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           Search results for: PD-0332991 (Palbociclib) Mechanisms: CDK4 CDK6 inhibitor   

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#28042706   2017/01/02 Save this To Up

Do CDK4/6 inhibitors have potential as targeted therapeutics for squamous cell cancers?

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. Areas covered This review focuses on the current research on the use of CDK4/6 inhibitors, comprising preclinical animal studies through phase II clinical trials across all SCCs. Expert opinion CDK4/6 inhibitors have a proven clinical benefit in breast cancer, but data on SCCs are sparse. Although frequent dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway in SCCs suggests that targeting CDK4/6 may hold promise for improved clinical outcomes, single-agent activity has been modest in preclinical studies and absent in clinical studies. Combinations with immunotherapy or inhibitors of the PI3 K/mTOR or EGFR pathway may be effective. Given that SCCs caused by human papillomavirus have high levels of p16 and low levels of Rb, the CDK4/6 inhibitors are predicted to be ineffective in these cancers.

1352 related Products with: Do CDK4/6 inhibitors have potential as targeted therapeutics for squamous cell cancers?

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#27030077   2016/06/21 Save this To Up

Treating cancer with selective CDK4/6 inhibitors.

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.

2615 related Products with: Treating cancer with selective CDK4/6 inhibitors.

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#26161698   2015/08/21 Save this To Up

Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).

Cell cycle deregulation is a common characteristic of cancer cells. Progression through the cell cycle is controlled by enzymes known as cyclin-dependent kinases (CDKs), whose activity can be upregulated by a wide range of molecular mechanisms. Based on these observations, small molecule CDK inhibitors are being developed as potential cancer therapeutics. Some of these compounds have entered Phase III clinical trials and one of them, palbociclib, recently received accelerated approval from the FDA. However, the complexity of CDK biology and the undesired side effects of the existing inhibitors mean that the hunt for new CDK-targeting drug candidates continues.

2069 related Products with: Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).

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#25991817   2015/11/14 Save this To Up

Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.

Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy-resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD- or SSH-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant ESR1(+) breast cancer.

1456 related Products with: Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.

Breast cancer tissue arra Breast disease spectrum t PI3-Kɣ Inhibitor, AS-605 PI3-Kɣ Inhibitor, AS-605 FAAH Inhibitor, PF-622 FAAH Inhibitor, PF-622; A FAAH Inhibitor, PF-622 FAAH Inhibitor, PF-622; A AZD-6244 Mechanisms: MEK PD-0332991 (Palbociclib) TAE-684 Mechanisms: ALK i BI-6727 Mechanisms: Polo-

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#25876993   2015/05/09 Save this To Up

The Role of CDK4/6 Inhibition in Breast Cancer.

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor-positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.

1376 related Products with: The Role of CDK4/6 Inhibition in Breast Cancer.

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#25703099   2015/10/17 Save this To Up

miR Profiling Identifies Cyclin-Dependent Kinase 6 Downregulation as a Potential Mechanism of Acquired Cisplatin Resistance in Non-Small-Cell Lung Carcinoma.

To identify the mechanisms of cisplatin resistance, global microRNA (miR) expression was tested. The expression of miR-145 was consistently higher in resistant cells. The expression of cyclin-dependent kinase 6 (CDK6), a potential target of miR-145, was lower in resistant cells, and inhibition of CDK4/6 protected cells from cisplatin. Cell cycle inhibition, currently being tested in clinical trials, might be antagonistic to cisplatin and other cytotoxic drugs.

2389 related Products with: miR Profiling Identifies Cyclin-Dependent Kinase 6 Downregulation as a Potential Mechanism of Acquired Cisplatin Resistance in Non-Small-Cell Lung Carcinoma.

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#25156567   2014/08/26 Save this To Up

CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, in part, due to the therapy-recalcitrant nature of the disease. Loss of the CDK4/6 inhibitor CDKN2A is a signature genetic event in PDA. Therefore, PDA may be amenable to treatment with pharmaceutical CDK4/6 inhibitors. Surprisingly, response to CDK4/6 inhibition was highly variable in PDA models, and associated with differential suppression of gene expression. Mitotic genes were repressed and FOXM1 was uniformly attenuated; however, genes involved in DNA replication were uniquely suppressed in sensitive models. Aberrant induction of Cyclin E1 was associated with resistance, and knockdown demonstrated synergistic suppression of the cell cycle with CDK4/6 inhibition. Combination therapies are likely required for the effective treatment of disease, and drug screening demonstrated additive/antagonistic interactions with CDK4/6 inhibitors. Agents dependent on mitotic progression (taxanes/PLK1 inhibitors) were antagonized by CDK4/6 inhibition, while the response to 5-FU and gemcitabine exhibited drug specific interactions. PI3K/MTOR and MEK inhibitors potently cooperated with CDK4/6 inhibition. These agents were synergistic with CDK4/6 inhibition, blocked the aberrant upregulation of Cyclin E1, and yielded potent inhibition of tumor cell growth. Together, these data identify novel mechanisms of resistance to CDK4/6 inhibitions and provide a roadmap for combination therapies in the treatment of PDA.

1075 related Products with: CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer.

Cell cycle antibody array Cancer Apoptosis Phospho- NF-kB Phospho-Specific Ar Lung cancer tissue array, Colon cancer, metastasize Rectum disease spectrum ( Infiltrating duct carcino Bladder cancer tissue arr Breast cancer tissue arra Breast disease spectrum t Colon cancer and lung can Colon cancer tissue array

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#22508966   2012/06/05 Save this To Up

The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway.

Loss of normal growth control is a hallmark of cancer progression. Therefore, understanding the early mechanisms of normal growth regulation and the changes that occur during preneoplasia may provide insights of both diagnostic and therapeutic importance. Models of dysplasia that help elucidate the mechanisms responsible for disease progression are useful in highlighting potential targets for prevention. An important strategy in cancer prevention treatment programs is to reduce hyperplasia and dysplasia. This study identified abnormal upregulation of cell cycle-related proteins cyclin D1, cyclin-dependent kinase (CDK)4, CDK6, and phosphorylated retinoblastoma protein (pRb) as mechanisms responsible for maintenance of hyperplasia and dysplasia following downregulation of the initiating viral oncoprotein Simian virus 40 (SV40) T antigen. Significantly, p53 was not required for successful reversal of hyperplasia and dysplasia. Ligand-induced activation of retinoid X receptor and PPARγ agonists attenuated cyclin D1 and CDK6 but not CDK4 or phosphorylated pRb upregulation with limited reversal of hyperplasia and dysplasia. PD0332991, an orally available CDK4/6 inhibitor, was able to prevent upregulation of cyclin D1 and CDK6 as well as CDK4 and phosphorylated pRb and this correlated with a more profound reversal of hyperplasia and dysplasia. In summary, the study distinguished CDK4 and phosphorylated pRb as targets for chemoprevention regimens targeting reversal of hyperplasia and dysplasia.

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#20100483   2010/04/26 Save this To Up

Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells.

Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide; current chemotherapeutic interventions for this disease are largely ineffective. The retinoblastoma tumor suppressor (RB) is functionally inactivated at relatively high frequency in hepatocellular carcinoma and hepatoma cell lines. Here, we analyzed the ability of CDK4/6 inhibition to inhibit hepatocyte proliferation and the effect of RB status on this process.

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Colon cancer, metastasize Liver cancer (hepatocellu High density liver cancer Alkaline Phospatase (ALP) Zearalenone Mycotoxins EL Cell cycle antibody array NF-kB Phospho-Specific Ar Liver disease spectrum ti Liver carcinoma (multi-ti Liver carcinoma (multi ti Liver carcinoma (multi ti Liver carcinoma (combinat

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