epz-5676 and Neoplasms

epz-5676 has been researched along with Neoplasms* in 2 studies

Reviews

1 review(s) available for epz-5676 and Neoplasms

ArticleYear
Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development.
    Drug metabolism and disposition: the biological fate of chemicals, 2016, Volume: 44, Issue:7

    Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

    Topics: Adolescent; Age of Onset; Antineoplastic Agents; Benzamides; Benzimidazoles; Biphenyl Compounds; Child; Child, Preschool; Drug Approval; Drug Discovery; Humans; Infant; Infant, Newborn; Medical Oncology; Models, Biological; Morpholines; Neoplasms; Pediatrics; Pharmacogenetics; Pyridones; United States; United States Food and Drug Administration; Young Adult

2016

Other Studies

1 other study(ies) available for epz-5676 and Neoplasms

ArticleYear
Rapid generation of drug-resistance alleles at endogenous loci using CRISPR-Cas9 indel mutagenesis.
    PloS one, 2017, Volume: 12, Issue:2

    Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel) mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors. We used this approach to identify novel resistance alleles of two lysine methyltransferases, DOT1L and EZH2, which are each essential for the growth of MLL-fusion leukemia cells. We biochemically characterized the DOT1L mutation, showing that it is significantly more active than the wild-type enzyme. These findings validate the on-target anti-leukemia activities of existing DOT1L and EZH2 inhibitors and reveal a simple method for deriving drug-resistance alleles for novel targets, which may have utility during early stages of drug development.

    Topics: Alleles; Animals; Antineoplastic Agents; Benzimidazoles; Cell Line; Cell Line, Tumor; Cell Proliferation; Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR-Cas Systems; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; HEK293 Cells; Histone-Lysine N-Methyltransferase; Humans; INDEL Mutation; Methyltransferases; Mice; Models, Molecular; Mutagenesis; Neoplasms

2017