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Clinical trials for BET inhibitors run ahead of the science.

ABSTRACT: Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV. BET inhibitors have been shown to reactivate HIV in human cells. Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles.

SUBMITTER: Andrieu G

PROVIDER: S-EPMC5116321 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Clinical trials for BET inhibitors run ahead of the science.

Andrieu Guillaume G Belkina Anna C AC Denis Gerald V GV

Drug discovery today. Technologies 20160301

Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are func ...[more]

PMID: 27769357

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Project description:BackgroundEarly identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability.MethodsWe conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666).ResultsOverall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF.ConclusionsThere were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention.Trial registrationClinicalTrials.gov: NCT00153816 . Registered September 2005.

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Clinical trials for BET inhibitors run ahead of the science.

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Clinical trials for BET inhibitors run ahead of the science.

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