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Palbociclib

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https://www.readbyqxmd.com/read/28283584/clinical-benefit-in-response-to-palbociclib-treatment-in-refractory-uterine-leiomyosarcomas-with-a-common-cdkn2a-alteration
#1
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...
March 10, 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
#2
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
#3
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
#4
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
#5
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)...
February 28, 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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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/28169231/palbociclib-a-new-hope-in-the-treatment-of-breast-cancer
#12
REVIEW
R Priyadharsini Palanisamy
Breast cancer being one of the common cancers has high morbidity and mortality. Despite the conventional treatment, the burden of the disease increases year after year. There is a need for newer drugs that target the different mechanisms in the pathogenesis. The interaction of cyclins with cyclin dependent kinases (CDKs) plays a major role in the abnormal cell cycle in cancer and it is considered to be an important target. Palbociclib is a CDK inhibitor currently approved for the treatment of breast cancer...
October 2016: Journal of Cancer Research and 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
#13
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 stabilised the drug in its binding site and that were not observed in the crystal structure of the protein-drug complex...
February 7, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28126188/-cell-cycle-inhibitors-in-endocrine-receptor-positive-breast-cancer
#14
Marie-Paule Sablin, Francesco Ricci, Delphine Loirat, Aude Jobard, Clémence Basse, Emanuela Romano, Christophe Le Tourneau, Véronique Dieras
Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4 and 6 revived interest in this therapeutic class after the failure of pan-inhibitors. Palbociclib, ribociclib, and abemaciclib are the 3 drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation...
February 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28099935/frequent-amplification-of-receptor-tyrosine-kinase-genes-in-welldifferentiated-dedifferentiated-liposarcoma
#15
Naofumi Asano, Akihiko Yoshida, Sachiyo Mitani, Eisuke Kobayashi, Bunsyo Shiotani, Motokiyo Komiyama, Hiroyuki Fujimoto, Hirokazu Chuman, Hideo Morioka, Morio Matsumoto, Masaya Nakamura, Takashi Kubo, Mamoru Kato, Takashi Kohno, Akira Kawai, Tadashi Kondo, Hitoshi Ichikawa
Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancer-related genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes...
January 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28054957/molecular-biomarkers-for-prediction-of-targeted-therapy-response-in-metastatic-breast-cancer-trick-or-treat
#16
REVIEW
Angela Toss, Marta Venturelli, Chiara Peterle, Federico Piacentini, Stefano Cascinu, Laura Cortesi
In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival...
January 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28050067/palbociclib-a-breakthrough-in-breast-carcinoma-in-women
#17
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
#18
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
#19
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/28039358/stromal-senescence-by-prolonged-cdk4-6-inhibition-potentiates-tumor-growth
#20
Xiangnan Guan, Kyle M LaPak, Rebecca C Hennessey, Christina Y Yu, Reena Shakya, Jianying Zhang, Christin E Burd
Senescent cells within the tumor microenvironment (TME) adopt a proinflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression, and therapeutic resistance. Here, exposure to palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage-independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-κB activation...
March 2017: Molecular Cancer Research: MCR
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