Aberrant Epigenetic Regulation: A Central Contributor to Lung Carcinogenesis and a New Therapeutic Target

2013 ◽  
pp. e295-e300
Author(s):  
Rosalyn A. Juergens ◽  
Charles M. Rudin
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Early Stage ◽  
Single Agent ◽  
Objective Response ◽  
Gene Promoter ◽  
Epigenetic Therapy ◽  
Lung Carcinogenesis

Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at “epigenetically targeted” doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in “priming” patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.

scholarly journals TRTH-28. HIGH THROUGHPUT SCREENING OF NOVEL HISTONE DEACETYLASE INHIBITORS FOR EPIGENETIC THERAPY OF PRIMARY BRAIN TUMORS

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv57-iv58
Author(s):  
Viktoria Marquardt ◽  
David Pauck ◽  
Finn K. Hansen ◽  
Daniel Picard ◽  
Jörg Felsberg ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Histone Deacetylase ◽  
High Throughput ◽  
High Throughput Screening ◽  
Histone Deacetylase Inhibitors ◽  
Epigenetic Therapy ◽  
Primary Brain Tumors

scholarly journals Histone Deacetylase Inhibitors: Synthesis of Tetrapeptide Analogue SAHA/TPX

2011 ◽  
Vol 8 (s1) ◽  
pp. S79-S84
Author(s):  
Lynda Ekou ◽  
Tchirioua Ekou ◽  
Isabelle Opalinski ◽  
Jean Pierre Gesson
Keyword(s):  
Clinical Trial ◽  
Cancer Therapy ◽  
Phase I ◽  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Growth Arrest ◽  
Suberoylanilide Hydroxamic Acid ◽  
Specific Inhibitors

The inhibition of HDAC (histone deacetylase) activity by specific inhibitors induces growth arrest, differentiation and apoptosis of transformed or several cancer cells. Some of these inhibitors are in clinical trial at phase I or phase II. The discovery and development of specific HDAC inhibitors are helpful for cancer therapy. In this paper we describe the synthesis of simple inhibitorBhybrid analogue suberoylanilide hydroxamic acid (SAHA), trapoxinB(TPX B) in as little as five steps. This compound is interesting lead for the design of potent inhibitors of histone deacetylase.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

Efficacy and safety of bevacizumab biosimilar FKB238 versus originator bevacizumab: Results from a phase III trial in patients with non-squamous non-small cell lung cancer (NS-NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21728-e21728
Author(s):  
Konstantinos N. Syrigos ◽  
Dongyue Fu ◽  
Stephanie Jones ◽  
Zahid Bashir ◽  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Small Cell ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Small Cell Lung ◽  
Double Blind

e21728 Background: Bevacizumab (bev) is a recombinant humanized monoclonal antibody that binds selectively to VEGF-A and prevents it from interacting with its receptors, thereby inhibiting formation of new tumor vasculature to block tumor growth. FKB238, a bev biosimilar, has similar pharmacokinetic and safety profiles to originator bev (o-bev). This phase 3 trial (NCT02810457) compared the efficacy and safety of FKB238 with o-bev in patients with advanced/recurrent non-squamous non-small cell lung cancer (NS-NSCLC). Methods: This global, multicenter, double-blind, parallel, randomized, comparative clinical trial enrolled and randomized 731 patients with advanced/recurrent NS-NSCLC to receive 15 mg/kg intravenous (IV) infusion of either FKB238 (N = 364) or o-bev (N = 367). All patients received IV infusions of paclitaxel (200 mg/m2) and carboplatin (AUC 6.0) immediately prior to investigational drugs for 4-6 cycles. FKB238 and o-bev were administered on day 1 of each 21-day cycle until objective progressive disease or other discontinuation criteria were met. Results: The objective response rate (ORR) based on blinded independent central review assessment for the intent-to-treat population was 51.6% and 53.7% for patients in the FKB238 and o-bev arms, respectively. The FKB238/o-bev ORR ratio was 0.96 (90% CI: 0.86 to 1.08) and the 90% CI fell within the pre-specified equivalence margin. The estimated proportion of patients alive and progression free at 12 months was 25.0% in the FKB238 arm vs 25.3% in the o-bev arm (HR of 0.97, 95% CI 0.82-1.16). The estimated median progression-free survival was 7.72 months in the FKB238 arm and 7.62 months in the o-bev arm. TEAEs were reported for 94.2% (FKB238) and 95.1% (o-bev) of patients. TEAEs ≥ grade 3 were reported for 53.6% (FKB238) and 55.5% (o-bev) of patients. SAEs were reported for 25.1% and 26.0% of patients treated with FKB238 and o-bev, respectively. Conclusions: There were no meaningful differences in efficacy and safety between FKB238 or o-bev in patients with NS-NSCLC. ORR efficacy equivalence was demonstrated, and the safety profiles of both drugs were similar. Clinical trial information: NCT02810457.

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