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Ping Chen, Nathan V Lee, Wenyue Hu, Meirong Xu, Rose Ann Ferre, Hieu Lam, Simon Bergqvist, James Solowiej, Wade Diehl, You-Ai He, Xiu Yu, Asako Nagata, Todd VanArsdale, Brion W Murray
Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities...
October 2016: Molecular Cancer Therapeutics
Romualdo Barroso-Sousa, Geoffrey I Shapiro, Sara M Tolaney
Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development...
June 2016: Breast Care
Joline S J Lim, Nicholas C Turner, Timothy A Yap
Patnaik and colleagues report on the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of abemaciclib for the treatment of advanced solid cancers, demonstrating antitumor activity in advanced breast cancers as well as glioblastoma, melanoma, non-small cell lung cancer, colorectal cancer, and ovarian cancer. The development of abemaciclib and other CDK4/6 inhibitors should now be fully optimized through the use of novel predictive biomarkers of response and rational combinations. Cancer Discov; 6(7); 697-9...
July 2016: Cancer Discovery
(no author information available yet)
According to results from a phase II study, abemaciclib shows single-agent activity in women with metastatic HER2-negative, ER-positive breast cancer whose disease has progressed on endocrine therapy and chemotherapy. The objective response rate to this investigational CDK4/6 inhibitor was 19.7%, with 28.2% of responses lasting at least a year.
August 2016: Cancer Discovery
Ciara C O'Sullivan
INTRODUCTION: Breast cancer remains a major cause of morbidity and mortality worldwide. Given the central role of cyclin-dependent kinases in regulating cell division, there has been a longstanding interest in developing compounds which target the cyclin D1: CDK4/6 axis in breast cancer. The recent discovery of potent and selective CDK4/6 inhibitors (CDK4/6i) was an important breakthrough. AREAS COVERED: There are three CDK4/6i in clinical development (palbociclib, ribociclib and abemaciclib)...
August 2016: Expert Opinion on Pharmacotherapy
Yutaka Fujiwara, Kenji Tamura, Shunsuke Kondo, Yuko Tanabe, Satoru Iwasa, Akihiko Shimomura, Shigehisa Kitano, Ken Ogasawara, P Kellie Turner, Joji Mori, Hiroya Asou, Edward Michael Chan, Noboru Yamamoto
PURPOSE: To confirm the safety and tolerability, evaluate the pharmacokinetics (PK), and investigate the antitumor activity of abemaciclib in Japanese patients with advanced cancer. METHODS: We conducted a non-randomized, single-arm, open-label, dose-escalation phase 1 study of abemaciclib administered orally every 12 h (Q12H) on a 28-day cycle at doses of 100 mg (Cohort 1, n = 3), 150 mg (Cohort 2, n = 3), or 200 mg [Cohort 3, n = 6, maximum tolerated dose (MTD)]...
August 2016: Cancer Chemotherapy and Pharmacology
Miguel Martin, Sara López-Tarruella
The natural history of HER2-positive breast cancer has progressively improved since the introduction of the first anti-HER2 directed therapy (trastuzumab). Trastuzumab has significantly increased survival of patients with HER2-positive metastatic breast cancer and, after the standardization of the use of this drug in the adjuvant setting in 2005, has also avoided many disease recurrences and, consequently, saved many lives. Later on, the introduction of lapatinib offered new choices for patients with advanced HER2-positive breast cancer, although the drug has failed to show a clear efficacy in the adjuvant setting...
2016: American Society of Clinical Oncology Educational Book
Maiko Okano, Tohru Ohtake, Shigehira Saji
In breast cancer treatment, molecular-targeted drugs such as trastuzumab and lapatinib have been used for many y ears, and the benefits have been seen in many patients. The molecular-targeted drugs have mainly been used in combination with cytotoxic agents; however, combination therapies with 2 molecular-targeted drugs are currently being investigated. The combination therapy of 2 HER2 receptor antibodies, pertuzumab and trastuzumab, has tremendous benefit for HER2 positive metastatic breast cancer patients...
April 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Amita Patnaik, Lee S Rosen, Sara M Tolaney, Anthony W Tolcher, Jonathan W Goldman, Leena Gandhi, Kyriakos P Papadopoulos, Muralidhar Beeram, Drew W Rasco, John F Hilton, Aejaz Nasir, Richard P Beckmann, Andrew E Schade, Angie D Fulford, Tuan S Nguyen, Ricardo Martinez, Palaniappan Kulanthaivel, Lily Q Li, Martin Frenzel, Damien M Cronier, Edward M Chan, Keith T Flaherty, Patrick Y Wen, Geoffrey I Shapiro
UNLABELLED: We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts...
July 2016: Cancer Discovery
Adam J DiPippo, Neelam K Patel, Chad M Barnett
Treatment of metastatic breast cancer (MBC) that is resistant to endocrine therapy presents a significant clinical challenge. The well-known role of cell cycle dysregulation in these patients is partly mediated by cyclin-dependent kinase (CDK) activity. Specific cyclin and CDK complexes regulate cell cycle progression by managing the transition through the cell cycle, and inhibition of CDKs represents an important target for novel agents. First-generation CDK inhibitors (e.g., flavopiridol) were relatively nonselective and had an unacceptable toxicity profile in early trials...
June 2016: Pharmacotherapy
Ben O'Leary, Richard S Finn, Nicholas C Turner
Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects...
July 2016: Nature Reviews. Clinical Oncology
Erika Hamilton, Jeffrey R Infante
The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components...
April 2016: Cancer Treatment Reviews
Robert Roskoski
Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1 phase of the cell cycle produce cyclins of the D type that activate CDK4/6...
May 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Sonya C Tate, Teresa F Burke, Daisy Hartman, Palaniappan Kulanthaivel, Richard P Beckmann, Damien M Cronier
BACKGROUND: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation...
March 15, 2016: British Journal of Cancer
Emmanuelle Kempf, Benoît Rousseau, Benjamin Besse, Luis Paz-Ares
KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes...
March 2016: European Respiratory Review: An Official Journal of the European Respiratory Society
Edith A Perez
Although survival rates among patients with breast cancer have improved in recent years, those diagnosed with advanced disease with distant metastasis face a 5-year survival rate of less than 25%, making the management of these patients an area still in significant need of continued research. Selecting the optimal treatment order from among the variety of currently available therapy options presents a relevant challenge for medical oncologists. With the understanding that the majority of patients with breast cancer and those who succumb to this disease have HR-positive disease, this review will focus on treatment options and treatment order in patients with HR-positive advanced breast cancer...
January 2016: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
Gottfried E Konecny
PURPOSE OF REVIEW: In this article, we not only review the preclinical and clinical studies of cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer, liposarcoma, mantel cell lymphoma, melanoma and germ cell tumors, but also examine promising preclinical data in glioblastoma, renal and ovarian cancer models that may provide directions for future development. RECENT FINDINGS: Targeting CDKs has been the focus of considerable basic science and clinical research...
February 2016: Current Opinion in Obstetrics & Gynecology
Neelima Vidula, Hope S Rugo
For millions of women, breast cancer remains a potentially life-endangering diagnosis. With advances in research, new therapies targeted to tumor biology are emerging to treat the most common form of this disease. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of therapeutic agents that have the potential to improve the outcomes of patients with hormone receptor-positive (HR(+)) breast cancer. Three CDK 4/6 inhibitors have been investigated for the treatment of HR(+) breast cancer, including palbociclib (PD 0332991), ribociclib (LEE011), and abemaciclib (LY2835219)...
February 2016: Clinical Breast Cancer
Thomas J Raub, Graham N Wishart, Palaniappan Kulanthaivel, Brian A Staton, Rose T Ajamie, Geri A Sawada, Lawrence M Gelbert, Harlan E Shannon, Concepcion Sanchez-Martinez, Alfonso De Dios
Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U...
September 2015: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Tim Dukelow, Divya Kishan, Mustafa Khasraw, Conleth G Murphy
Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated...
September 2015: Anti-cancer Drugs
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