Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC. Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. .

These results demonstrate, for the first time, that drug treatment can reverse an established subnormal DeltaPo2. Furthermore, this effect could not be predicted by a drugs' ability to prevent the development of subnormal DeltaPo2.

We aimed to test the hypothesis that the inducible form of nitric oxide synthase (iNOS) contributes to the development of an early subnormal retinal oxygenation response in preclinical models of diabetic retinopathy. In urethane anesthetized Sprague Dawley rats or C57BL/6 mice, functional magnetic resonance imaging was used to noninvasively measure the change in retinal oxygen tension (⌬PO 2 ) during a carbogen-inhalation challenge. In the rat experiments, the retinal ⌬PO 2 of the following groups were compared: control rats (n ‫؍‬ 9), 3-month diabetic rats (n ‫؍‬ 5), and 3-month diabetic rats treated orally with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide, a prodrug of an inhibitor of iNOS (n ‫؍‬ 6). In addition, the retinal ⌬PO 2 of the following mouse groups were compared: C57BL/6 mice (n ‫؍‬ 20), C57BL/6-Nos2 tm1Lau mice (n ‫؍‬ 10), 4-month diabetic mice (n ‫؍‬ 13), and 4-month diabetic knockout mice (n ‫؍‬ 6). Only the ⌬PO 2 of the superior hemiretina of the diabetic rat and mice groups were significantly subnormal (P < 0.05). The superior ⌬PO 2 of the diabetic rats treated with the prodrug was not significantly (P > 0.05) different from their respective normal controls. In the mice experiments, the superior retinal ⌬PO 2 of the iNOS null mice was not statistically different (P > 0.05) from that of normal control mice. iNOS is required for the development of an early subnormal ⌬PO 2 in experimental diabetic retinopathy. Diabetes 53: [173][174][175][176][177][178] 2004 N itric oxide (NO), a potent regulator of retinal vascular function, is elevated in the vitreous humor of patients with proliferative diabetic retinopathy and with tractional retinal detachment, as well as in the retina of rodents, 2-4 months after the induction of diabetes (1-4). NO synthase (NOS) converts L-arginine to NO and L-citrulline. Excessive NO production by the inducible isoform of NOS (iNOS) in particular has been implicated in the pathogenesis of various ocular diseases (5,6). iNOS is induced in the retina in diabetes, but it is not yet known if iNOS regulates aspects of retinal circulatory pathophysiology associated with diabetes (4).Previously, we developed a novel functional magnetic resonance imaging (MRI) method for measuring the retinal oxygenation response to a hyperoxic inhalation challenge in the newborn and adult rat, rabbit, cat, and human (7-10). In this technique, hyperoxia increases vitreous partial oxygen pressure over room-air values (⌬PO 2 ). Because oxygen is paramagnetic, this ⌬PO 2 will produce an increase in the vitreous signal intensity on a T 1 -weighted image. Furthermore, good agreement is found between the MRI-measured response and that determined by other investigators (11) using an oxygen electrode in normal rat retina under similar conditions. In normal adult and newborn rats, carbogen breathing oxygenated the retina significantly better than pure oxygen breathing (11). Carbogen is a gas mixture of carbon dioxide (5%) and oxygen (95%) that has been used clinically, instead of 100% oxygen, to minim...

Background Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Methods We investigated the anti-tumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAF V600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Results Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of anti-proliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. Conclusions These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.

Background Ulixertinib is a novel oral ERK inhibitor that has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers. Methods We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS). Results Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively. Conclusion Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229).