226 research outputs found
Pharmacology and pharmacokinetics of tazemetostat
No full textTazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies
VDR activity is differentially affected by Hic-5 in prostate cancer and stromal cells
No full textPublished OnlineFirst May 13, 2014.
Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).Abstract not availableJoshua D. Solomon, Marjet D. Heitzer, Teresa T. Liu, Jan H. Beumer, Robert A. Parise, Daniel P. Normolle, Damien A. Leach, Grant Buchanan and Donald B. DeFranc
Quantitation of tazemetostat in human plasma using liquid chromatography–tandem mass spectrometry
No full textTo support a phase 1 trial in patients with lymphomas, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for tazemetostat quantitation in 20 mu L of human plasma. After protein precipitation, chromatographic separation employed a Kinetex C18 column and a gradient of 0.1% formic acid in both water and acetonitrile, during a 3-min run time. Detection was achieved using a SCIEX 6500+ tandem mass spectrometer with electrospray positive-mode ionization. Validation was based on the latest Food and Drug Administration guidance. With a stable isotopic internal standard, the assay was linear within the range of 10-5000 ng/mL and proved to be accurate (91.9%-103.7%) and precise (<4.4% imprecision). Recovery varied between 93.3% and 121.1%, and matrix effect ranged from -25.5% to -4.9%. Hemolysis, lipemia, and dilution did not impact quantitation. Plasma stability was confirmed after three freeze-thaw cycles, 24 h at room temperature, and 4 months at -80 degrees C. Incurred sample reanalysis yielded 94.4% samples within 20% difference (n = 36). External validation showed a mean bias of -11.1%. Pharmacokinetic (PK) data obtained from three patients suggested variable concentration time profiles, warranting collection of further data. The assay proved to be suitable for tazemetostat quantitation in human plasma and will support clinical studies by defining tazemetostat PKs
Abstract 5270: Disease subtype independent biomarkers of breast cancer prevention by withaferin a
No full textAbstract
Breast cancer is a rather complex and heterogeneous disease broadly grouped into four major subtypes, including luminal-type, basal-like, HER2 amplified, and normal-like, and each with a distinct molecular signature. A non-toxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study not only demonstrates chemoprevention of breast cancer in rats by the Ayurvedic medicine phytochemical withaferin A (WA) but also identifies its mechanistic biomarkers common to different subtypes of this disease. Chemopreventive efficacy of WA (4 and 8 mg per kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by western blotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat and/or mouse mammary tumor virus-neu (MMTV-neu) models. Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and MDA-MB-231 cells. Incidence, multiplicity, and burden of MNU-induced breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8 mg per kg group was lower by 67% compared with controls (P = 0.004). Mitotic arrest and apoptosis induction were common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured MCF-7 and MDA-MB-231 cell lines. WA is a promising phytochemical with the ability to inhibit at least two different subtypes of breast cancer, including neu-driven estrogen receptor negative (ER-) breast cancer in MMTV-neu model and MNU-induced ER+ breast cancer in rats. This study was supported by the grant RO1 CA142604-07 awarded by the National Cancer Institute.
Citation Format: Eun-Ryeong Hahm, Suman K. Samanta, Anuradha Sehrawat, Su-Hyeong Kim, Subrata K. Pore, Krishna B. Singh, Susan M. Christner, Yongli Shuai, Jan H. Beumer, Ruchi Roy, Nancy E. Davidson, Shivendra V. Singh. Disease subtype independent biomarkers of breast cancer prevention by withaferin a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5270. doi:10.1158/1538-7445.AM2017-5270</jats:p
Abstract 4549: Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice
No full textAbstract
Introduction
Cytidine drugs, such as gemcitabine, undergo rapid, inactivating catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine drug metabolism. However, p.o. THU is at most 20% bioavailable (Beumer et al.), which limits its preclinical evaluation and clinical use. Therefore, the more lipophilic prodrug triacetyl THU (taTHU) was developed. We characterized THU pharmacokinetics after administration of taTHU to mice.
Methods
Mice were dosed 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma and urine pharmacokinetic parameters and p.o. bioavailability were calculated non-compartmentally and compartmentally. We assessed taTHU inhibition of metabolism of gemcitabine by recombinant CD.
ResultsTHU parameterstaTHU i.v. 150 mg/kgtaTHU p.o. 150 mg/kgCmax (µg/mL)10611.8Tmax (min)560Half-life (min)235122AUC0-inf (mg/mL*min)7.553.36Vd/F (L/kg)4.495.26Cl/F (mL/min/kg)13.229.8F-THUi.v. (%)68.030.3% dose in 0-16 h urine405.6% dose in 0-24 h urine5512
THU, after 150 mg/kg taTHU i.v., had a 235 min terminal half-life and produced plasma THU concentrations &gt;1 µg/mL, the concentration shown to inhibit CD, for 10 h. A multi-compartment model fit the data best. 150 mg/kg p.o. taTHU produced a concentration versus time profile with a plateau of approximately 10 µg/mL from 0.5-2 h, followed by a decline with a 122 min half-life. Approximately 68% of i.v. taTHU was converted to THU. Approximately 30% of p.o. taTHU reached the systemic circulation as THU. After i.v dosing, renal excretion accounted for 40-55% of the taTHU dose, 26-35% as THU and an additional 14-19% as acetylated forms of THU. After p.o. dosing, the renal excretion percentages were 6-12%, 5.2-11%, and 0.42-0.71%, respectively. taTHU did not inhibit recombinant CD.
Conclusion
The availability of THU after p.o. taTHU in mice is 30%, as compared to the 20% achieved after p.o. THU. Clinical studies are warranted to evaluate availability of THU from taTHU in humans.
Support: N01-CM07106, N01-CM52202, P30-CA47904 from the NCI and P41-EB001978.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4549.</jats:p
Abstract 5450: Enhanced cytotoxicity of carboplatin and paclitaxel (CP) by vorinostat (SAHA), a histone deacetylase (HDAC) inhibitor, in melanoma cell lines
No full textAbstract
Background: CP is the mainstay of therapy in NSCLC and ovarian cancer and recently gained wide use in melanoma. Vorinostat (SAHA) is a histone deacetylase inhibitor that affects tumor growth via histone and non-histone targets. Combination of CP + SAHA was safe and showed impressive activity in NSCLC in a Phase I trial. We hypothesized that SAHA will enhance CP cytotoxicity in melanoma cells.
Methods: IC50 values in A375 and FEMX-1 human melanoma cells were determined using MTS after incubation for 72 h. Carboplatin and paclitaxel were combined at their IC50 ratio and considered a single drug. Schedules were: a) 72 h concomitant SAHA and CP; b) 48 h SAHA + 48 h rest + 72 h CP; c) 96 h SAHA + 72 h CP; d) 96 h SAHA + 72 h CP and SAHA. SAHA was used at 1 µM or the single agent IC50. CP was used at dilutions of the combined IC50. Experiments were repeated 3 times.
Results: SAHA displayed single-agent activity at clinically achievable concentrations (IC50 1.48 µM for FEMX-1, 2.45 µM for A375). Addition of SAHA enhanced cytotoxicity of CP. Concomitant treatment for 72 h led to &gt;50% cell kill even at 50% of CP IC50. Pretreatment for 48 h followed by 48 h of rest and 72 hr CP demonstrated enhancement that was less pronounced, suggesting that the effect of SAHA may be partly reversible. SAHA pretreatment for 96 h followed by SAHA+CP for 72 h was most effective with &gt;90% cell kill even at CP as low as 25% of IC50. Higher doses of SAHA gave consistently greater effects.
Conclusion: Treatment with SAHA enhances CP cytotoxicity in melanoma cells at all doses and schedules evaluated, but SAHA pretreatment followed by the 3-drug combination had the highest activity. Our results support the clinical evaluation of the combination of SAHA and CP in metastatic melanoma in a Phase II trial.
Support: Hillman Foundation for Innovative Cancer Research; NCI-CTEPExp. % Survival (+/− Standard Error) 0 - 48 h48 - 168 h96-168 h SAHASAHACP 0CP 0.25CP 0.5CP 0.751--10076.8 (+/− 2.5)72.6 (+/− 1.5)67.9 (+/− 4.4)2-1 µM99.8 (+/− 7.1)67.5 (+/− 4.8)52.7 (+/− 2.3)40.2 (+/− 3.2)3-1.48 µM76.5 (+/− 6.6)60.6 (+/− 3.6)40.2 (+/− 0.7)35.9 (+/− 0.7)41 µM-78.5 (+/− 13.3)56.7 (+/− 9.7)42.2 (+/− 13.4)23.9 (+/− 6.1)51 µM1 µM50.7 (+/− 9.8)25.4 (+/− 4.9)19.7 (+/− 4.3)13.1 (+/− 1.9)61.48 µM-33.1 (+/− 6.1)18.4 (+/− 2.2)11.6 (+/− 1.4)7.2 (+/− 1.2)71.48 µM1.48 µM15.0 (+/− 2.5)8.1 (+/− 0.9)6.1 (+/− 0.2)5.9 (+/− 1.0)
Results for FEMX-1 represented as % cells surviving after treatment as indicated. CP was added at dilutions of IC50 (0, 0.25, 0.5 and 0.75).
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5450.</jats:p
Abstract CT013: NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC)
No full textAbstract
Background:
T-DM1, an antibody-drug conjugate that delivers the maytansinoid antimicrotubule agent DM1 to antigen-expressing HER2+ cells thereby improving the therapeutic index, is FDA- approved as 2nd-line therapy in HER2+ MBC patients (pts) after prior trastuzumab (T) and a taxane. Most pts currently receive T and pertuzumab (P) as neoadjuvant for 1st-line therapy for MBC. A retrospective analysis of T-DM1 after T-P found a much lower tumor response rate (17%) than T-DM1 after T and taxane, as reported in EMILIA (43%). In NSABP FB-8, combining T, N, and paclitaxel achieved responses after T-DM1 progression, raising the possibility that N could reverse resistance to T-DM1.
Methods:
Eligible pts had prior T-P as neoadjuvant therapy for 1st-line metastatic treatment for HER2+ measurable disease, ECOG PS &lt;2, adequate hematologic, renal, and liver function. Treatment consisted of T-DM1 at 3.6 mg/kg iv q 3 wk and N at escalating doses of 120, 160, 200, and 240 mg/d continuously, using 3+3 design. Each cycle was 21 d. Clinical endpoints include determination of safety and efficacy. Primary diarrhea prophylaxis with intensive loperamide was required. To compare steady-state blood levels of N across dose levels samples were drawn at the start of cycle 2.
Results:
The RP2D is still undergoing evaluation. 17 T-P resistant pts were enrolled. Treatment-related grade 3 toxicities included diarrhea (2 pts), thrombocytopenia (3 pts), hypertension (2 pts), ALT elevation (1 pt), nausea (1 pt), and neutropenia (1 pt). Of 14 pts who were evaluable after 2 cycles of therapy, 3 had CRs and 6 had PRs (ORR 64%).
Dose (mg/day)No. of objective responses (CR/PR)/No. of evaluable (CR/PR/SD/PD)Duration of objective response (weeks)DLTs1205/5 (CR 2, PR 3)66+,51,26,15,91 (nausea and dehydration)1602/4 (CR 1, PR 1, PD 2)39+,6No2001/3 (PR 1, SD 1, PD 1)21No2401/2 (PR 1, SD 1)152 (diarrhea, nausea, vomiting)
Conclusions:
T-DM1 plus N was well tolerated at doses of 120, 160, and 200 mg/d. Anti-tumor activity did not appear to be dose-dependent. 5 evaluable pts treated at lowest dose of N (120 mg/d) responded. A randomized phase II study comparing N at 120 mg/d and 200 mg/d with T-DM1 is planned to better define efficacy and tolerance.
Support: Puma Biotechnology
Citation Format: Jame Abraham, Shannon L. Puhalla, Wiliam M. Sikov, Alberto J. Montero, Jan H. Beumer, Marc E. Buyse, Laura M. Adamson, Ashok Srinivasan, Katherine L. Pogue-Geile, Samuel A. Jacobs. NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT013. doi:10.1158/1538-7445.AM2017-CT013</jats:p
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