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Palbociclib

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https://www.readbyqxmd.com/read/28438180/recent-advances-of-highly-selective-cdk4-6-inhibitors-in-breast-cancer
#1
REVIEW
Hanxiao Xu, Shengnan Yu, Qian Liu, Xun Yuan, Sridhar Mani, Richard G Pestell, Kongming Wu
Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219)...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28430398/impact-of-acid-reducing-agents-on-the-pharmacokinetics-of-palbociclib-a-weak-base-with-ph-dependent-solubility-with-different-food-intake-conditions
#2
Wan Sun, Karen J Klamerus, Lisa M Yuhas, Sylvester Pawlak, Anna Plotka, Melissa O'Gorman, Leonid Kirkovsky, Maha Kosa, Diane Wang
Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by food. A drug-drug interaction study (study 1) was conducted first under fasted conditions and showed that coadministration of multiple doses of the proton-pump inhibitor rabeprazole substantially reduced palbociclib mean area under the concentration-time curve from time 0 to infinity and maximum observed plasma concentration by 62% and 80%, respectively...
April 21, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28419480/characterization-of-neutropenia-in-advanced-cancer-patients-following-palbociclib-treatment-using-a-population-pharmacokinetic-pharmacodynamic-modeling-and-simulation-approach
#3
Wan Sun, Peter J O'Dwyer, Richard S Finn, Ana Ruiz-Garcia, Geoffrey I Shapiro, Gary K Schwartz, Angela DeMichele, Diane Wang
Neutropenia is the most commonly reported hematologic toxicity following treatment with palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for metastatic breast cancer. Using data from 185 advanced cancer patients receiving palbociclib in 3 clinical trials, a pharmacokinetic-pharmacodynamic model was developed to describe the time course of absolute neutrophil count (ANC) and quantify the exposure-response relationship for neutropenia. These analyses help in understanding neutropenia associated with palbociclib and its comparison with chemotherapy-induced neutropenia...
April 18, 2017: Journal of Clinical Pharmacology
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
#4
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/28404587/cic-dux4-induces-small-round-cell-sarcomas-distinct-from-ewing-sarcoma
#5
Toyoki Yoshimoto, Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Yutaka Takazawa, Cristina R Antonescu, Takuro Nakamura
CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a  subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA...
April 12, 2017: Cancer Research
https://www.readbyqxmd.com/read/28403773/progress-of-cdk4-6-inhibitor-palbociclib-in-the-treatment-of-cancer
#6
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/28382802/major-clinical-research-advances-in-gynecologic-cancer-in-2016-10-year-special-edition
#7
REVIEW
Dong Hoon Suh, Miseon Kim, Kidong Kim, Hak Jae Kim, Kyung Hun Lee, Jae Weon Kim
In 2016, 13 topics were selected as major research advances in gynecologic oncology. For ovarian cancer, study results supporting previous ones regarding surgical preventive strategies were reported. There were several targeted agents that showed comparable responses in phase III trials, including niraparib, cediranib, and nintedanib. On the contrary to our expectations, dose-dense weekly chemotherapy regimen failed to prove superior survival outcomes compared with conventional triweekly regimen. Single-agent non-platinum treatment to prolong platinum-free-interval in patients with recurrent, partially platinum-sensitive ovarian cancer did not improve and even worsened overall survival (OS)...
May 2017: Journal of Gynecologic Oncology
https://www.readbyqxmd.com/read/28359238/hr-her2-advanced-breast-cancer-and-cdk4-6-inhibitors-mode-of-action-clinical-activity-and-safety-profiles
#8
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/28356261/ribociclib-approved-for-advanced-breast-cancer
#9
(no author information available yet)
The FDA has approved ribociclib combined with aromatase inhibitor therapy for women with metastatic HR-positive, HER2-negative breast cancer. It is the second CDK 4/6 inhibitor approved for these patients, behind palbociclib; a third is under investigation.
March 29, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28351928/ribociclib-lee011-mechanism-of-action-and-clinical-impact-of-this-selective-cyclin-dependent-kinase-4-6-inhibitor-in-various-solid-tumors
#10
Debu Tripathy, Aditya Bardia, William R Sellers
The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which was granted priority review by the US Food and Drug Administration in November 2016, and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib...
March 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28349562/palbociclib-has-anti-tumor-effects-on-pten-deficient-endometrial-neoplasias
#11
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/28283584/clinical-benefit-in-response-to-palbociclib-treatment-in-refractory-uterine-leiomyosarcomas-with-a-common-cdkn2a-alteration
#12
Julia A Elvin, Laurie M Gay, Rita Ort, Joseph Shuluk, Jennifer Long, Lauren Shelley, Ronald Lee, Zachary R Chalmers, Garrett M Frampton, Siraj M Ali, Alexa B Schrock, Vincent A Miller, Philip J Stephens, Jeffrey S Ross, Richard Frank
BACKGROUND: Uterine leiomyosarcoma (uLMS) responds poorly to conventional chemotherapeutic agents, and personalized therapies have yet to be systematically explored. Comprehensive genomic profiling (CGP) can identify therapeutic targets and provide insight into the biology of this highly aggressive tumor. We report a case of uLMS treated with the CGP-matched therapy palbociclib, a CDK4/6 inhibitor, with sustained clinical benefit in this rare and deadly malignancy. MATERIALS AND METHODS: This study analyzed 279 clinically advanced/recurrent uLMS samples...
April 2017: Oncologist
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
#13
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/28266967/liver-resection-for-breast-cancer-liver-metastases-a-cost-utility-analysis
#14
Gaya Spolverato, Alessandro Vitale, Fabio Bagante, Roisin Connolly, Timothy M Pawlik
OBJECTIVE: To estimate the cost-effectiveness of liver resection followed by adjuvant systemic therapy relative to systemic therapy alone for patients with breast cancer liver metastasis. BACKGROUND: Data on cost-effectiveness of liver resection for advanced breast cancer with liver metastasis are lacking. METHODS: A decision-analytic Markov model was constructed to evaluate the cost-effectiveness of liver resection followed by postoperative conventional systemic therapy (strategy A) versus conventional therapy alone (strategy B) versus newer targeted therapy alone (strategy C)...
April 2017: Annals of Surgery
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
#15
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/28245148/prior-authorization-for-medications-in-a-breast-oncology-practice-navigation-of-a-complex-process
#16
Ankit Agarwal, Rachel A Freedman, Felicia Goicuria, Catherine Rhinehart, Kathleen Murphy, Eileen Kelly, Erin Mullaney, Myra St Amand, Phuong Nguyen, Nancy U Lin
INTRODUCTION: The cost and burden associated with prior authorization (PA) for specialty medications are concerns for oncologists, but the impact of the PA process on care delivery has not been well described. We examined PA processes and approval patterns within a high-volume breast oncology clinic at a major academic cancer center. METHODS: We met with institutional staff to create a PA workflow and process map. We then abstracted pharmacy and medical records for all patients with breast cancer (N = 279) treated at our institution who required a PA between May and November 2015 (324 prescriptions)...
April 2017: Journal of Oncology Practice
https://www.readbyqxmd.com/read/28243976/inhibition-of-cdk4-sensitizes-multidrug-resistant-ovarian-cancer-cells-to-paclitaxel-by-increasing-apoptosiss
#17
Yan Gao, Jacson Shen, Edwin Choy, Henry Mankin, Francis Hornicek, Zhenfeng Duan
PURPOSE: Overexpression of cyclin-dependent kinase (CDK) 4 has been observed in a variety of cancers and has been found to contribute to tumor cell growth and proliferation. However, the effect of inhibition of CDK4 in ovarian cancer is unknown. We investigated the therapeutic effect of the CDK4 inhibitor palbociclib in combination with paclitaxel in ovarian cancer cells. METHODS: Cell viabilities were determined by MTT assay after exposure to different dosages of palbociclib and/or paclitaxel...
February 27, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28205554/the-oncoppi-network-of-cancer-focused-protein-protein-interactions-to-inform-biological-insights-and-therapeutic-strategies
#18
Zenggang Li, Andrei A Ivanov, Rina Su, Valentina Gonzalez-Pecchi, Qi Qi, Songlin Liu, Philip Webber, Elizabeth McMillan, Lauren Rusnak, Cau Pham, Xiaoqian Chen, Xiulei Mo, Brian Revennaugh, Wei Zhou, Adam Marcus, Sahar Harati, Xiang Chen, Margaret A Johns, Michael A White, Carlos Moreno, Lee A D Cooper, Yuhong Du, Fadlo R Khuri, Haian Fu
As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4...
February 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28204912/effect-of-food-on-the-bioavailability-of-palbociclib
#19
Ana Ruiz-Garcia, Anna Plotka, Melissa O'Gorman, Diane D Wang
PURPOSE: This phase I study estimated the effect of food on bioavailability of palbociclib (IBRANCE(®)), and a selective inhibitor of cyclin-dependent kinase 4/6 approved for oncology indications has pH-dependent solubility and high permeability. METHODS: In this randomized, four-sequence, four-period crossover study, 28 healthy volunteers received a single 125-mg dose of palbociclib (free-base capsule) following an overnight fast or (1) after a high-fat/-calorie meal, (2) after a low-fat/-calorie meal, and (3) between two moderate-fat/standard-calorie meals...
February 15, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28203301/progress-with-palbociclib-in-breast-cancer-latest-evidence-and-clinical-considerations
#20
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
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