible...
May 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28530853/designing-clinical-trials-that-accept-new-arms-an-example-in-metastatic-breast-cancer
#18
Steffen Ventz, Brian M Alexander, Giovanni Parmigiani, Richard D Gelber, Lorenzo Trippa
Purpose The majority of randomized oncology trials are two-arm studies that test the efficacy of new therapies against a standard of care, thereby assigning a large proportion of patients to nonexperimental therapies. In contrast, multiarm studies efficiently share a common control arm while evaluating multiple experimental therapies. A major bottleneck for traditional multiarm trials is the requirement that all therapies-often drugs from different companies-have to be available at the same time when the trial starts...
May 22, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28529550/hormonoresistance-in-advanced-breast-cancer-a-new-revolution-in-endocrine-therapy
#19
REVIEW
Paule Augereau, Anne Patsouris, Emmanuelle Bourbouloux, Carole Gourmelon, Sophie Abadie Lacourtoisie, Dominique Berton Rigaud, Patrick Soulié, Jean Sebastien Frenel, Mario Campone
Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway...
May 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28526299/mir-200a-regulates-cdk4-6-inhibitor-effect-by-targeting-cdk6-in-metastatic-melanoma
#20
Matias A Bustos, Shigeshi Ono, Diego M Marzese, Takashi Oyama, Yuuki Iida, Garrett Cheung, Nellie Nelson, Sandy C Hsu, Qiang Yu, Dave S B Hoon
Cyclin-dependent kinase (CDK) 4 and 6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we demonstrate that miR-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of miR-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, miR-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity...
May 16, 2017: Journal of Investigative Dermatology
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