Abstract The blood-brain barrier (BBB) is one of the greatest barriers for the effective treatment of brain tumors, including H3K27-altered diffuse midline glioma (DMG), a near universally fatal ...childhood brain cancer. The BBB typically requires drugs to be given at maximally tolerated doses that are limited by systemic toxicities, particularly in settings of combination therapy. We have developed a clinically compatible fucoidan nanoparticle (Fi-NP) that homes to P-selectin on tumor vasculature after low-dose radiation (RT) to breach the BBB through an active caveolin-1-dependent mechanism and deliver several classes of targeted therapies. In non-CNS cancer xenograft models and a transgenic mouse model of SHH-driven medulloblastoma with an intact BBB, this approach improved survival while eliminating on-target systemic toxicities. We have now applied this approach to both brainstem and non-brainstem RCAS-TVA mouse models of DMG with an intact BBB. Specifically, we have found that DMG tumor vasculature expresses P-selectin, and that a single low-dose 2 Gy fraction of ionizing radiation further enhances it in a time-dependent manner up to 24 hours post-treatment. Importantly, we have also found that this P-selectin targeted drug delivery approach facilitates DMG tumor localization of Fi-NP encapsulated EZH2 inhibitor tazemetostat (EPZ-6438) as well as larger macromolecules including the PROTAC BET degrader dBET6, two promising targeted therapies for DMG limited by extremely poor BBB-penetration, while sparing drug delivery to non-tumor healthy brain regions. Work to measure PK, biodistribution, survival benefit, and drug target inhibition is ongoing. Our findings will provide the foundation for this P-selectin targeted Fi-NP approach to be evaluated in clinical trials for children with this lethal cancer.
Abstract
BACKGROUND: The management of CNS tumors arising among AYA represents an unmet challenge. Treatment may be split between pediatric and adult centers, often with conflicting approaches. ...Biology also appears to be distinct compared to younger/older age groups but has yet to be fully characterized. Such features would have important implications for prognostication and informing vulnerabilities for targeted therapies.METHODS: To establish the clinical and molecular landscape of these tumors, we analyzed all cases in patients aged 15-39 years old who were treated at MSKCC between 2018-2021. RESULTS: 302 patients with accompanying MSK-IMPACT targeted sequencing, copy number analysis, Archer fusion panel, and clinical data were found. 239/302 cases (79%) were gliomas, with the remaining consisting mainly of neuro-epithelial tumors (n=15; 5%), meningiomas (9; 3%), ependymomas (10; 3%), and embryonal tumors (7; 2%). Among gliomas, 163/239 (68%) had IDH1/2 mutations, which were significantly more enriched for TP53 (121/163; 74%) and ATRX (90/163; 55%) co-mutations compared to IDH-wild type (IDH-WT) (q<0.0001). In comparison, IDH-WT gliomas (n=76) were enriched for alterations in BRAF (16/76 with SNV, 9/76 fusion; q<0.0001), H3F3A (14/76; q<0.0001), PTEN (10/76; q=0.038), and CDKN2A (16/76; q=0.038). Among 113 patients with high-grade gliomas (WHO grade 3/4), those with IDH-WT tumors (n=34) had a poorer prognosis that those with IDH-mutant tumors (n=79) (1 and 5-year OS of 68% and 28% vs. 97% and 76%, respectively) (p<0.0001). Further, a lower frequency of alterations in TERT (26/113; 23%), EGFR (6/113; 5%), and PDGFRA (4/113; 4%) were observed compared to previous studies for adult-only cohorts (~50-70%, 40%, and 10%, respectively). CONCLUSIONS: IDH-mutant gliomas were the most common tumor type seen in this AYA cohort. However, some alterations characteristic of adult high-grade gliomas (TERT, EGFR, PDGFRA) were not as frequently observed. Additional identification of molecular features that predict response to conventional and targeted therapies is underway.
Abstract
Deep brain stimulation targeting the subcallosal cingulate area, a hub with multiple axonal projections, has shown therapeutic potential for treatment-resistant mood disorders. While ...subcallosal cingulate deep brain stimulation drives long-term metabolic changes in corticolimbic circuits, the brain areas that are directly modulated by electrical stimulation of this region are not known.
We used 3.0 T functional MRI to map the topography of acute brain changes produced by stimulation in an initial cohort of 12 patients with fully implanted deep brain stimulation devices targeting the subcallosal cingulate area. Four additional subcallosal cingulate deep brain stimulation patients were also scanned and employed as a validation cohort. Participants underwent resting state scans (n = 78 acquisitions overall) during (i) inactive deep brain stimulation; (ii) clinically optimal active deep brain stimulation; and (iii) suboptimal active deep brain stimulation. All scans were acquired within a single MRI session, each separated by a 5-min washout period.
Analysis of the amplitude of low-frequency fluctuations in each sequence indicated that clinically optimal deep brain stimulation reduced spontaneous brain activity in several areas, including the bilateral dorsal anterior cingulate cortex, the bilateral posterior cingulate cortex, the bilateral precuneus and the left inferior parietal lobule (PBonferroni < 0.0001). Stimulation-induced dorsal anterior cingulate cortex signal reduction correlated with immediate within-session mood fluctuations, was greater at optimal versus suboptimal settings and was related to local cingulum bundle engagement. Moreover, linear modelling showed that immediate changes in dorsal anterior cingulate cortex, posterior cingulate cortex and precuneus activity could predict individual long-term antidepressant improvement. A model derived from the primary cohort that incorporated amplitude of low-frequency fluctuations changes in these three areas (along with preoperative symptom severity) explained 55% of the variance in clinical improvement in that cohort. The same model also explained 93% of the variance in the out-of-sample validation cohort. Additionally, all three brain areas exhibited significant changes in functional connectivity between active and inactive deep brain stimulation states (PBonferroni < 0.01).
These results provide insight into the network-level mechanisms of subcallosal cingulate deep brain stimulation and point towards potential acute biomarkers of clinical response that could help to optimize and personalize this therapy.
We have successfully adapted a Suzuki–Miyaura coupling reaction to a continuous flow process. The reaction was a triphasic mixture involved with two liquid phases that are only partially miscible in ...addition to the presence of an insoluble catalyst as a solid phase. The reaction required very rapid reaction heat up and mixing, which were difficult to achieve under batch conditions. A plug flow reactor (PFR) equipped with a static mixer was implemented in this continuous flow process, and the heterogenous reaction mixture was well handled, which is attributed to the high velocity flow rates and fast reaction kinetics. The reaction was successfully carried out on a 1.6 kg scale to give 80% isolated yield of the product with superior reaction high-performance liquid chromatography profile to the batch process.
Discovery chemistry efforts within Pfizer identified a new vanin-1 inhibitor, ( S )-1, bearing a chiral methyl substituent, which exhibited an excellent profile as a potential drug-candidate ...selection except for the propensity to exist as an amorphous solid. Based on an improved solid form proposition, the project team chose to prioritize 2, the corresponding des-methyl compound. Both compounds were scaled to supply toxicology studies in preclinical species, and kilograms of compound 2 were manufactured to support the preclinical development work. The development of our synthetic chemistry and solid form work on this program are described in the paper. Included are computational studies to rationalize both an expected TBD-mediated epimerization as well as the control of ambident reactivity of activated 2-chloro-pyrimidine-5-carboxylic acid.
Pyrido4,3-dpyrimidin-4(3H)-one (1) was prepared by reacting 2-trifluoromethyl-4-iodo-nicotinic acid (2) with amidine 9a catalyzed by Pd(2)(dba)(3) and Xantphos, followed by cyclization effected with ...HBTU and subsequent demethylation using PhBCl(2). The amidine arylation method was found applicable for the syntheses of quinazolin-4(3H)-ones. Thus, reaction of 2-bromo or 2-iodo benzoate esters with amdidines afforded substituted quinazolin-4(3H)-ones in 44-89% yields.
A multigram scale synthetic procedure for the preparation of a complex and polar macrocyclic peptidic C5aR antagonist is described. The route was developed through improvements to an initial ...small-scale research synthesis and hinged on optimized solid-phase peptide synthesis featuring an early side chain decoration, a highly efficient off-resin macrolactamization, and global deprotection steps. These improvements resulted in a reduction in off-resin peptide manipulations and ultimately to a 6-fold increase in overall yield from 2-chlorotrityl-bound intermediate SP-7c.
Anhydrous tert-butyl hydroperoxide (TBHP) is a powerful oxidizing agent in many chemical transformations. Despite the versatility in organic reactions, the use of anhydrous TBHP has been greatly ...limited because of safety concerns over its shipping, handling, and storage, particularly on production scale. Herein we describe a membrane pervaporation method that allows the production of the anhydrous TBHP solution in continuous manner. The system consists of membrane modules in series that are made of perfluorinated polymer with very high gas permeability, allowing it to remove water efficiently. The pervaporation skid has been successfully implemented in production by continuously generating anhydrous 1.5 M TBHP solution in nonane at a rate of up to 100 mL·min–1 for more than 96 h, achieving the target of 0.15 wt % water. An integrated flow oxidation of a γ-butyrolactam substrate provides an efficient and diastereoselective synthesis of a key lactam intermediate for the preparation of a drug candidate targeting interleukin-1 receptor associated kinase 4 for the treatment of inflammation and oncology diseases.
Synthesis of (S)-5-fluoro-3-methylisobenzofuran-1(3H)-one (6), a key intermediate to lorlatinib, is described. A few synthetic methodologies, that is, boron reduction, enzymatic reduction, ...asymmetric hydrogenation, and asymmetric transfer hydrogenation, were evaluated for the chiral reduction of the substituted acetophenone intermediate (8). A manufacturing process, on the basis of the asymmetric transfer hydrogenation, was developed. This process was successfully scaled up to prepare 400 kg of 6.