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Journal ArticleDOI

Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma

TL;DR: Treatment with theCDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.
Abstract: Purpose CDK4 is amplified in 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.

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Citations
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TL;DR: In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively, and antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.
Abstract: Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events - senescence, followed by clearance and then regeneration - may not be efficiently completed in aged tissues or in pathological contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.

1,830 citations

Journal ArticleDOI
TL;DR: How CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity is discussed.
Abstract: Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.

1,276 citations

Journal ArticleDOI
TL;DR: The role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors are discussed.
Abstract: Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. In this Review, we focus on proteins that directly regulate cell cycle progression (such as cyclin-dependent kinases (CDKs)), as well as checkpoint kinases, Aurora kinases and Polo-like kinases (PLKs). We discuss the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors.

1,250 citations

Journal ArticleDOI
TL;DR: Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile.
Abstract: 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. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.

760 citations

Journal ArticleDOI
TL;DR: Rapidly emerging data with selective inhibitors of CDK4/6 have validated these cell-cycle kinases as anticancer drug targets, corroborating longstanding preclinical predictions.
Abstract: Biochemical and genetic characterization of D-type cyclins, their cyclin D–dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16INK4 over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell-division cycle in a retinoblastoma protein–dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with coinhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers. Significance: Rapidly emerging data with selective inhibitors of CDK4/6 have validated these cell-cycle kinases as anticancer drug targets, corroborating longstanding preclinical predictions. This review addresses the discovery of these CDKs and their regulators, as well as translation of CDK4/6 biology to positive clinical outcomes and development of rational combinatorial therapies. Cancer Discov; 6(4); 353–67. ©2015 AACR .

682 citations

References
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Journal ArticleDOI
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.

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Book
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TL;DR: In this paper, the basic theory of Maximum Likelihood Estimation (MLE) is used to detect a difference between two different proportions of a given proportion in a single proportion.
Abstract: Preface.Preface to the Second Edition.Preface to the First Edition.1. An Introduction to Applied Probability.2. Statistical Inference for a Single Proportion.3. Assessing Significance in a Fourfold Table.4. Determining Sample Sizes Needed to Detect a Difference Between Two Proportions.5. How to Randomize.6. Comparative Studies: Cross-Sectional, Naturalistic, or Multinomial Sampling.7. Comparative Studies: Prospective and Retrospective Sampling.8. Randomized Controlled Trials.9. The Comparison of Proportions from Several Independent Samples.10. Combining Evidence from Fourfold Tables.11. Logistic Regression.12. Poisson Regression.13. Analysis of Data from Matched Samples.14. Regression Models for Matched Samples.15. Analysis of Correlated Binary Data.16. Missing Data.17. Misclassification Errors: Effects, Control, and Adjustment.18. The Measurement of Interrater Agreement.19. The Standardization of Rates.Appendix A. Numerical Tables.Appendix B. The Basic Theory of Maximum Likelihood Estimation.Appendix C. Answers to Selected Problems.Author Index.Subject Index.

16,435 citations

Journal ArticleDOI

9,528 citations


"Phase II Trial of the CDK4 Inhibito..." refers methods in this paper

  • ...A one-stage design was used.(14) The initial study design called for a sample size of 28....

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Journal Article
TL;DR: This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.
Abstract: This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.

3,673 citations


"Phase II Trial of the CDK4 Inhibito..." refers background in this paper

  • ...1).(12) Patients must have received at least one other systemic treatment for advanced disease....

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Journal Article
TL;DR: Results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.
Abstract: PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.

1,150 citations


"Phase II Trial of the CDK4 Inhibito..." refers background in this paper

  • ...PD0332991 is a potent oral inhibitor of CDK4 and CDK6 that prevents downstream phosphorylation of the retinoblastoma (RB) protein.(9,10) The drug inhibits the growth of WDLS/DDLS cells in vitro and in xenograft models....

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