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Palbociclib

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https://www.readbyqxmd.com/read/28099935/frequent-amplification-of-receptor-tyrosine-kinase-genes-in-welldifferentiated-dedifferentiated-liposarcoma
#1
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
#2
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
#3
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
#4
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...
January 1, 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
#5
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...
December 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/28039358/stromal-senescence-by-prolonged-cdk4-6-inhibition-potentiates-tumor-growth
#6
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 pro-inflammatory, 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-kappaB activation...
December 30, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27995453/laparoscopic-glissonean-pedicle-transection-takasaki-for-negative-fluorescent-counterstaining-of-segment-6
#7
Takashi Mizuno, Rahul Sheth, Masakazu Yamamoto, Hyun Seon C Kang, Suguru Yamashita, Thomas A Aloia, Yun Shin Chun, Jeffrey E Lee, Jean-Nicolas Vauthey, C Conrad
BACKGROUND: The portal pedicles are wrapped in connective tissue known as the Walaeus sheath, which abut Laennec's capsule covering the liver parenchyma. Precise knowledge of this anatomic relationship allows for dissection of this interspace and early control of the segmental portal pedicle (Glissonean pedicle transection method [GPTM], Takasaki approach). (1,2) Subsequent systemic administration of indocyanine green (ICG) leads to negative counterstaining of the segment to be resected...
December 19, 2016: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/27972414/network-meta-analysis-comparing-palbociclib-with-chemotherapies-for-treatment-of-postmenopausal-women-with-hr-her2-advanced-metastatic-breast-cancer
#8
F R Wilson, A Varu, D Mitra, C Cameron, S Iyer
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27972394/efficacy-of-palbociclib-combinations-versus-endocrine-therapies-in-advanced-metastatic-breast-cancer-network-meta-analysis
#9
C Chirila, D Mitra, A Colosia, C Ling, D Odom, S Iyer, J A Kaye
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27959613/palbociclib-and-letrozole-in-advanced-breast-cancer
#10
RANDOMIZED CONTROLLED TRIAL
Richard S Finn, Miguel Martin, Hope S Rugo, Stephen Jones, Seock-Ah Im, Karen Gelmon, Nadia Harbeck, Oleg N Lipatov, Janice M Walshe, Stacy Moulder, Eric Gauthier, Dongrui R Lu, Sophia Randolph, Véronique Diéras, Dennis J Slamon
Background A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication. Methods In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole...
November 17, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27903987/mapping-heterogeneity-in-patient-derived-melanoma-cultures-by-single-cell-rna-seq
#11
Tobias Gerber, Edith Willscher, Henry Loeffler-Wirth, Lydia Hopp, Dirk Schadendorf, Manfred Schartl, Ulf Anderegg, Gray Camp, Barbara Treutlein, Hans Binder, Manfred Kunz
Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27890465/palbociclib-improves-survival-in-advanced-breast-cancer
#12
Talha Khan Burki
No abstract text is available yet for this article.
November 24, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27883943/targeted-therapy-for-breast-cancer-and-molecular-mechanisms-of-resistance-to-treatment
#13
REVIEW
Guowei Gu, Derek Dustin, Suzanne Aw Fuqua
In recent years, clinical trials investigating new drugs and therapeutic combinations have led to promising advances in breast cancer therapy. Subtyping breast cancers into hormone receptor (HR) positive, epidermal growth factor receptor (HER2) positive, and triple negative breast cancer (TNBC) is currently the basis of diagnosing and treating this disease. In addition to endocrine and HER2-targeted therapies in their respective subtypes, evidence from recent preclinical studies have shown several targetable pathways that overcome resistance in the clinical setting...
December 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27864574/enhancing-endocrine-therapy-combination-strategies-for-the-treatment-of-postmenopausal-hormone-receptor-positive-her2-advanced-breast-cancer
#14
REVIEW
Kathleen I Pritchard, Stephen K Chia, Christine Simmons, Deanna McLeod, Alexander Paterson, Louise Provencher, Daniel Rayson
: : Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor (HR)-positive tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR-positive, HER2-negative advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients...
November 18, 2016: Oncologist
https://www.readbyqxmd.com/read/27849562/palbociclib-pd-0332991-a-selective-cdk4-6-inhibitor-restricts-tumour-growth-in-preclinical-models-of-hepatocellular-carcinoma
#15
Julien Bollard, Verónica Miguela, Marina Ruiz de Galarreta, Anu Venkatesh, C Billie Bian, Mark P Roberto, Victoria Tovar, Daniela Sia, Pedro Molina-Sánchez, Christie B Nguyen, Shigeki Nakagawa, Josep M Llovet, Yujin Hoshida, Amaia Lujambio
OBJECTIVE: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. DESIGN: The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo...
November 14, 2016: Gut
https://www.readbyqxmd.com/read/27843622/review-of-hormone-based-treatments-in-postmenopausal-patients-with-advanced-breast-cancer-focusing-on-aromatase-inhibitors-and-fulvestrant
#16
REVIEW
Iben Kümler, Ann S Knoop, Christina A R Jessing, Bent Ejlertsen, Dorte L Nielsen
BACKGROUND: Endocrine therapy constitutes a central modality in the treatment of oestrogen receptor (ER)-positive advanced breast cancer. PURPOSE: To evaluate the evidence for endocrine treatment in postmenopausal patients with advanced breast cancer focusing on the aromatase inhibitors, letrozole, anastrozole, exemestane and fulvestrant. METHODS: A review was carried out using PubMed. Randomised phase II and III trials reporting on ≥100 patients were included...
2016: ESMO Open
https://www.readbyqxmd.com/read/27832204/expression-of-the-lncrna-maternally-expressed-gene-3-meg3-contributes-to-the-control-of-lung-cancer-cell-proliferation-by-the-rb-pathway
#17
Traci L Kruer, Susan M Dougherty, Lindsey Reynolds, Elizabeth Long, Tanya de Silva, William W Lockwood, Brian F Clem
Maternally expressed gene 3 (MEG3, mouse homolog Gtl2) encodes a long noncoding RNA (lncRNA) that is expressed in many normal tissues, but is suppressed in various cancer cell lines and tumors, suggesting it plays a functional role as a tumor suppressor. Hypermethylation has been shown to contribute to this loss of expression. We now demonstrate that MEG3 expression is regulated by the retinoblastoma protein (Rb) pathway and correlates with a change in cell proliferation. Microarray analysis of mouse embryonic fibroblasts (MEFs) isolated from mice with genetic deletion of all three Rb family members (TKO) revealed a significant silencing of Gtl2/MEG3 expression compared to WT MEFs, and re-expression of Gtl2/MEG3 caused decrease in cell proliferation and increased apoptosis...
2016: PloS One
https://www.readbyqxmd.com/read/27785059/impact-of-palbociclib-combinations-on-treatment-of-advanced-estrogen-receptor-positive-human-epidermal-growth-factor-2-negative-breast-cancer
#18
REVIEW
Katalin Boér
Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2)-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers demonstrate de novo or acquired resistance to endocrine therapy. Despite intensive research to develop new strategies to enhance the efficacy of currently available treatment options for hormone receptor-positive breast cancer, progress has been slow, and there were few advances for a period of 10 years...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27775259/major-clinical-research-advances-in-gynecologic-cancer-in-2015
#19
REVIEW
Dong Hoon Suh, Miseon Kim, Hak Jae Kim, Kyung Hun Lee, Jae Weon Kim
In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed...
November 2016: Journal of Gynecologic Oncology
https://www.readbyqxmd.com/read/27765908/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#20
Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 18, 2016: Oncotarget
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