To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.
This was a first-in-human, multicenter, open-label study in patients with ...advanced solid tumors harboring
gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.
A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were
amplifications (40%) and mutations in
(12%) and
(17%); 12 patients (21%) showed
fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with
fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.
Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
Objective
To evaluate the contributions of autophagic, necrotic, and apoptotic cell death mechanisms after neonatal cerebral ischemia and hence define the most appropriate neuroprotective approach ...for postischemic therapy.
Methods
Rats were exposed to transient focal cerebral ischemia on postnatal day 12. Some rats were treated by postischemic administration of pan‐caspase or autophagy inhibitors. The ischemic brain tissue was studied histologically, biochemically, and ultrastructurally for autophagic, apoptotic, and necrotic markers.
Results
Lysosomal and autophagic activities were increased in neurons in the ischemic area from 6 to 24 hours postinjury, as shown by immunohistochemistry against lysosomal‐associated membrane protein 1 and cathepsin D, by acid phosphatase histochemistry, by increased expression of autophagosome‐specific LC3‐II and by punctate LC3 staining. Electron microscopy confirmed the presence of large autolysosomes and putative autophagosomes in neurons. The increases in lysosomal activity and autophagosome formation together demonstrate increased autophagy, which occurred mainly in the border of the lesion, suggesting its involvement in delayed cell death. We also provide evidence for necrosis near the center of the lesion and apoptotic‐like cell death in its border, but in nonautophagic cells. Postischemic intracerebroventricular injections of autophagy inhibitor 3‐methyladenine strongly reduced the lesion volume (by 46%) even when given >4 hours after the beginning of the ischemia, whereas pan‐caspase inhibitors, carbobenzoxy‐valyl‐alanyl‐aspartyl(OMe)‐fluoromethylketone and quinoline‐val‐asp(OMe)‐Ch2‐O‐phenoxy, provided no protection.
Interpretation
The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia. Ann Neurol 2009
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent
fusions among ...patients with intrahepatic cholangiocarcinoma (IHCC), we identified
extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with
p.H167_N173del. Expression of this
EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with
EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F
kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal
EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE:
EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These
EIDs are sensitive to FGFR inhibition
, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.
.
Cerebral ischemia is associated with the activation of glial cells, infiltration of leukocytes and an increase in inflammatory mediators in the ischemic brain and systemic circulation. How this ...inflammatory response influences lesion size and neurological outcome remains unclear. D-JNKI1, an inhibitor of the c-Jun N-terminal kinase pathway, is strongly neuroprotective in animal models of stroke. Intriguingly, the protection mediated by D-JNKI1 is high even with intravenous administration at very low doses with undetectable drug levels in the brain, pointing to a systemic mode of action, perhaps on inflammation.
We evaluated whether D-JNKI1, administered intravenously 3 h after the onset of middle cerebral artery occlusion (MCAO), modulates secretion of the inflammatory mediators interleukin-6 and keratinocyte-derived chemokine in the plasma and from the spleen and brain at several time points after MCAO. We found an early release of both mediators in the systemic circulation followed by an increase in the brain and went on to show a later systemic increase in vehicle-treated mice. Release of interleukin-6 and keratinocyte-derived chemokine from the spleen of mice with MCAO was not significantly different from sham mice. Interestingly, the secretion of these inflammatory mediators was not altered in the systemic circulation or brain after successful neuroprotection with D-JNKI1.
We demonstrate that neuroprotection with D-JNKI1 after experimental cerebral ischemia is independent of systemic and brain release of interleukin-6 and keratinocyte-derived chemokine. Furthermore, our findings suggest that the early systemic release of interleukin-6 and keratinocyte-derived chemokine may not necessarily predict an unfavorable outcome in this model.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of various cardiovascular and inflammatory diseases. Here, we report that the gender-specific inflammatory ...response is preferentially down-regulated by PARP in male animals. Female mice produce less tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha in response to systemic inflammation induced by endotoxin than male mice and are resistant to endotoxin-induced mortality. Pharmacological inhibition of PARP is effective in reducing inflammatory mediator production and mortality in male, but not in female, mice. Ovariectomy partially reverses the protection seen in female mice. Endotoxin-induced PARP activation in circulating leukocytes is reduced in male, but not female, animals by pharmacological PARP inhibition, as shown by flow cytometry. Pretreatment of male mice with 17-beta-estradiol prevents endotoxin-induced hepatic injury and reduces poly(ADP-ribosyl)ation in vivo. In male, but not female, animals, endotoxin induces an impairment of the endothelium-dependent relaxant responses, which is prevented by PARP inhibition. In vitro oxidant-induced PARP activation is reduced in cultured cells placed in female rat serum compared with male serum. Estrogen does not directly inhibit the enzymatic activity of PARP in vitro. However, PARP and estrogen receptor alpha form a complex, which binds to DNA in vitro, and the DNA binding of this complex is enhanced by estrogen. Thus, estrogen may anchor PARP to estrogen receptor alpha and to the DNA and prevent its recognition of DNA strand breaks and hence its activation. In conclusion, the gender difference in the inflammatory response shows preferential modulation by PARP in male animals.
Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension, and ...aging. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury, circulatory shock, and aging. Here, we investigated the effect of a new PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction associated with advanced aging using Millar's new Aria pressure-volume conductance system and isolated aortic rings. Young adult (3 months old) and aging (24 months old) Fischer rats were treated for 2 months with vehicle, or the potent PARP inhibitor INO-1001. In the vehicle-treated aging animals, there was a marked reduction of both systolic and diastolic cardiac function and loss of endothelial relaxant responsiveness of aortic rings to acetylcholine. Treatment with INO-1001 improved cardiac performance in aging animals and also acetylcholine-induced, nitric oxide-mediated vascular relaxation. Thus, pharmacological inhibition of PARP may represent a novel approach to improve cardiac and vascular dysfunction associated with aging.
Angiotensin II (AII) contributes to the pathogenesis of many cardiovascular disorders. Oxidant-mediated activation of poly(adenosine diphosphate-ribose) polymerase (PARP) plays a role in the ...development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. We have investigated whether activation of the nuclear enzyme PARP contributes to the development of AII-induced endothelial dysfunction. AII in cultured endothelial cells induced DNA single-strand breakage and dose-dependently activated PARP, which was inhibited by the AII subtype 1 receptor antagonist, losartan; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin; and the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester. Infusion of sub-pressor doses of AII to rats for 7 to 14 d induced the development of endothelial dysfunction ex vivo. The PARP inhibitors PJ34 or INO-1001 prevented the development of the endothelial dysfunction and restored normal endothelial function. Similarly, PARP-deficient mice infused with AII for 7 d were found resistant to the AII-induced development of endothelial dysfunction, as opposed to the wild-type controls. In spontaneously hypertensive rats there was marked PARP activation in the aorta, heart, and kidney. The endothelial dysfunction, the cardiovascular alterations and the activation of PARP were prevented by the angiotensin-converting enzyme inhibitor enalapril. We conclude that AII, via AII receptor subtype 1 activation and reactive oxygen and nitrogen species generation, triggers DNA breakage, which activates PARP in the vascular endothelium, leading to the development of endothelial dysfunction in hypertension.
Abstract
Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by
FGFR2
) occur in multiple types of cancer
1
. However, ...clinical responses to FGFR inhibitors have remained variable
1–9
, emphasizing the need to better understand which
FGFR2
alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening
10,11
and tumour modelling in mice
12,13
, and find that the truncation of exon 18 (E18) of
Fgfr2
is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of
FGFR2
alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated
FGFR2
(
FGFR2
ΔE18
). Functional in vitro and in vivo examination of a compendium of
FGFR2
ΔE18
and full-length variants pinpointed
FGFR2
-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of
FGFR2
full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable
FGFR2
ΔE18
variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any
FGFR2
variant with a truncated E18 should be considered for FGFR-targeted therapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background: Debio 1143 is an oral antagonist of IAPs, currently in clinical development, which sensitizes tumor cells to radiation- or chemotherapy-induced apoptosis. IAPs inhibitors ...modulate NF-κB signaling and drive the expression of genes relevant for inflammation and immunity. Here, we hypothesized that Debio 1143 could improve antitumor immunity by directly enhancing T-lymphocyte activation and by improving the effects of immune checkpoint inhibitors in vitro and in vivo.
Methods: Ex vivo human PBMC anti-CD3/CD28 stimulation and modified mixed-lymphocyte reaction assays were performed to evaluate the immunostimulatory potential of Debio 1143 alone or in combination with the anti-PD-1 antibody nivolumab (N= 5 donors). T cells' proliferation and activation were measured by flow cytometry and cytokine release was measured by ELISA. The antitumor activity of an anti-PD-L1 antibody (5 mg/kg BIW IP) was tested either alone or in combination with Debio 1143 (100 mg/kg QD1-5 PO) in MBT-2 immunocompetent mouse model of bladder cancer over 3 weeks (n=8 /group).
Results: Debio 1143 significantly enhanced CD4+ and CD8+ intracellular IFNγ expression in a concentration-dependent manner following anti-CD3/CD28 stimulation. This result was confirmed using a mixed-lymphocyte reaction assay, where Debio 1143 at concentrations achieved in clinical studies significantly increased IFNγ expression by activated CD4+ cells, and this effect was even further increased in presence of nivolumab. In MBT-2 tumor-bearing mice, the combination of Debio 1143 and anti-PD-L1 antibody significantly decreased tumor growth (P=0.001 using two-sided t-test) and increased survival, whereas monotherapies only displayed moderate activities (median survival time of 42 days vs. 33 or 28 days for Debio 1143 or anti-PD-L1 alone, respectively).
Conclusion: These data show a key mechanistic role for future combination therapy of the IAP antagonist Debio 1143 and immune-checkpoint agents in cancer patients. This synergy will be further explored in a phase-Ib dose-finding clinical study combining Debio 1143 and Avelumab (anti-PD-L1) in patients with advanced solid malignancies and non-small cell lung cancer (CT# 03270176).
Citation Format: Antoine Attinger, Bruno Gavillet, Anne Vaslin Chessex, Norbert Wiedemann, Gregoire Vuagniaux. The inhibitor of apoptosis protein (IAP) antagonist Debio 1143 enhances the immune response to anti-PD1/L1 inhibitors in vitro and in vivo abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4703.
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