A phase II randomized study of bortezomib/dexamethasone (Bort/Dex) with or without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RR MM) (CA204-009).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8114-TPS8114
Author(s):  
Andrzej J. Jakubowiak ◽  
Darrell White ◽  
Philippe Moreau ◽  
Thierry Facon ◽  
Ravi Vij ◽  
...  
Keyword(s):  
Nk Cell ◽  
Randomized Study ◽  
Objective Response ◽  
Xenograft Model ◽  
Progression Free Survival ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Normal Tissues ◽  
Mouse Xenograft Model ◽  
Secondary Endpoints

TPS8114 Background: MM is rarely curable and pts typically relapse or become refractory to current treatments. Elo is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells with little to no expression on normal tissues. The mechanism of action of Elo is primarily natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against myeloma cells. Elo + Bort significantly enhanced antimyeloma activity in a mouse xenograft model vs either agent alone. The addition of Bort enhanced the ADCC activity of Elo in preclinical studies. In a phase I study of Elo + Bort in pts with RR MM, objective response rate (ORR) was 48%, median progression-free survival (PFS) was 9.5 months, and activity was observed in 2/3 patients (67%) refractory to Bort (Jakubowiak et al. J Clin Oncol, in press). This study will assess if the addition of Elo to Bort/Dex improves PFS and, if so, whether magnitude of the improvement is linked to FcγRIIIa polymorphism. Methods: Pts (N=150) with RR MM after 1 or 2 prior therapies will be randomized in a 1:1 ratio to receive Bort 1.3 mg/m2 IV or SQ (Cycles 1-8: days 1, 4, 8, and 11; Cycles ≥9: days 1, 8, and 15) and Dex with or without Elo. Elo dose and schedule is 10 mg/kg IV (Cycles 1-2: days 1, 8, and 15 [21-day cycles]; Cycles 3-8: days 1 and 11 [21-day cycles]; Cycles ≥9: days 1 and 15 [28-day cycles]). In the arm without Elo, Dex 20 mg PO is scheduled for Cycles 1-8: days 1, 2, 4, 5, 8, 9, 11, and 12; and Cycles ≥9: days 1, 2, 8, 9, 15, 16. In the arm with Elo, Dex 20 mg PO is scheduled for Cycles 1-2: days 2, 4, 5, 9, and 11; Cycles 3-8: days 2, 4, 5, 8, 9, 12; Cycles ≥9: days 2, 8, 9, and 16) on weeks without Elo, and on weeks with Elo, Dex 8 mg PO and 8 mg IV is scheduled on the same day as Elo. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Patients refractory or intolerant to Bort will be excluded. Efficacy will be assessed on day 1 of each cycle by IMWG criteria. The primary endpoint is PFS. Secondary endpoints include ORR and PFS/ORR in pts with ≥1 FcγRIIIa V allele. As of February 1, 2012, 1 pt was enrolled. NCT01478048.

ELOQUENT-2: A phase III, randomized, open-label trial of lenalidomide/dexamethasone (Len/Dex) with or without elotuzumab (Elo) in relapsed or refractory multiple myeloma (RR MM) (CA204-004).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8112-TPS8112
Author(s):  
Sagar Lonial ◽  
Paul Gerard Guy Richardson ◽  
Philippe Moreau ◽  
Robert Z. Orlowski ◽  
Jesùs F. San-Miguel ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Response Duration ◽  
Surface Glycoprotein ◽  
Phase Iii ◽  
Open Label ◽  
Cell Surface Glycoprotein ◽  
Open Label Phase ◽  
Related Quality ◽  
Duration Of Response

TPS8112 Background: MM remains incurable and patients (pts) typically relapse or become refractory to current treatments. Novel regimens are needed to improve pt outcomes. Elo is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells. Len/Dex is approved for treatment of relapsed MM and an objective response rate (ORR) of ~60% was reported in phase III trials of this combination in RR MM. In a phase II study (N=73) of Elo (10 or 20 mg/kg) in combination with Len/Dex in pts with RR MM, the 10 mg/kg group (n=36) demonstrated an ORR of 92% and median progression-free survival (PFS) that was not reached after a median follow-up of 14.1 months. Encouraging activity was seen in patients with high-risk cytogenetics and/or stage 2-3 disease. Based on these data, a randomized, open-label phase III trial has been initiated to determine if the addition of Elo to Len/Dex will improve PFS in patients with RR MM compared with Len/Dex alone. Methods: Pts (N=640) with RR MM and 1-3 prior therapies are eligible, including pts with mild or moderate renal impairment. Pts are randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days 1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 in subsequent cycles. Dex 8 mg IV + 28 mg PO is used during the weeks with Elo. Treatment will continue until disease progression, death, or withdrawal of consent. Patients will be followed for tumor response every 4 weeks until progressive disease and then survival every 12 weeks. The primary endpoint is PFS (90% power for a hazard ratio [experimental to control arm] of 0.74) and the secondary endpoints are ORR and overall survival. Exploratory endpoints are safety, time to response, duration of response, time to subsequent therapy, health-related quality of life, and pharmacokinetics and immunogenicity of Elo. Potential biomarkers will also be assessed. As of January 10th, 2012, 107 pts were enrolled and 68 pts were treated. NCT01239797.

ELOQUENT-1: A phase III, randomized, open-label trial of lenalidomide/dexamethasone with or without elotuzumab in subjects with previously untreated multiple myeloma (CA204-006).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8113-TPS8113 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Thierry Facon ◽  
Paul Gerard Guy Richardson ◽  
Robert Z. Orlowski ◽  
Jesùs F. San-Miguel ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Response Duration ◽  
Surface Glycoprotein ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Cell Surface Glycoprotein ◽  
Prior Therapy

TPS8113 Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells. In a MM xenograft mouse model, the combination of Elo + lenalidomide (Len) significantly reduced tumor volume in a synergistic manner compared with either agent alone. In a phase 2 study (N=73) of Elo (10 or 20 mg/kg) in combination with Len and low-dose-dexamethasone (Dex) in pts with RR MM, the 10 mg/kg dose group (n=36) demonstrated objective response rates (ORR) of 92% in all pts, and 100% in pts who had received only 1 prior therapy (n=16). The higher response rate in pts with fewer prior lines of therapy provides a rationale for investigating this combination earlier in the disease course. This randomized, open-label, phase 3 trial will determine if the addition of Elo to Len/Dex improves progression-free survival (PFS) in pts with newly diagnosed, untreated MM. Methods: Pts (N=750) with newly diagnosed symptomatic MM ineligible for stem cell transplant will be randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 of cycles 3-18 followed by 20 mg/kg on day 1 of cycle 19 onward. Dex 8 mg IV + 28 mg PO is used during the weeks with Elo. Treatment will continue until disease progression, death, or withdrawal of consent. Pts will be followed up for response every 4 weeks until progressive disease and for survival every 16 weeks. The primary endpoint is PFS (90% power for a hazard ratio [experimental to control arm] of 0.74) and the secondary endpoints are ORR and overall survival. Exploratory endpoints are safety, time to response, duration of response, time to subsequent therapy, health-related quality of life, and pharmacokinetics and immunogenicity of Elo. Potential biomarkers will also be assessed. As of January 1, 2012, 13 pts were enrolled and 9 pts were treated. NCT01335399.

Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7503-7503 ◽  
Author(s):  
Pasi A. Janne ◽  
Alice Tsang Shaw ◽  
Jose Rodrigues Pereira ◽  
Gaelle Jeannin ◽  
Johan Vansteenkiste ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Hematologic Toxicity ◽  
Kras Mutations ◽  
Double Blind ◽  
Secondary Endpoints ◽  
Grade 3

7503 Background: KRAS mutations are the most common (~20%) oncogenic alteration in NSCLC. There are no effective targeted therapies for this subset of NSCLC. Selumetinib (AZD6244, ARRY-142866) inhibits MEK1/2 signaling downstream of KRAS. We prospectively evaluated SEL + DOC vs DOC + placebo in advanced KRAS mutant NSCLC based on preclinical observations (NCT00890825). Methods: Patients (pts) with stage IIIB-IV, KRAS mutant NSCLC, who had received prior chemotherapy, received iv DOC 75 mg/m2, and po SEL 75 mg or placebo BD. The primary endpoint was overall survival (OS); secondary endpoints included: progression-free survival (PFS), objective response rate (RR), duration of response, change in tumor size, proportion of patients alive and progression-free at 6 mo, and safety and tolerability. Results: Between April 2009 and June 2010, 422 pts were screened across 67 centers in 12 countries; 113 had KRAS mutant NSCLC and 87 were randomized (DOC, 43; SEL/DOC, 44). Baseline characteristics were balanced (DOC vs SEL/DOC): WHO PS 0, 49%/48%; Female, 54%/52%; KRAS codon 12, 90%/93%. Median number of cycles: DOC, 4; SEL/DOC, 5. Most frequent grade 3/4 hematologic toxicity (DOC vs SEL/DOC): neutropenia (54.8%/67.4%), febrile neutropenia (0%/15.9%); most frequent grade 3/4 non-hematologic toxicity: dyspnea (11.9%/2.3%) asthenia (0%/9.1%), respiratory failure (4.8%/6.8%), acneiform dermatitis (0%/6.8%). Discontinuation due to AEs was similar: 18.2% SEL/DOC vs 11.9% DOC. OS was longer for SEL/DOC vs DOC (9.4 mo vs 5.2 mo; 56 events, median follow-up 219 days) but did not reach statistical significance; hazards were non proportional (HR 0.80; 80% CI 0.56, 1.14; 1-sided p=0.2069). All secondary endpoints, including RR (DOC 0%, SEL/DOC 37%; p<0.0001) and PFS (DOC 2.1 mo, SEL/DOC 5.3 mo; 71 events; HR = 0.58; 80% CI 0.42, 0.79; 1-sided p=0.0138), were significantly improved for SEL/DOC vs DOC. Conclusions: This is the first prospective study to demonstrate a clinical benefit of a targeted therapy (SEL + DOC) for patients with KRAS mutant cancer of any type. Our findings could have implications for the treatment of NSCLC and other KRAS mutant cancers.

scholarly journals CTIM-03. PHASE II STUDY OF REGORAFENIB IN BEVACIZUMAB REFRACTORY RECURRENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii33
Author(s):  
Yasmeen Rauf ◽  
Cathy Schilero ◽  
David Peereboom ◽  
Manmeet Ahluwalia
Keyword(s):  
Dose Escalation ◽  
Therapeutic Option ◽  
Objective Response ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Weekly Dose ◽  
Cellular Functions ◽  
Molecule Inhibitor ◽  
Secondary Endpoints ◽  
Magnetic Resonance Imaging Mri

Abstract BACKGROUND Most patients with glioblastoma (GBM) receive bevacizumab as part of their treatment. There is no good therapeutic option after bevacizumab failure. Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. METHODS Patients with progression of GBM after treatment with Bevacizumab will be eligible for the study. Oral administration of Regorafenib at 160 mg once daily will be administered for 3 weeks on /1 week off. Weekly dose escalation of regorafenib from 80 mg to 160 mg/day will be employed as per the Redos strategy. Patients start the treatment 80 mg/day in week 1, with weekly dose escalation to 120 mg in week 2, then 160 mg week in 3 if no significant drug-related toxicities are observed. They will be continued on treatment with Regorafenib 160 md /day till tumor progression or toxicity. They will get MRI brain every 4 weeks during the study. RESULTS Primary endpoint is median Overall survival. Secondary endpoints include progression free survival at 6 months and the median time to progression and objective response rate using the modified RANO criteria. The overall safety and tolerability of regorafenib by CTCAE version 5.0. will also be reported. CONCLUSION This is an ongoing clinical trial.

Palbociclib (P) in patients (pts) with soft tissue sarcoma (STS) with CDK4 amplification: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11565-11565
Author(s):  
Scott Schuetze ◽  
Michael Rothe ◽  
Pam K. Mangat ◽  
Liz Garrett-Mayer ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Stage Design ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps ◽  
Stage 1 ◽  
Anti Tumor Activity

11565 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of STS pts with CDK4 amplification treated with P are reported. Methods: Eligible pts had advanced STS, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDK4 amplification and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts (66% male) with STS with CDK4 amplification were enrolled from July 2016 to Nov 2019. 1 pt was not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One pt with partial response (PR) and 12 pts with SD16+ were observed for DC and objective response (OR) rates of 48% (95% CI: 31%, 62%) and 3.7% (95% CI: 0.1%, 19%), respectively, and the null DC rate of 15% was rejected (p<0.001). 9/13 pts with DC continued on treatment for >32 weeks. 14 pts had at least one grade 3-4 AE at least possibly related to P with the most common being low WBC/platelets. Other grade 3 AEs included increased alanine aminotransferase, anemia, and fatigue. Conclusions: Monotherapy P demonstrated anti-tumor activity in heavily pre-treated pts with STS with CDK4 amplification. Additional study is warranted to confirm the efficacy of P in pts with STS with CDK4 amplification. Clinical trial information: NCT02693535. [Table: see text]

Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4576-4576
Author(s):  
Marc-Oliver Grimm ◽  
Emilio Esteban ◽  
Philippe Barthélémy ◽  
Manuela Schmidinger ◽  
Jonas Busch ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Remission Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Poor Risk ◽  
Secondary Endpoints ◽  
Tailored Approach

4576 Background: TITAN-RCC uses a tailored immunotherapy approach in renal cell carcinoma (RCC), starting with nivolumab (nivo) induction followed by nivo + ipilimumab (ipi) as immunotherapeutic “boost” in non-responders. Patients with initial partial or complete response (PR/CR) continued with nivo maintenance but received later “boosts” for progressive disease (PD). Here we report updated results focusing on the efficacy of nivo+ipi in patients with initial PD vs. initial responders with later PD. Methods: Patients with IMDC intermediate and poor risk advanced clear cell RCC were recruited between OCT 2016 and DEC 2018. Patients started with nivo 240 mg Q2W induction. Patients with early significant PD (week 8) or non-responders at week 16 received 2-4 nivo+ipi “boost” cycles. Responders (PR/CR) to nivo monotherapy continued with maintenance but could receive nivo+ipi for later PD. The primary endpoint is confirmed investigator assessed objective response rate (ORR) per RECIST in first line (1L) and second line (2L). Secondary endpoints included activity of nivo monotherapy, remission rate with nivo+ipi “boost”, safety and overall survival (OS). Results: 109 1L and 98 2L (after TKI) patients were analyzed for efficacy. Median age was 65 years (range 20-87). 71 % were intermediate and 25 % poor risk. Confirmed ORR with nivo monotherapy was 28 % for 1L and 17 % for 2L. After a median follow-up of 12.8 months best overall response after nivo induction ± nivo+ipi was 36 % in 1L and 30 % in 2L. Of all patients, 38 received nivo+ipi for stable disease (SD) up to week 16, with 1 (3 %), 4 (11 %) and 26 (68 %) achieving CR, PR and SD, respectively. 28 patients in 1L and 43 in 2L were boosted with nivo+ipi for initial PD. Of these, 3 (11 %) and 8 (29 %) achieved PR and SD, respectively, in 1L, whereas 3 (7.0 %) achieved CR, 6 (14 %) PR and 13 (30 %) SD in 2L. 16 and 10 patients received “boosts” later than week 16 for PD during nivo maintenance in 1L and 2L, respectively. Thereof, 3 (19 %) achieved PR and 5 (31 %) SD in 1L, whereas 2 (20 %) achieved PR and 3 (30 %) SD in 2L. Progression-free survival was 6.3 months (95 % CI 3.7 – 10.1) and 3.7 months (95 % CI 2.0 - 4.5) in 1L and 2L, respectively. OS was 27.2 months (95 % CI 19.9 – not estimable (NE)) in 1L and 20.2 months (95 % CI 15.6 – NE) in 2L. Treatment-related adverse events will be presented. Conclusions: Our tailored approach with nivo+ipi “boosts” results in improved response rates compared to nivo monotherapy. Our updated analysis suggests that almost half of the patients receiving “boosts” for PD improve to either PR/CR (18 %) or SD (30 %), irrespective of initial or later progression with nivo. Clinical trial information: NCT02917772. [Table: see text]

Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study.

2021 ◽  
Vol 39 (18_suppl) ◽  
pp. LBA4001-LBA4001
Author(s):  
Ian Chau ◽  
Yuichiro Doki ◽  
Jaffer A. Ajani ◽  
Jianming Xu ◽  
Lucjan Wyrwicz ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Endpoints ◽  
First Results ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Previously Treated Patients

LBA4001 Background: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase III study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC. Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons were OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, and chemo arms (49% with tumor cell PD-L1 ≥ 1%). With 13 months (mo) minimum follow-up, NIVO + chemo and NIVO + IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO + chemo vs chemo (HR 0.65 [98.5% CI 0.46–0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥ 1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% did not meet the prespecified boundary for significance. The objective response rate (per BICR) was 53% (NIVO + chemo), 35% (NIVO + IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥ 1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer median (95% CI) duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥ 1%: 8.4 (6.9–12.4), 11.8 (7.1–27.4), and 5.7 (4.4–8.7) mo and for all randomized pts: 8.2 (6.9–9.7), 11.1 (8.3–14.0), and 7.1 (5.7–8.2) mo, respectively. No new safety signals were identified (Table). Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option. Clinical trial information: NCT03143153. [Table: see text]

GSK3β Inhibition Synergizes with PARP Inhibitors through the Induction of Homologous Recombination Deficiency in Colorectal Cancer

2020 ◽  
Author(s):  
Ning Zhang ◽  
Yu-Nan Tian ◽  
Li-Na Zhou ◽  
Meng-Zhu Li ◽  
Shan-Shan Song ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Homologous Recombination ◽  
High Throughput Screening ◽  
Glycogen Synthase ◽  
Objective Response ◽  
Xenograft Model ◽  
Parp Inhibitors ◽  
High Rate ◽  
Parp Inhibition ◽  
Mouse Xenograft Model

Abstract Background: Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in limited objective response rate (≤ 60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Methods: The effects of PARPi combined with glycogen synthase kinase 3 (GSK3) inhibitors were investigated in vitro with respect to cell viability, cell cycle and apoptosis. The synergy was assessed by calculation of the combination index (CI). GSK3α null and GSK3β null cells were generated using CRISPR/Cas9 technique. The underlying mechanism was examined by western blotting, flow cytometry, qRT-PCR and fluorescence microscopy. This combination was also evaluated in the mouse xenograft model; tumor growth and tumor lysates were analyzed, and the immunohistochemistry assay was performed. All data are presented as mean ± SD. Comparison between two groups was performed with the Student’s t-test.Result: The data showed that ~25% of oncological drugs and kinase inhibitors that were evaluated displayed synergy with PARPi in HCT-15 cells. Among the tested agents, GSK3 inhibitors (GSK3i) exhibited the strongest synergistic effect with PARPi. Moreover, the synergistic antitumor effect of GSK3 and PARP inhibition was confirmed in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. Additionally, inhibition or genetic depletion of GSK3β was found to impair HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity.Conclusion: Our results provide a mechanistic understanding of combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

scholarly journals LINC00152 down-regulated miR-193a-3p to enhance MCL1 expression and promote gastric cancer cells proliferation

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Yong Huang ◽  
Hui Luo ◽  
Fang Li ◽  
Yun’e Yang ◽  
Guangsheng Ou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Xenograft Model ◽  
Cell Counting ◽  
Gastric Cancer Cells ◽  
Normal Tissues ◽  
Non Coding Rna ◽  
Mouse Xenograft Model ◽  
Vitro Effect

The present work aimed to probe into the effect of long non-coding RNA (lncRNA) LINC00152 on gastric cancer (GC) cells proliferation by regulating miR-193a-3p and its target gene MCL1. Transfected si-LINC00152 was used to down-regulate LINC00152, and cells proliferation was measured by the cell counting kit-8 (CCK-8) assay. Cell apoptosis and cell cycle were analyzed by flow cytometry (FCM). Besides, we also detected the potential functional effects of differential expression of LINC00152 in vivo using nude mouse xenograft model. We overexpressed and downexpressed miR-193a-3p to study the in vitro effect of miR-193a-3p on GC cells proliferation and vitality. And MCL1 was silenced by shRNA to investigate the effect of MCL1 on proliferation of GC cells. In this research, LINC00152 was proven to have a higher expression level in GC tissues than in the adjacent normal tissues. GC cells proliferation was inhibited after LINC00152 was down-regulated. LINC00152 inhibited the expression of miR-193a-3p, which negatively regulated MCL1. In addition, GC cells proliferation was inhibited by cell transfection with shRNA-MCL1, and enhanced by transfection with miR-193a-3p mimics. Our study suggested that LINC00152 was overexpressed in GC tissues, and it down-regulated miR-193a-3p to enhance MCL1 expression thereby promoting GC cells proliferation.

Phase II randomized study of gefitinib alone or plus vinorelbine every 2 weeks’ treatment in patients with adenocarcinoma of the lung who failed at least two regimens

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17095-17095
Author(s):  
Y. Chen ◽  
R. Perng ◽  
C. Tsai ◽  
J. Whang-Peng
Keyword(s):  
Disease Progression ◽  
Low Dose ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Chinese Patients ◽  
Lung Cancer Patients ◽  
Ethnic Chinese ◽  
Adenocarcinoma Of The Lung ◽  
Treatment Objective

17095 Background: To assess the feasibility and the efficacy of adding chronic intermittent low-dose vinorelbine to gefitinib (Iressa) treatment for lung cancer patients with adenocarcinoma who failed 2 previous regimens of chemotherapy. Methods: Patients who had adenocarcinoma and failed at least 2 regimens, including taxanes and platinum, were enrolled and randomized into 2 arms: oral Iressa 250 mg daily (I) or vinorelbine 15 mg/m2 intravenous infusion day 1 and oral Iressa 250 mg daily from day 2 to 14, every 2 weeks (IV). From August 2004 to October 2005, 48 patients were enrolled. Results: Twenty-four patients were randomized into Iressa plus vinorelbine treatment. However, 3 patients refused vinorelbine treatment and received Iressa treatment only. Thus, 27 patients received I treatment and 21 patients received IV treatment. Objective response rates were 55.6% in I and 57.1% in IV. Any grade of leukopenia, neutropenia, and fatigue sensation was significantly higher in the IV arm (p=0.035, 0.001, 0.012, respectively). All the toxicities in both arms were generally mild and no toxic death occurred. However, many patients in the IV arm stopped V treatment before disease progression, including port-A occlusion in 4 patients (after 2, 5, 20, and 23 injections, respectively), mucositis in 1 (after 4 injections), and fatigue sensation in 1 (after 7 injections). After a median follow-up of 8 months, median time to disease progression was higher in IV than I (longer than 12 months vs. 7.1 months, p = 0.0271), more than half of the patients in each arm were still alive (p = 0.2269), and more than 9 patients in each arm survived longer than 1 year. Conclusions: Iressa is highly effective in ethnic Chinese patients with adenocarcinoma of the lung who have failed previous platinum and taxane treatment. The addition of low-dose V every 2 weeks produced a signiificantly better progression-free survival. Replacement of intravenous V with oral V should be considered to prevent the early termination of V treatment. No significant financial relationships to disclose.

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