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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The regulatory submission was based on positive results from the NCI-sponsored SPRINT Phase II Stratum 1 trial in 50 patients which demonstrated an Objective Response Rate (ORR) of 66% in pediatric patients with NF1 or symptomatic, inoperable PNs. Three registration trials of selumetinib in patients with advanced disease are currently progressing, which include patients with K-RAS-mutated advanced or metastatic non-small-cell lung cancer (NSCLC) and differentiated thyroid cancer. K-RAS mutations, which are among the most common mutations in NSCLC, are found in approximately 26% of patients and are associated with a shorter mean survival time. There are currently no approved therapies targeting K-RAS-mutated NSCLC, and so novel agents such as selumetinib that target the RAS/RAF/MEK/ERK pathway have the potential to address an unmet clinical need for this disease. Similarly, there is a strong scientific rationale to investigate agents of this type in thyroid cancers which are often characterized by mutations in B-RAF (i.e., approximately 39% of patients) and N-RAS (i.e., approximately 7% of patients).
Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
The BRAF gene, located on chromosome arm 7q34, encodes BRAF, a serine-threonine kinase that is part of the RAS-RAF-MEK-ERKMAPK (referred to below as the mitogen-activated protein kinase (MAPK) pathway) signaling. In mammalian cells, there are three RAF proteins, ARAF, BRAF, and CRAF (also known as RAF1). RAF family members have three conserved domains—conserved regions (CR) 1, 2, and 3. CR1 is a RAS GTP-binding self-regulatory domain, CR2 is a serine-rich hinge region, and CR3 is a serine/threonine protein kinase catalytic domain that phosphorylates a consensus sequence on protein substrates (Fig. 17.1) [1, 5–7]. In normal cells, external growth stimuli activate receptor tyrosine kinase (RTK) and RAS, which relays growth signals to the MAPK pathway kinase cascade. Activation of this pathway has been implicated in promoting growth, proliferation, and differentiation of cells.
Germ Cell Tumors of the Central Nervous System
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Matthew J. Murray, Ute Bartels, James C. Nicholson
These studies suggest potential novel therapeutic strategies in high-risk or refractory cases, which may focus on inhibition of KIT/RAS/RAF/MAPK and/or AKT1/PI3K/mTOR pathways. However, although patients with GCTs harboring activating KIT mutations would be predicted to respond to the KIT tyrosine kinase inhibitor imatinib, responses in clinical studies have been disappointing, with no complete or even partial remissions.34 The feasibility of delivering the alternative tyrosine kinase inhibitor dasatinib has been shown in CNS GCTs35 but efficacy data are also lacking.
Erdheim–Chester disease and vemurafenib: a review of ophthalmic presentations and clinical outcomes
Published in Orbit, 2023
Ji Kwan Park, Laura C. Huang, Andrea L. Kossler
For patients with isolated or concomitant intraocular findings such as choroidal mass, subretinal fluid or serous retinal detachment, the standard of treatment for intraocular ECD is yet to be determined. In a series of three cases of ECD with intraocular involvement, intravitreal anti-VEGF agents with bevacizumab resulted in a short-term resolution of subretinal fluid; however, recurrences were common.14 One patient received a combination of intravitreal anti-VEGF, intravitreal methotrexate, photodynamic therapy but succumbed to vision loss from optic atrophy. In this series, another patient had a chorioretinal biopsy that confirmed a positive ARAF mutation and was treated successfully with a MEK-inhibitor, sorafenib.14 In another case of intraocular ECD with a choroidal infiltrate, oral and topical steroids without any intravitreal injections were sufficient to regress the lesion and improvement in the vision.6 Although our results showed no statistical benefit in the mean change of BCVA with intravitreal injections, concomitant treatment with intravitreal injections may be beneficial for macula-threatening pathologies and neovascularizations, while systemic therapies treat diffuse cellular infiltration.
An overview of current and emerging antifungal pharmacotherapy for invasive fungal infections
Published in Expert Opinion on Pharmacotherapy, 2021
Scott W. Mueller, Sonya K. Kedzior, Matthew A. Miller, Paul M. Reynolds, Tyree H. Kiser, Martin Krsak, Kyle C. Molina
Posaconazole retains the most in vitro activity against ARAF, and in vivo studies suggest that it may achieve PD targets in isolates with MICs of 0.5 mg/L (European Committee on Antimicrobial Susceptibility Testing [EUCAST] breakpoint of 0.125 mg/L) [40,41]. There is interest in augmenting posaconazole exposure to overcome elevated MICs, which is supported by PK modeling [23,41,42]. Ninety-percent target attainment (AUC0-24/MIC ≥167) was obtained with standard IV and delayed-release posaconazole dosing at an MIC of 0.125 mg/L, but a cumulative fractional response of <80% was predicted for all simulated Aspergillus spp., except for Aspergillus terreus. High-dose steady state regimens (200 mg twice daily) may be needed to meet cumulative fractional response PD efficacy targets for Aspergillus flavus, Aspergillus fumigatus, and Aspergillus nidulans. Additionally, a clinical case series suggests that troughs >3 mg/L may be a reasonable target to overcome ARAF infections [42]. More clinical data are needed, but TDM-guided higher posaconazole exposures as a step-down therapy (with or without an echinocandin) could improve outcomes in patients with ARAF with posaconazole MICs of 0.5 mg/L; however, aggressive dosing may incur additional toxicities [39,43]. Similar PK simulations suggest that doubling the standard dose of isavuconazole could achieve 90% target attainment for ARAF with MICs of 2 mg/L, although more data are needed confirming safety at higher dosages [44].
Awareness, knowledge and practice of healthcare professionals following implementation of a Pregnancy Prevention Program for sodium valproate in Ireland: a multi-stakeholder cross-sectional study
Published in Expert Opinion on Drug Safety, 2021
John E. Hughes, Niamh Buckley, Yvonne Looney, Gráinne Kirwan, Sinead Curran, Colin P Doherty, Maeve Mullooly, Kathleen E. Bennett
The valproate PPP targets specialist prescribers (defined as a consultant psychiatrist or neurologist who regularly manages bipolar disorder or complex epilepsy), GPs and pharmacists, and includes specific actions which each individual HCP group is required to fulfil in order to minimize the teratogenic risk of valproate [21]. “Prevent” includes regulatory-approved educational materials which were distributed to all three HCP groups in May 2018 to support clinical implementation. These included the “prevent” HCP Guide and Patient Guide, which are relevant to all three HCP groups, the annual risk acknowledgment form (ARAF) which is most relevant to neurologists and GPs, and the Patient Card and pharmacy warning stickers which are most relevant to pharmacists.