PharmStatus.com
Oncology Intelligence

CDK
CDK CDK(2)
CDKs are a family of serine-threonine kinases involved in cell cycle regulation, regulating transcription, mRNA processing, and the differentiation of nerve cells.(1) CDK inhibitors interact with cyclin-CDK complexes to block kinase activity, during G1 or in response to signals from the environment or from damaged DNA.(2) There are two major CDK inhibitor families: The INK4 family proteins are inhibitory and bind CDK monomers. The CIP/KIP family proteins bind both the cyclin and the CDK of a complex and can be inhibitory or activating. CIP/KIP family proteins activate cyclin D and CDK4 or CDK6 complexes by enhancing complex formation.(1, 3)
Cyclin D1 is a central player both in the differentiation of mammary epithelium and BC development. It is involved in the regulation of mammary epithelial differentiation by C/EBP and PPAR, as both a regulator and a target of these transcription factors.(4) Loss or mutational inactivation of p53 tumor suppressor protein results in a high frequency of CA by allowing the activation of the CDK 2-cyclin E (and CDK2-cyclin A) which is a key factor for the initiation of centrosome duplication.(5)

Drugs/Indications




News
References

1. Hultin LE HM, Hultin PM, Giorgi JV. CD20 (pan-B cell) antigen is expressed at a low level on a subpopulation of hu-man T lymphocytes. Cytometry. 1993;14:196-204.

2. Eymin B GS. Role of cell cycle regulators in lung carcinogenesis. Cell Adh Migr. 2010;4(1):114-23. PMCID: 20139697.

3. Morgan DO. The Cell Cycle: Principles of Control. 1st ed. London: New Science Press; 2007.

4. Caldon CE SR, Musgrove E. Cell cycle proteins in epithelial cell differentiation: implications for breast cancer. Cell Cycle. 2010;9(10):1918-28. PMCID: 20473028.

5. K F. P53, cyclin-dependent kinase and abnormal amplification of centrosomes. Biochim Biophys Acta. 2008;1786(1):15-23. PMCID: 18472015.



News


Monday, October 24, 2016 11:07 AM|Onclive Articles|Labels: CDK, breast cancer
Gabriel N. Hortobagyi, MD, discusses the MONALEESA-2 trial, in which the addition of the CDK4/6 inhibitor ribociclib to letrozole significantly improved progression-free survival in women with hormone receptor–positive advanced breast cancer.
Monday, October 17, 2016 12:10 PM|Infante, J. R., Cassier, P. A., Gerecitano, J. F., Witteveen, P. O., Chugh, R., Ribrag, V., Chakraborty, A., Matano, A., Dobson, J. R., Crystal, A. S., Parasuraman, S., Shapiro, G. I.|Clinical Cancer Research Online First Articles|Labels: CDK, clinical trial

Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas.

Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle.

Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months.

Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I–III studies of ribociclib are under way in various indications. Clin Cancer Res; 1–10. ©2016 AACR.

Friday, October 14, 2016 12:05 AM|R.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: CDK, breast cancer, regulatory

FDA Approval Summary: Palbociclib
Walker, A. J Wedam, S, Amiri-Kordestani, L, Bloomquist, E, Tang, S, Sridhara, R, Chen, W, Palmby, T. R, Fourie Zirkelbach, J, Fu, W, Liu, Q, Tilley, A, Kim, G, Kluetz, P. G, McKee, A. E, Pazdur, R.
Clinical Cancer Research, Vol. 22, No. 20 (2016) pp. 4968 - 4972
On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36&ndash;0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 4968&ndash;72. &copy;2016 AACR.

Friday, October 14, 2016 12:05 AM|Walker, A. J., Wedam, S., Amiri-Kordestani, L., Bloomquist, E., Tang, S., Sridhara, R., Chen, W., Palmby, T. R., Fourie Zirkelbach, J., Fu, W., Liu, Q., Tilley, A., Kim, G., Kluetz, P. G., McKee, A. E., Pazdur, R.|Clinical Cancer Research current issue|Labels: CDK, breast cancer

On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36–0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 4968–72. ©2016 AACR.

Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: CDK, breast cancer, clinical trial
This study is a multi-institution, Phase I/IIa open-label, dose-finding, safety, pharmacokinetics (PK), and proof-of-concept study of GDC-0810 administered orally on a continuous daily dosing regimen with a PK lead-in period (dose escalation period only). The incidence of dose limiting toxicity will be evaluated from Day -7 through the first cycle of treatment (35 days total). Depending on safety and tolerability, patients will be assigned sequentially to escalating doses of study drug using standard 3+3 design. During the phase IIa portion of the study, there will be no PK lead-in period and all eligible patients will start continuous daily dosing treatment on Cycle 1 Day 1. All patients will be treated until disease progression, unacceptable toxicity, or patient withdrawal of consent.
Wednesday, October 12, 2016 3:26 PM|Adriana Priscila Trapé, Shuying Liu, Andrea Carolina Cortes, Naoto T. Ueno, Ana Maria Gonzalez-Angulo|Journal of Cancer|Labels: CDK, EGFR, breast cancer

Among patients with hormone receptor (HR)-positive breast cancer, those with residual disease after neoadjuvant chemotherapy have a higher risk of relapse and poorer survival than those with a complete response. Previous studies have revealed a correlation between activation of cell cycle-regulating pathways in HR-positive breast cancer, particularly cyclin-dependent kinase (CDK) 4 and 6/cyclin D1 signaling, and resistance to standard therapies. Although CDK4/6 inhibition by palbociclib in combination with endocrine therapy has shown potent antiproliferative effects in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the potential role of palbociclib in re-sensitizing chemotherapy-resistant HR-positive breast cancer is not well defined. We hypothesized that CDK4/6 inhibition by palbociclib re-sensitizes HR-positive/HER2-negative residual breast cancer to taxane-based adjuvant therapy. Using cell counting, flow cytometry, and western blotting, we evaluated the efficacy of palbociclib alone and in concurrent or sequential combination with paclitaxel in parental and paclitaxel-resistant T47D HR-positive/HER2-negative breast cancer cells. The CDK4/6 pathway was constitutively active in both parental and paclitaxel-resistant T47D cells; thus, both cell types were highly sensitive to the inhibitory effects of single-agent palbociclib on cell growth and cell cycle progression. However, palbociclib did not re-sensitize resistant cells to paclitaxel-induced G2/M arrest and cell death in any of the combinations tested. Our results suggest that CDK4/6 inhibition by palbociclib does not re-sensitize HR-positive/HER2-negative residual breast cancer to chemotherapy. Nevertheless, the fact that CDK4/6 activation remained intact in paclitaxel-resistant cells indicates that patients who have HR-positive/HER2-negative residual disease after taxane-based neoadjuvant chemotherapy may still benefit from palbociclib in combination with other regimens, such as endocrine therapies, for adjuvant therapy.

Wednesday, October 12, 2016 3:24 PM|Yasuhiro Torikoshi, Keigo Gohda, Michelle L. Davis, W. Fraser Symmans, Lajos Pusztai, Anna Kazansky, Satoshi Nakayama, Tomokazu Yoshida, Tomoko Matsushima, Gabriel N. Hortobagyi, Hideki Ishihara, Seung Jin Kim, Shinzaburo Noguchi, Naoto T. Ueno|Journal of Cancer|Labels: CDK, breast cancer, biomarker diagnostic

Taxanes are among the drugs most commonly used for preoperative chemotherapy for breast cancer. Taxanes induce mitotic arrest and subsequent apoptosis. The spindle-assembly checkpoint (SAC) is known to be activated during mitosis, along with cyclin-dependent kinase-1 (CDK1), and is required for taxane-induced cell death. We hypothesized that CDK1 activity predicts response to taxane-containing chemotherapy.

This study included breast cancer patients who received preoperative chemotherapy— taxane-containing treatment followed by anthracycline-based treatment—and then underwent surgery. Before starting taxane-containing chemotherapy, patients underwent fine-needle aspiration biopsy, and the biopsy samples were incubated in paclitaxel solution to measure CDK activity. Clinical were evaluated after taxane therapy, and pathological resposes were evaluated after completion of all preoperative chemotherapy. Thirty five patients were eligible for analysis of clinical response to taxane-containing therapy. Twenty-six patients had taxane-sensitive and 9 taxane-resistant tumors.

Using a cut-off of CDK activity determined by the ROC analysis, patients were classified into SAC function and dysfunction groups. Univariate logistic regression analysis with clinicopathologic parameters showed that only CDK-based SAC functionality was significantly correlated with clinical response (P =0.017). No significant correlation was observed between SAC functionality and pathologic response.

CDK-based SAC functionality significantly predicted clinical response (P =.0072, overall agreement = 71.4%), and this is a unique mechanism-based marker for predicting taxane chemosensitivity. Further, large prospective study is needed to determine CDK-based SAC functionality could be developed as a predictive biomarker.

Wednesday, October 12, 2016 3:23 PM|Sanaz Koosha, Mohammed A. Alshawsh, Chung Yeng Looi, Atefehalsadat Seyedan, Zahurin Mohamed|International Journal of Medical Sciences|Labels: CDK, NFKb, P53, CRC

Colorectal cancer (CRC) is the third most common type of cancer in the world, causing thousands of deaths annually. Although chemotherapy is known to be an effective treatment to combat colon cancer, it produces severe side effects. Natural products, on the other hand, appear to generate fewer side effects than do chemotherapeutic drugs. Flavonoids are polyphenolic compounds found in various fruits and vegetables known to possess antioxidant activities, and the literature shows that several of these flavonoids have anti-CRC propertiesFlavonoids are classified into five main subclasses: flavonols, flavanones, flavones, flavan-3-ols, and flavanonols. Of these subclasses, the flavanonols have a minimum effect against CRC, whereas the flavones play an important role. The main targets for the inhibitory effect of flavonoids on CRC signaling pathways are caspase; nuclear factor kappa B; mitogen-activated protein kinase/p38; matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9; p53; β-catenin; cyclin-dependent kinase (CDK)2 and CDK4; and cyclins A, B, D, and E.

In this review article, we summarize the in vitro and in vivo studies that have been performed since 2000 on the anti-CRC properties of flavonoids. We also describe the signaling pathways affected by flavonoids that have been found to be involved in CRC. Some flavonoids have the potential to be an effective alternative to chemotherapeutic drugs in the treatment of colon cancer; well-controlled clinical studies should, however, be conducted to support this proposal.

Wednesday, October 12, 2016 10:53 AM|Verma, S., Bartlett, C. H., Schnell, P., DeMichele, A. M., Loi, S., Ro, J., Colleoni, M., Iwata, H., Harbeck, N., Cristofanilli, M., Zhang, K., Thiele, A., Turner, N. C., Rugo, H. S.|The Oncologist current issue|Labels: CDK, EGFR, breast cancer
Background.

Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib’s safety profile to effectively manage toxicity and optimize clinical benefit.

Materials and Methods.

Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data.

Results.

A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3–4 neutropenia with palbociclib. Dose modifications for grade 3–4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1–2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients.

Conclusion.

Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135.

Implications for Practice:

Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.

Tuesday, October 11, 2016 11:51 AM|Hart, L. S., Rader, J., Raman, P., Batra, V., Russell, M. R., Tsang, M., Gagliardi, M., Chen, L., Martinez, D., Li, Y., Wood, A., Kim, S., Parasuraman, S., Delach, S., Cole, K. A., Krupa, S., Boehm, M., Peters, M., Caponigro, G., Maris, J. M.|Clinical Cancer Research Online First Articles|Labels: CDK, MapK, RAS

Purpose: Neuroblastoma is treated with aggressive multi-modal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell cycle analysis, Ki67 immunostaining, timelapse microscopy and xenograft studies. Results: Sensitivity to binimetinib and ribociclib was inversely related (r=-0.58, p=0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas, increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell cycle progression that was reversible upon removal of drugs. Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling.

Tuesday, October 11, 2016 9:00 AM|Anonymous|American Pharmacists Association - Improving medication use. Advancing patient care.|Comments|Labels: CDK, breast cancer, clinical trial

In a new study, researchers speculated that, by inhibiting cyclin-dependent kinases 4 and 6, the drug ribociclib might delay or even completely counter resistance to endocrine therapy for certain breast cancers. They tested the theory in a Phase III study of postmenopausal women with advanced breast cancer positive for hormone receptor and negative for human epidermal growth factor receptor 2. The patients, all receiving their first systemic treatment for advanced disease, were randomly assigned to either ribociclib paired with letrozole or placebo paired with letrozole.

Tuesday, October 11, 2016 3:00 AM|Ben Fidler|MIT Biotech Group - Essential Biotech RSS Feed|Labels: CDK, EGFR, PARP, lung cancer, biomarker diagnostic, clinical trial, regulatory
Nyhavn canal as seen from Kongens Nytorv square, Copenhagen, Denmark, Northern Europe.

The European Society for Medical Oncology’s annual conference wraps up in Copenhagen today. We’ve seen updates on heavyweight immunotherapy programs, potential options for patients with advanced breast cancer, and more. Here’s a quick roundup of the major news.

LUNG CHECKS

ESMO provided more evidence that the treatment of lung cancer is changing fast. Going into the meeting, pembrolizumab (Keytruda) from Merck (NYSE: MRK) had already leapfrogged (NYSE: BMY) nivolumab (Opdivo) from Bristol-Myers Squibb (NYSE: BMY) in the race to make checkpoint inhibitors, a type of cancer immunotherapy already approved for hard-to-treat skin, bladder, lung, and liver cancers, the standard of care for newly diagnosed lung cancer patients.

The first news of nivolumab’s Phase 3 failure in these first-line patients came in August and eliminated billions of dollars from Bristol’s market value. Conversely, Merck got a boost. At ESMO this weekend it reported more positive Phase 3 pembrolizumab data, particularly in patients whose tumors express high levels of a protein called PD-L1, while Bristol detailed nivolumab’s poor Phase 3 showing. (Both were compared to chemotherapy.)

Evercore ISI analyst John Scotti wrote in a research note that Bristol’s data were “even worse than expected,” widening the gap between the two drugs. Merck’s shares rose 1.6 percent Monday to close at $63.80 apiece, and Bristol’s fell 10.3 percent to $49.72. TheStreet.com has more on the data here.

Merck is expected to seek FDA approval of pembrolizumab in newly diagnosed lung cancer patients this year.

—Meanwhile, Roche’s Genentech division reported that its checkpoint blocker atezolizumab (Tecentriq) posted positive Phase 3 results in non-small cell lung cancer patients whose disease progressed after at least one round of chemotherapy. The FDA could approve atezolizumab for this group of patients within the next few weeks. The FDA approved atezolizumab earlier this year for a type of bladder cancer.

T CELL TIDBITS

—Among the three developers of CAR-T cell therapies pushing toward the field’s first approval, Kite Pharma (NASDAQ: KITE) was the sole presenter at ESMO. Santa Monica, CA-based Kite noted that three patients whose non-Hodgkin’s lymphoma was wiped out with Kite’s KTE-C19 remained in remission after 12 months. Kite recently reported that a larger group of NHL patients had a similar response to KTE-C19 after three months. CAR-T treatments use live, modified immune cells to attack a patient’s cancer.

—Adaptimmune (NASDAQ: ADAP), which is developing a form of cell therapy called T-cell receptor (TCR) therapy, updated its most advanced clinical program, a treatment for synovial sarcoma, which is a rare cancer that forms in the soft tissues around joints.

PARP WALK

—ESMO was also the latest forum for data for cancer drugs known as PARP inhibitors. These drugs disable a mechanism that tumor cells use to repair their own DNA. The idea is to keep cancer from bouncing back after chemotherapy. The first PARP blocker to win approval was AstraZeneca’s olaparib (Lynparza), for certain forms of ovarian cancer, in 2014. But more seem poised for a green light.

Tesaro (NASDAQ: TSRO), of Waltham, MA, for instance, could win FDA approval of niraparib next year and make an impact on the treatment of ovarian cancer. Right now, surgery is the main option, followed by chemotherapy. But the cancer is stubborn, and there is a big need for “maintenance therapy”— drugs that delay the cancer’s recurrence. Phase 3 data from Tesaro show that adding niraparib to chemotherapy helps delay recurrence compared to chemo alone. Tesaro released top-line data from this trial in June, and investors cheered the better-than-expected results.

The company released detailed data at ESMO and published the results in the New England Journal of Medicine. The data solidified Tesaro’s case that nirapirib appears to help a broad group of ovarian cancer patients, not just those with a particular biomarker making them more likely to respond to treatment. (News that the drug might not need a companion diagnostic test from Myriad Genetics (NASDAQ: MYGN) sent the Salt Lake City test maker’s shares down more than 11 percent.) Tesaro expects to file for approval of niraparib next year. Some 20,000 women in the U.S. and Europe each year are eligible for maintenance therapy, according to Tesaro. Shares of the company climbed another 18 percent and closed at $117.90 apiece on Monday. Here’s more from OncLive.

—A rival PARP drug, rucaparib from Clovis Oncology (NASDAQ: CLVS), of Boulder, CO, didn’t fare as well this weekend. Clovis touted data from a “pooled” study of two mid-stage trials of rucaparib in ovarian cancer. The results, as Bloomberg noted here, underwhelmed investors, who sent Clovis shares down about 20 percent. Clovis aims to win FDA approval of rucaparib next year, and has recently been the subject of takeover speculation, which has caused shares to climb over the past several months. Pfizer, after all, paid $14 billion for Medivation earlier this year partly for a PARP drug in Phase 3 testing.

OTHERS OF NOTE

—Novartis revealed in May that its breast cancer drug ribociclib did so well in a 668-patient Phase 3 trial that the study was halted early. Novartis gave more details at ESMO and in the NEJM: Compared to the standard of care letrozole, ricociclib plus letrozole improved by 44 precent first-line patients’ chances to live without their cancer starting to grow again. The drug is meant for hormone dependent (HR+/HER2-) breast cancer and could compete with Pfizer’s palbociclib (Ibrance), which blocks the same cancer proteins, CDK 4 and 6, as ricociclib. Forbes weighed the ricociclib side effects here against the benefits of living longer without a growing tumor.

—Alex Lash contributed to this report

Reprints | Share:   Retweet  Facebook  LinkedIn  Google Plus  E-mail
Tuesday, October 11, 2016 12:00 AM|EurekAlert! - Cancer Research News|Labels: CDK, breast cancer, clinical trial
(University of Texas M. D. Anderson Cancer Center) In a randomized, Phase III trial led by researchers at The University of Texas MD Anderson Cancer Center, ribociclib, in combination with the aromatase inhibitor letrozole, dramatically improved progression-free survival of post-menopausal women with hormone receptor-positive metastatic breast cancer, compared to the hormone therapy alone.
Monday, October 10, 2016 3:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: CDK, clinical trial
Novartis AG (NYSE:NVS; SIX:NOVN) announced interim data from the Phase III MONALEESA-2 trial of ribociclib (LEE011) as a first-line therapy for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, including response rates and survival data for the cyclin dependent kinase 4 (CDK4) and CDK6 inhibitor. The data were presented Saturday at the European Society for Medical Oncology meeting and published concurrently in the New England Journal of Medicine. Among MONALEESA-2 patients with measurable disease, ribociclib plus letrozole led to an ORR of 53% vs. 37% for letrozole plus placebo (p=0.00028). Data presented at the American Society of Clinical Oncology meeting in June showed that approved CDK4/6 inhibitor Ibrance palbociclib from Pfizer Inc. (NYSE:PFE) plus letrozole led to an ORR of 55% vs. 44% for letrozole alone plus placebo (p=0.013) in the same population as of a Feb. 26 cutoff in the 666-patient Phase III PALOMA-2 study. Among all MONALEESA-2 patients, the ribociclib group had an ORR of 41% vs. 28% for the placebo group, while in PALOMA-2, the ORRs were 42% for Ibrance vs. 35% for letrozole alone. The 668-patient MONALEESA-2 was halted in May after an interim analysis showed the trial met the primary endpoint of improving progression-free survival (PFS). Data presented Saturday showed that ribociclib plus letrozole reduced the risk of death or progression by 44% vs. letrozole plus placebo (p=0.00000329). Median PFS was not reached for the ribociclib group, and was 14.7 months for letrozole alone. In PALOMA-2, Ibrance plus letrozole met the study's primary endpoint by showing a PFS of 24.8 months vs. 14.5 months for letrozole plus placebo (p<0.000001), and reduced the risk of death or progression by 42% vs. letrozole (p<0.000001) (see BioCentury Extra, May 18). Eleven patients (3.3%) in the ribociclib group had at least one average QTcF interval of more than 480 msec after baseline, vs. none for placebo. One death was considered related to ribociclib; it occurred in association with Grade 3 hypokalemia, Grade 2 prolongation in QTcF interval, and use of methadone, a prohibited concomitant medication with a known risk for QT prolongation. Ibrance's label does not mention screening patients for QT interval or limiting concomitant use of medications known to cause QT prolongation or torsades de pointes; it was not shown to cause a large change (>20 msec) in QT in a study of 184 patients with advanced cancer. Ibrance is approved in the U.S. as a first-line treatment for HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women, and as a second-line treatment following endocrine therapy in combination with Faslodex fulvestrant. Pfizer has rights to Ibrance from Amgen Inc. (NASDAQ:AMGN). Novartis is also studying ribociclib in the Phase III MONALEESA-3 trial in combination with Faslodex in men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer who have received up to one prior endocrine therapy, and the Phase III MONALEESA-7 study in combination with endocrine therapy and goserelin in premenopausal women with HR-positive, HER2-negative advanced breast cancer who have not received prior endocrine therapy. Global Head of Oncology Development and Medical Affairs Alessandro Riva said Novartis plans to submit regulatory applications for ribociclib worldwide by year end. He said Novartis plans to report data from MONALEESA-3 by YE17 and from MONALEESA-7 in 1Q18.
Sunday, October 9, 2016 4:16 PM|Google News on 'breast cancer'|Labels: CDK, breast cancer

Forbes

Encouraging Results For Ribociclib In Advanced Breast Cancer
Forbes
At the European Society for Medical Oncology (ESMO) Congress this week, investigators presented data for a new and potentially important drug, ribociclib (Novartis). This oral medication is clearly active in hormone receptor-positive (ER+ or PR+ ...
Ribociclib Offers 'Paradigm Shift' in Advanced Breast CancerMedscape
Ribociclib improves progression-free survival in advanced breast cancerScience Daily
Targeting estrogen receptor improves progression-free survival in advanced breast cancerEurekAlert (press release)
MedPage Today -Business Wire (press release)
all 19 news articles »
Sunday, October 9, 2016 2:26 PM|Google News on 'cancer for a feed'|Labels: CDK, breast cancer

UDPATE2: Novartis' Ibrance challenger cuts breast cancer progression risk by 44%
FiercePharma
COPENHAGEN, Denmark--Back in May, Novartis called an early halt to a Phase III study of breast cancer med LEE011--a future rival to Pfizer's Ibrance--because the drug had already shown it could beat a standard treatment at stalling the disease ...

and more »
Saturday, October 8, 2016 1:48 PM|Cancer News -- ScienceDaily|Labels: CDK, breast cancer
The addition of the CDK4/6 inhibitor ribociclib to letrozole therapy significantly improves progression-free survival in postmenopausal women with hormone receptor-positive advanced breast cancer, researchers report.
Saturday, October 8, 2016 5:13 AM|Medications/Drugs News Headlines - Yahoo! News|Attachments|Labels: CDK, breast cancer

A Novartis logo is pictured on its headquarters building in MumbaiBy Ben Hirschler COPENHAGEN (Reuters) - An experimental Novartis pill given with an older drug kept advanced breast cancer in check far longer than standard treatment alone, putting it on track to challenge Pfizer's blockbuster Ibrance, data showed on Saturday. Novartis' ribociclib works in a similar way to Ibrance and is set to be second to market in the category. Ibrance has been quickly adopted by oncologists and is tipped by analysts to sell some $2.1 billion in 2016, according to Thomson Reuters consensus forecasts.


Saturday, October 8, 2016 2:35 AM|Google News on 'cancer for a feed'|Labels: CDK, breast cancer

Reuters

Novartis challenges Pfizer with strong breast cancer drug data
Reuters
Alessandro Riva, head of cancer drug development at Novartis, told Reuters he believed the data showed that ribociclib was "at least as good" as Ibrance. Like Ibrance, ribociclib caused a decline in white blood cells. The Novartis drug was also ...

and more »
Thursday, October 6, 2016 10:27 AM|Elsevier|JournalTOCs API - Biochemical Pharmacology (50 articles)|Labels: CDK, PDGF, AML

Combination screening in vitro identifies synergistically acting KP372-1 and cytarabine against acute myeloid leukemia

Biochemical Pharmacology, Vol. , No. (2016) pp. -
Publication date: 15 October 2016 Source:Biochemical Pharmacology, Volume 118 Author(s): A. Österroos, M. Kashif, C. Haglund, K. Blom, M. Höglund, C. Andersson, M.G. Gustafsson, A. Eriksson, R. Larsson Cytogenetic lesions often alter kinase signaling in acute myeloid leukemia (AML) and the addition of kinase inhibitors to the treatment arsenal is of interest. We have screened a kinase inhibitor library and performed combination testing to find promising drug-combinations for synergistic killing of AML cells. Cytotoxicity of 160 compounds in the library InhibitorSelect™ 384-Well Protein Kinase Inhibitor I was measured using the fluorometric microculture cytotoxicity assay (FMCA) in three AML cell lines. The 15 most potent substances were evaluated for dose-response. The 6 most cytotoxic compounds underwent combination synergy analysis based on the FMCA readouts after either simultaneous or sequential drug addition in AML cell lines. The 4 combinations showing the highest level of synergy were evaluated in 5 primary AML samples. Synergistic calculations were performed using the combination interaction analysis package COMBIA, written in R, using the Bliss independence model. Based on obtained results, an iterative combination search was performed using the therapeutic algorithmic combinatorial screen (TACS) algorithm. Of 160 substances, cell survival was ⩽50% at &lt;0.5μM for Cdk/Crk inhibitor, KP372-1, synthetic fascaplysin, herbimycin A, PDGF receptor tyrosine kinase inhibitor IV and reference-drug cytarabine. KP372-1, synthetic fascaplysin or herbimycin A obtained synergy when combined with cytarabine in AML cell lines MV4-11 and HL-60. KP372-1 added 24h before cytarabine gave similar results in patient cells. The iterative search gave further improved synergy between cytarabine and KP372-1. In conclusion, our in vitro studies suggest that combining KP372-1 and cytarabine is a potent and synergistic drug combination in AML. Graphical abstract

Thursday, October 6, 2016 10:27 AM|M. Kashif; C. Haglund; K. Blom; M. Höglund; C. Andersson; M.G. Gustafsson; A. Eriksson; R. Larsson|JournalTOCs API - Biochemical Pharmacology (50 articles)|Labels: CDK, AML

Combination screening in vitro identifies synergistically acting KP372-1 and cytarabine against acute myeloid leukemia
A. Österroos M. Kashif; C. Haglund; K. Blom; M. Höglund; C. Andersson; M.G. Gustafsson; A. Eriksson; R. Larsson
Biochemical Pharmacology, Vol. 118, No. (2016) pp. 40 - 49
Publication date: 15 October 2016 Source:Biochemical Pharmacology, Volume 118 Author(s): A. Österroos, M. Kashif, C. Haglund, K. Blom, M. Höglund, C. Andersson, M.G. Gustafsson, A. Eriksson, R. Larsson Cytogenetic lesions often alter kinase signaling in acute myeloid leukemia (AML) and the addition of kinase inhibitors to the treatment arsenal is of interest. We have screened a kinase inhibitor library and performed combination testing to find promising drug-combinations for synergistic killing of AML cells. Cytotoxicity of 160 compounds in the library InhibitorSelect™ 384-Well Protein Kinase Inhibitor I was measured using the fluorometric microculture cytotoxicity assay (FMCA) in three AML cell lines. The 15 most potent substances were evaluated for dose-response. The 6 most cytotoxic compounds underwent combination synergy analysis based on the FMCA readouts after either simultaneous or sequential drug addition in AML cell lines. The 4 combinations showing the highest level of synergy were evaluated in 5 primary AML samples. Synergistic calculations were performed using the combination interaction analysis package COMBIA, written in R, using the Bliss independence model. Based on obtained results, an iterative combination search was performed using the therapeutic algorithmic combinatorial screen (TACS) algorithm. Of 160 substances, cell survival was ⩽50% at &lt;0.5μM for Cdk/Crk inhibitor, KP372-1, synthetic fascaplysin, herbimycin A, PDGF receptor tyrosine kinase inhibitor IV and reference-drug cytarabine. KP372-1, synthetic fascaplysin or herbimycin A obtained synergy when combined with cytarabine in AML cell lines MV4-11 and HL-60. KP372-1 added 24h before cytarabine gave similar results in patient cells. The iterative search gave further improved synergy between cytarabine and KP372-1. In conclusion, our in vitro studies suggest that combining KP372-1 and cytarabine is a potent and synergistic drug combination in AML. Graphical abstract

Tuesday, October 4, 2016 10:51 AM|Alves, C. L., Elias, D., Lyng, M., Bak, M., Kirkegaard, T., Lykkesfeldt, A. E., Ditzel, H. J.|Clinical Cancer Research Online First Articles|Labels: CDK, breast cancer

Purpose: Resistance to endocrine therapy in estrogen receptor–positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole or fulvestrant was approved for treatment of ER+ advanced breast cancer. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains undefined.

Experimental Design: We investigated the specific role of increased CDK6 expression in fulvestrant-resistant cells by gene knockdown and treatment with palbociclib, and evaluated the effect in cell proliferation, apoptosis, and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant.

Results: We found increased expression of CDK6 in two fulvestrant-resistant cell models versus sensitive cells. Reduction of CDK6 expression impaired fulvestrant-resistant cell growth and induced apoptosis. Treatment with palbociclib resensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma protein phosphorylation. High CDK6 levels in metastatic samples from two independent cohorts of breast cancer patients treated with fulvestrant (N = 45 and 46) correlated significantly with shorter progression-free survival (PFS) on fulvestrant treatment (P = 0.0006 and 0.018), whereas no association was observed in patients receiving other first- or second-/third-line endocrine treatments (N = 68, P = 0.135 and 0.511, respectively).

Conclusions: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens. Clin Cancer Res; 1–13. ©2016 AACR.

Monday, October 3, 2016 12:05 AM|Beck, T. N., Georgopoulos, R., Shagisultanova, E. I., Sarcu, D., Handorf, E. A., Dubyk, C., Lango, M. N., Ridge, J. A., Astsaturov, I., Serebriiskii, I. G., Burtness, B. A., Mehra, R., Golemis, E. A.|Molecular Cancer Therapeutics current issue|Labels: CDK, EGFR, HNN, biomarker diagnostic

Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response–predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6-regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and pT356RB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC. Mol Cancer Ther; 15(10); 2486–97. ©2016 AACR.

Monday, October 3, 2016 12:05 AM|Chen, P., Lee, N. V., Hu, W., Xu, M., Ferre, R. A., Lam, H., Bergqvist, S., Solowiej, J., Diehl, W., He, Y.-A., Yu, X., Nagata, A., VanArsdale, T., Murray, B. W.|Molecular Cancer Therapeutics current issue|Labels: CDK

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. Tumor cell studies of ATP-competitive CDK drugs (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve this apparent disconnect, drug behaviors are described at the molecular level. Nonkinase binding studies and kinome interaction analysis (recombinant and endogenous kinases) reveal that proteins outside of the CDK family appear to have little role in dinaciclib/palbociclib/ribociclib pharmacology, may contribute for abemaciclib, and confounds AG-024322 analysis. CDK2 and CDK6 cocrystal structures with the drugs identify the molecular interactions responsible for potency and kinase selectivity. Efficient drug binding to the unique hinge architecture of CDKs enables selectivity toward most of the human kinome. Selectivity between CDK family members is achieved through interactions with nonconserved elements of the ATP-binding pocket. Integrating clinical drug exposures into the analysis predicts that both palbociclib and ribociclib are CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, and dinaciclib is a broad-spectrum CDK inhibitor (CDK2/3/4/6/9). Understanding the molecular components of potency and selectivity also facilitates rational design of future generations of kinase-directed drugs. Mol Cancer Ther; 15(10); 2273–81. ©2016 AACR.

Monday, September 26, 2016 2:21 PM|Walker, A. J., Wedam, S., Amiri-Kordestani, L., Bloomquist, E., Tang, S., Sridhara, R., Chen, W., Palmby, T. R., Fourie Zirkelbach, J., Fu, W., Liu, Q., Tilley, A., Kim, G., Kluetz, P. G., McKee, A. E., Pazdur, R.|Clinical Cancer Research Online First Articles|Labels: CDK, breast cancer, regulatory

On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36–0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 1–5. ©2016 AACR.

Friday, September 23, 2016 12:47 PM|Au-Yeung, G., Lang, F., Azar, W. J., Mitchell, C., Jarman, K. E., Lackovic, K., Aziz, D., Cullinane, C., Pearson, R. B., Mileshkin, L., Rischin, D., Karst, A. M., Drapkin, R., Etemadmoghadam, D., Bowtell, D. D. L.|Clinical Cancer Research Online First Articles|Labels: AKT, CDK, ovarian cancer

Purpose: Cyclin E1 (CCNE1) amplification is associated with primary treatment resistance and poor outcome in high grade serous ovarian cancer (HGSC). Here, we explore approaches to target CCNE1 amplified cancers and potential strategies to overcome resistance to targeted agents. Experiment Design: To examine dependency on CDK2 in CCNE1 amplified HGSC, we utilised siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small molecule CDK2 inhibitor. High throughput compound screening was used to identify selective synergistic drug combinations, as well as combinations that may overcome drug resistance. An observed relationship between CCNE1 and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells. Results: We validate CDK2 as a therapeutic target by demonstrating selective sensitivity to gene suppression. However, we found that dinaciclib did not trigger amplicon-dependent sensitivity in a panel of HGSC cell lines. A high throughput compound screen identified synergistic combinations in CCNE1 amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated co-amplification of CCNE1 and AKT2. Over-expression of Cyclin E1 and AKT isoforms, in addition to mutant TP53, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC. Conclusions: These findings suggest a specific dependency of CCNE1 amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with CCNE1 amplified HGSC.

Thursday, September 15, 2016 8:45 AM|Teh, J. L. F., Purwin, T. J., Greenawalt, E. J., Chervoneva, I., Goldberg, A., Davies, M. A., Aplin, A. E.|Cancer Research recent issues|Labels: BRAF, CDK, melanoma, skin cancer, regulatory
Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma. Cancer Res; 76(18); 5455–66. ©2016 AACR.
Wednesday, September 14, 2016 9:55 AM|YUN, C. W., YUN, S., LEE, J. H., HAN, Y.-S., YOON, Y. M., AN, D., LEE, S. H.|Anticancer Research recent issues|Labels: CDK, CRC

Background: The putative functions of the cellular prion protein (PrPc) are believed to be associated with cell signaling, differentiation, survival, and cancer progression. With respect to cancer development and progression, elevations and mutations of PrPc expression have been shown to increase the risk for malignancy and metastasis in breast and colorectal cancer. Since both natural supplements and direct regulation of PrPc expression contribute to inhibition of cancer progression and growth, we hypothesized that knockdown of PrPc could lead to an enhanced synergic effect on the inhibition of cancer growth by fucoidan. Materials and Methods: PrPc expression was suppressed in HT29 human colon cancer cells by utilizing small-interfering RNA (si-PRNP), and cells were subsequently used to study the antiproliferative and anticancer effects of fucoidan treatment of HT29 human colon cancer cells. Results: Fucoidan treatment significantly inhibited growth and reduced cyclin and cyclin-dependent kinase (CDK) expression in HT29 colon cancer cells. Furthermore, silencing PrPc expression with si-PRNP amplified the fucoidan-induced changes in cell proliferation, apoptosis, and migration. Intraperitoneal injection of si-PRNP with fucoidan reduced proliferation and tumor volume in Balb/c nude mice. This enhanced antitumor efficacy was associated with decreased angiogenesis. Conclusion: Combination of fucoidan with silencing of PrPc has a synergic effect on the inhibition of HT29 colon cancer cell growth. Furthermore, we provide evidence for the therapeutic application of PrPc silencing with other anticancer drugs for cancer.

Monday, August 15, 2016 12:05 AM|Salvador, B., Lopez-Casas, P. P., Menendez, C., Banos, N., Sarno, F., Min-Jean, Y., Olson, P., VanArsdale, T., Shields, D. J., Hidalgo, M.|Clinical Cancer Research recent issues|Labels: CDK, pancreatic cancer, biomarker diagnostic, regulatory

Pancreatic Ductal Adenocarcinoma (PDAC) continues to be the deadliest human cancer with a 5-year survival rate of 7%. One of the current standards of care for advanced PDAC is gemcitabine plus nab-paclitaxel, a regimen our group helped develop. Finding new agents to combine with this regimen remains necessary, particularly using drug targeting strategies. At the molecular level, genetic and genomic profiling identified CDKN2A as a very frequently disrupted gene in PDAC (<90%). This gene encodes the tumor suppressor p16, a cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor, that controls cell cycle progression. Recently, the selective CDK4/6 inhibitor palbociclib was approved by the FDA for certain types of breast cancer patients. Whether palbociclib can also benefit patients with PDAC is unknown.

In the current study, we aimed to evaluate the effectiveness of palbociclib monotherapy and in combination with nab-paclitaxel and gemcitabine/nab-paclitaxel in a cohort of PDACs patient derived xenograft (PDX) models.

PDX models obtained from late stage PDAC patients were treated with palbociclib alone and in combination with gemcitabine/nab-paclitaxel. The majority of models displayed >50% tumor growth inhibition (TGI) following treatment with single agent palbociclib. Treatment with palbociclib plus nab-paclitaxel or palbociclib plus gemcitabine/nab-paclitaxel increased TGI to a greater degree than the gemcitabine/nab-paclitaxel combination and also increased the duration of response as compared to the standard of care therapy.

Moving forward, the palbociclib/nab-paclitaxel combination will be evaluated in a clinical trial for PDAC patients. We are currently expanding our analyses to a larger cohort of PDX models and performing molecular characterization of these models in order to gain insights on biomarkers and mechanism of action of the drug combinations in PDAC.

Citation Format: Beatriz Salvador, Pedro P. López-Casas, Camino Menéndez, Natalia Baños, Francesca Sarno, Yin Min-Jean, Peter Olson, Todd VanArsdale, David J. Shields, Manuel Hidalgo. Assessment of effectiveness and molecular markers of CDK4/6 inhibitor Palbociclib in Pancreatic Ductal Adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A36.

Monday, August 15, 2016 12:05 AM|Hidalgo, M.|Clinical Cancer Research recent issues|Labels: CDK, pancreatic cancer, biomarker diagnostic

Pancreatic cancer remains one of the most deadly cancers. Very few therapeutics advanced have been achieved in this disease. Over the last few years, several studies have started to elucidate the molecular biology of PDAC including the genomic landscape of the disease, the importance of the stroma and the immunesuppressive environment characteristic of PDAC. One important development in translational research in PDAC is the availability of preclinical models of the disease. This includes genetically engineered mouse models of cancer, patient derived xenografts (aka Avatar models) and organoids. These models are becoming useful for drug screening, biomarker development and personalize medicine. Using Avatar models we identified Nab-paclitaxel as an effective agent in pancreas cancer in contrast to paclitaxel that does not result antitumor effects. We also showed that Nab-paclitaxel disrupts PDAC stroma, an observation, however, has not been confirmed by others. In addition, studies in mouse models revealed the lack of predictability of SPARC expression for clinical outcome. More recently, we have identified demcizumab and palbociclib as potentially effective agents in PDX models as the basis for their clinical development. PDX models have also de potential to be used as a platform for personalizes cancer treatment. In this regard, we are now conducting the AVATAR clinical trial in which patients with advanced cancer are randomized to receive either a conventional treatment or a treatment based on integrating genomic data with AVATAR mouse mode development.

Citation Format: Manuel Hidalgo. Application of PDX models to pancreas cancer research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA17.

Tuesday, August 2, 2016 12:05 AM|Unknown Author|Cancer Discovery recent issues|Labels: CDK, breast cancer, clinical trial

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.

Monday, July 11, 2016 10:20 PM|Cho‐Ming Loi, Justin Hoffman, Diane Wang|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: CDK

Physiologically‐Based Pharmacokinetic (PBPK) Modeling Of Palbociclib
Yanke Yu Cho‐Ming Loi, Justin Hoffman, Diane Wang
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. n/a - n/a
Palbociclib is an orally available CDK4/6 inhibitor. In humans, palbociclib undergoes metabolism mediated primarily by CYP3A and SULT2A1, and it is also a weak time‐dependent CYP3A inhibitor. The objectives of the current study are to: (1) develop a physiologically‐based pharmacokinetic (PBPK) model of palbociclib based on the in silico, in vitro and in vivo pharmacokinetic data of palbociclib, (2) to verify the PBPK model with clinical drug‐drug interaction (DDI) results of palbociclib with strong CYP3A inhibitor (itraconazole), inducer (rifampin), and a sensitive CYP3A substrate (midazolam), and (3) to predict the DDI risk of palbociclib with moderate/weak CYP3A inhibitors. The developed PBPK model adequately described the observed pharmacokinetics of palbociclib after administration of a single oral or intravenous dose of palbociclib. The model predicted DDI of palbociclib with itraconazole, rifampin, and midazolam were consistent with the observed DDIs, with the discrepancies of the predicted versus observed AUCR and CmaxR within 20%, except for the AUCR of palbociclib with coadministration of rifampin. Using this final PBPK model, it was predicted that weak CYP3A inhibitors (fluoxetine and fluvoxamine) are anticipated to have negligible DDI risk with palbociclib, while moderate CYP3A inhibitors (diltiazem and verapamil) may increase plasma palbociclib AUC by ∼40%. Moderate CYP3A inducer (efavirenz) may decrease plasma palbociclib AUC by ∼40%. The established model is considered sufficiently robust for other applications in support of the continued development for palbociclib. This article is protected by copyright. All rights reserved

Friday, July 1, 2016 12:05 AM|Lim, J. S. J., Turner, N. C., Yap, T. A.|Cancer Discovery recent issues|Labels: CDK, breast cancer, skin cancer

Summary: 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. ©2016 AACR.

See related article by Patnaik et al., p. 740.

Friday, July 1, 2016 12:05 AM|Patnaik, A., Rosen, L. S., Tolaney, S. M., Tolcher, A. W., Goldman, J. W., Gandhi, L., Papadopoulos, K. P., Beeram, M., Rasco, D. W., Hilton, J. F., Nasir, A., Beckmann, R. P., Schade, A. E., Fulford, A. D., Nguyen, T. S., Martinez, R., Kulanthaivel, P., Li, L. Q., Frenzel, M., Cronier, D. M., Chan, E. M., Flaherty, K. T., Wen, P. Y., Shapiro, G. I.|Cancer Discovery recent issues|Labels: CDK, skin cancer, clinical trial

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. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor–positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months.

Significance: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740–53. ©2016 AACR.

See related commentary by Lim et al., p. 697.

This article is highlighted in the In This Issue feature, p. 681

Tuesday, June 14, 2016 10:02 AM|Patel, H., Abduljabbar, R., Lai, C. F., Periyasamy, M., Harrod, A., Gemma, C., Steel, J., patel, n., Busonero, C., Jerjees, D., Remenyi, J., Smith, S., Gomm, J. J., Magnani, L., Gyorffy, B., Jones, J. L., Fuller-Pace, F. V., Shousha, S., Buluwela, L., Rakha, E. A., Ellis, I. O., Coombes, R. C., Ali, S.|Clinical Cancer Research Online First Articles|Labels: CDK, breast cancer

Purpose: CDK-activation kinase (CAK) is required for the regulation of the cell-cycle and is a trimeric complex consisting of Cyclin Dependent Kinase 7 (CDK7), Cyclin H and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-alpha(ERalpha).). Deregulation of cell cycle and transcriptional control is aare general featurefeatures of cancertumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics in cancer. Experimental Design: mRNA and protein expression of CDK7 and its essential co-factors cyclinH and MAT1, were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathological features and patient outcome. Results: We show that expression of CDK7, cyclinH and MAT1 are all closely linked at the mRNA and protein level and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumour grade and size and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ERalpha expression and in particular with phosphorylation of ERalpha at serine 118, a site important for ERalpha transcriptional activity. Conclusions: Expression of components of the CAK complex, CDK7, MAT1 and Cyclin H are elevated in breast cancer and correlates with ERalpha.. Like ERalpha, CDK7 expression is inversely proportional to poor prognostic factors and survival.

Wednesday, January 13, 2016 6:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: CDK
Cyclin-dependent kinases (CDKs) with primary roles in transcription regulation are emerging as tractable therapeutic targets in cancers driven by the aberrant expression of oncogenic transcription factors. Our goal is to disrupt the myriad and pleomorphic features of oncogenic MYC through inhibiting CDKs involved in its transcriptional amplifier role. CDK7 participates in transcription initiation by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase (Pol) II and also functions as a CDK-activating kinase, while CDK12 functions in transcription elongation and RNA processing. Using a novel covalent CDK7 inhibitor, THZ1, we demonstrated striking activity and selectivity in neuroblastoma (NB) cells driven by high MYCN expression. This response translated to significant tumor re...

MedWorm Sponsor Message: Directory of the best January Sales in the UK. Find the best Christmas presents too.

Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: CDK, pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a 5 year survival rate of less than 5%. Deaths caused by pancreatic cancer are projected to exceed the number from colorectal carcinoma by 2020, making PDAC the second leading cause of cancer-related death in the United States, behind only NSCLC. At the molecular level, PDAC is enriched for a number of genetic events central to CDK4/6:CyclinD1 control of cell cycle progression - 90% of tumors harbor oncogenic KRAS mutations, which are synthetic lethal with CDK4/6 inhibition, while the majority of PDAC cases also feature loss of p16INK4A, the endogenous inhibitor of CDK4/6. Rb loss is uncommon in PDAC and phosphorylation of Rb, the canonical CDK4/6 substrate, is detectable at high frequencies, suggesting th...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: CDK, lung cancer
Lung cancer remains one of the leading causes of cancer-related mortality. Squamous cell lung cancer (SqCLC) is the second most common subtype of non-small cell lung cancer (NSCLC). Despite recent development of effective targeted therapeutic agents for lung adenocarcinoma, patients with SqCLC often receive conventional cytotoxic chemotherapy as this cancer subtype lacks genomic alterations that can be targeted by personalized medicine. Hence, novel approaches that enhance the efficacy of chemotherapy will benefit treatment outcomes in this patient population. CDK inhibitors comprise a class of drugs that targets the dysregulated cell cycle in malignant cells. Treatment of tumor cells with the CDK4/6 inhibitor palbociclib inhibits tumor growth by decreasing retinoblastoma (RB) protein phos...