Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing.
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http://dx.doi.org/10.1002/cpt.1211 | DOI Listing |
Proc Natl Acad Sci U S A
January 2025
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405.
Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Cancer Biology & Genetics Program, Sloan Kettering Institute, New York, NY 10065.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Laboratory of Precision Medicine and Biopharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Recurrent missense mutations in the human epidermal growth factor receptor 2 (HER2) have been identified across various human cancers. Among these mutations, the active S310F mutation in the HER2 extracellular domain stands out as not only oncogenic but also confers resistance to pertuzumab, an antibody drug widely used in clinical cancer therapy, by impeding its binding. In this study, we have successfully employed computational-aided rational design to undertake directed evolution of pertuzumab, resulting in the creation of an evolved pertuzumab variant named Ptz-SA.
View Article and Find Full Text PDFOtol Neurotol
February 2025
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Background Introduction: Vestibular schwannoma (VS) tumors typically present with sensorineural hearing loss (SNHL). Losartan has recently demonstrated prevention of tumor-associated SNHL in a mouse model of VS through suppression of inflammatory and pro-fibrotic factors, and the current study investigates this association in humans.
Methods: This is a retrospective study of patients with unilateral VS and hypertension followed with sequential audiometry at a tertiary referral hospital from January 1994 to June 2023.
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