jeannie hou - Academia.edu (original) (raw)

Papers by jeannie hou

Thorax, 2014

Results Compared with normoxia, hypoxia promoted PMN survival (mean% ± SEM apoptotic cells at 20 ... more Results Compared with normoxia, hypoxia promoted PMN survival (mean% ± SEM apoptotic cells at 20 h; 30.9 ± 1.9 vs. 59.0 ± 1.8 respectively, p < 0.0001). Both pan-PI3-K inhibitors reversed the pro-survival effect of hypoxia in a concentrationdependent manner, LY294002 (10 µM; 60.3 ± 4.0, p < 0.0001) and ZSTK474 (10 µM; 58.3 ± 2.6, p < 0.0001) without affecting the basal rate of apoptosis. This effect was not seen with the dual PI3-Kdg inhibitor (3 µM; 43.8 ± 7.6) or individual PI3-Kd (1 µM; 43.0 ± 5.8) and g inhibitors (3 µM; 34.9 ± 4.5 and 10 µM; 32.6 ± 3.6). Conclusions Our results indicate that hypoxia-induced PMN survival is PI3-K dependent. Targeting this pathway may accelerate PMN apoptosis, resulting in resolution of inflammation.

Annals of Oncology, Sep 1, 2017

Blood, Jun 15, 2007

Humanized anti-CD25 antibodies (eg, daclizumab) have been successfully used to treat several auto... more Humanized anti-CD25 antibodies (eg, daclizumab) have been successfully used to treat several autoimmune diseases. Paradoxically, IL-2 blockade in mice can induce autoimmunity. An interspecies difference in the relative contribution of IL-2 to CD25 ؉ T regulatory cell (CD25 ؉ Treg) versus CD25 ؉ effector cell function might explain this conundrum. Consistent with this are reports that daclizumab inhibits human CD25 ؉ effector cell cytokine production by blocking the expression of CD40L. However, in mice, IL-4 and IL-12 regulate CD40L expression. As human Th1/Th2 cytokine production is also dependent on IL-2, daclizumab's inhibition of CD40L expression could be due to an indirect, rather than a direct, effect of IL-2. Here, we clarify the mechanisms underlying CD40L expression. In contrast to the mouse, human CD40L is regulated by CD28 signaling and IL-2, not the principal Th1/Th2-polarizing cytokines. We find that CD40L is expressed on naive and memory cells and inhibited by daclizumab independently of cell division. Collectively, our results indicate that daclizumab could inhibit CD25 ؉ effector T-cell function in vivo by directly blocking CD40L expression. This difference between mice and human may help explain the paradoxical effects of IL-2R blockade in the 2 species.

Journal of Clinical Oncology, Jun 20, 2006

7016 Background: ZD6474, a once-daily oral agent, targets key signaling pathways in cancer by inh... more 7016 Background: ZD6474, a once-daily oral agent, targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. ZD6474 in combination with docetaxel (Doc) was assessed in patients (pts) with refractory non-small-cell lung cancer (NSCLC). Methods: Pts eligible for this randomized, double-blind study had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of 1st-line platinum-based chemotherapy. The primary objective was to determine whether once-daily oral ZD6474 (100 or 300 mg) + Doc (75 mg/m2 i.v. infusion every 21 days) prolonged progression-free survival (PFS) vs Doc alone (80% power to detect 50% prolongation at P<0.2). Overall survival was a secondary objective. Results: A total of 127 pts (73 male/54 female; median age 59 yrs, range 29–82) received ZD6474 100 mg + Doc (n=42), ZD6474 300 mg + Doc (n=44) or Doc (n=41). The study met its primary objective of PFS prolongation with the addition of ZD6474: median PFS was 19 wks for ZD6474 100 mg + Doc (HR=0.64; P=0.074); 17 wks for ZD6474 300 mg + Doc (HR=0.83; P=0.461); and 12 wks for Doc. A total of 64 pts (50%) presented with histology other than adenocarcinoma, including 37 with squamous, and 13 pts (10%) entered with CNS metastases. Exploratory subgroup analyses suggest advantages in PFS for ZD6474 + Doc vs Doc both for adenocarcinoma and for other lung cancer histologies. Common adverse events (AEs) included diarrhea, rash and asymptomatic QTc prolongation, all responded to standard management or dose interruption/reduction. Four pts with squamous experienced hemoptysis (ZD6474 100 mg + Doc, n=2 CTC grade 1/2; Doc, n=2 CTC grade 3/4). No fatal episodes of hemoptysis or any CNS hemorrhage AEs were reported in pts receiving ZD6474. Overall survival data were immature at the time of PFS analysis, and a mature survival analysis will be conducted at ∼75% of deaths (anticipated April 2006, and will be presented at the meeting). As of December 2005, 40/127 (31%) pts were alive, 5 of whom continue to receive ZD6474. The minimum follow-up of pts still alive was 17 months. Conclusions: ZD6474 + Doc prolonged PFS vs Doc alone, and these promising data have led to the initiation of Phase III evaluation of ZD6474 + Doc in 2nd-line NSCLC. [Table: see text]

Journal of Clinical Oncology, Sep 20, 2007

Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and ep... more Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of vandetanib plus docetaxel was assessed in patients with previously treated non-small-cell lung cancer (NSCLC). This two-part study comprised an open-label run-in phase and a double-blind randomized phase. Eligible patients had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of first-line platinum-based chemotherapy. The primary objective of the randomized phase was to prolong progression-free survival (PFS) in patients receiving vandetanib (100 or 300 mg/d) plus docetaxel (75 mg/m2 intravenous infusion every 21 days) versus placebo plus docetaxel. The study was designed to have more than 75% power to detect 50% prolongation at a one-sided significance level of P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .20. Secondary objectives included objective response rate, overall survival, safety and tolerability. In the randomized phase (n = 127), median PFS was 18.7 weeks for vandetanib 100 mg plus docetaxel (n = 42; hazard ratio v docetaxel = 0.64; one-sided P = .037); 17.0 weeks for vandetanib 300 mg plus docetaxel (n = 44; hazard ratio v docetaxel = 0.83; one-sided P = .231); and 12 weeks for docetaxel (n = 41). There was no statistically significant difference in overall survival among the three treatment arms. Common adverse events included diarrhea, rash, and asymptomatic prolongation of corrected QT (QTC) interval. The primary objective was achieved, with vandetanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level. On the basis of these encouraging data, phase III evaluation of vandetanib 100 mg plus docetaxel in second-line NSCLC has been initiated.

Journal of Clinical Oncology, Jun 20, 2011

LBA4 Background: About 50% of melanomas have an activating V600EBRAF mutation which led to the hy... more LBA4 Background: About 50% of melanomas have an activating V600EBRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in V600EBRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with V600EBRAF mutation. Methods: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m2, IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. Results: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of vemurafenib. The confirmed RR was 48.4% and 5.5% to vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date. Benefit in OS, PFS, and RR was seen in all subgroups examined. Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib. At the time of data analysis, 66% of vemurafenib pts and 25% DTIC pts were still on treatment. The most common toxicities of vemurafenib were: diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. Conclusions: Vemurafenib is associated with significantly improved OS and PFS compared to DTIC in pts with previously untreated, V600EBRAF-mutated metastatic melanoma.

Journal of Clinical Oncology, May 20, 2018

Annales De Dermatologie Et De Venereologie, Dec 1, 2014

Introduction Une activation anormale de la voie de signalisation Hedgehog (HP) est impliquee dans... more Introduction Une activation anormale de la voie de signalisation Hedgehog (HP) est impliquee dans la physiopathologie du carcinome basocellulaire (CBC). Dans l’essai ERIVANCE BCC, le vismodegib, premier inhibiteur de la voie Hedgehog (HPI) autorise par la FDA, montrait des taux de reponses objective (ORR) de 30 % dans le CBC metastatique et de 43 % dans le CBC localement avance (comite independant), avec une duree mediane de reponse (DOR) de 7,6 mois dans les deux cas. Selon les investigateurs (INV), les ORR etaient de 45 % et 60 % respectivement, et les DOR de 12,9 et 7,6 mois respectivement. Dans cette meme etude, certains patients ont poursuivi le traitement pendant plus de 3 ans. Nous presentons une reactualisation a 30 mois (30 mai 2013) apres l’analyse principale (26 novembre 2010) de la tolerance et l’efficacite evaluees par les investigateurs. Materiel et methodes ERIVANCE BCC est une etude multicentrique, internationale, non randomisee chez 104 patients avec CBC metastatique mesurable radiologiquement ou CBC localement avance (pour lequel la chirurgie etait inappropriee en raison d’une recidive multiple ou de l’anticipation d’une morbidite ou difformite substantielle). Un traitement par vismodegib (150 mg/j po) etait administre jusqu’a progression ou tolerance inacceptable. Les criteres secondaires d’evaluation etaient l’ORR (INV), la survie sans progression (SSP), la DOR, la survie globale, et la tolerance. Observations A la date d’analyse, 9 patients (9 %) poursuivaient l’evaluation selon le protocole et 69 patients (66 %) etaient en suivi pour la survie. Le ORR (INV) etait de 48,5 % (CBCm) et 60,3 % (CBCla), semblables a l’analyse principale. La DOR mediane (INV) etait modifiee de 7,6 a 26,2 mois pour les CBCla et de 12,9 a 14,8 mois pour les CBCm. La mediane de survie globale etait de 33,4 mois (18,1 - non mesurable) pour le CBCm et non atteinte pour le CBCla. Les effets indesirables etaient en accord avec l’analyse principale : > 30 % des patients rapportaient des crampes musculaires, alopecie, dysgueusie, amaigrissement, fatigue et nausees. Les arrets de traitement pour effets indesirables etaient notes chez 23 patients (22,1 %). Dix-sept deces (10 CBCm et 7 CBCla) ont ete rapportes depuis l’analyse principale, tous consideres comme non relies au medicament. Seize deces sont intervenus dans le suivi. Un patient decedait d’alteration de l’etat general. Discussion L’analyse de l’etude ERIVANCE, actualisee a 30 mois de suivi, confirme l’efficacite du vismodegib dans le traitement du CBC avance et montre une tolerance a long terme semblable a celle notee dans l’analyse principale. Conclusion Cette etude a permis l’enregistrement du vismodegib dans le traitement du carcinome basocellulaire localement avance ou metastatique symptomatique pour lequel la chirurgie ou la radiotherapie sont inappropriees.

Journal of Clinical Oncology, May 20, 2012

Board on MEK/BRAF inhibitors in Melanoma. A. Testori: I declare to have a consultant or advisory ... more Board on MEK/BRAF inhibitors in Melanoma. A. Testori: I declare to have a consultant or advisory relationship with Bristol Meyers Squibb, AMGEN, GlaxoSmithKline advisory boards and I received honoraria from them. I have other remuneration to disclose: travel expenses refunded by Oncovision and IGEA. J. Utikal: I dońt have any financial interest in products or processes involved in this research abstract. I dońt own GSK stocks. I served as a member on an advisory of GSK and Roche in the past time.

Journal of Clinical Oncology, May 20, 2011

Regular and Young Investigator Award Abstracts, Nov 1, 2022

Investigator-assessed response across patient subgroups (efficacy-evaluable patients). Assessment... more Investigator-assessed response across patient subgroups (efficacy-evaluable patients). Assessments and demographics for patients with metastatic BCC and locally advanced BCC. (DOCX 16Â kb)

Science, 1993

The tumor suppressor p53 is a nuclear phosphoprotein with characteristics of a transcription fact... more The tumor suppressor p53 is a nuclear phosphoprotein with characteristics of a transcription factor. It displays sequence-specific DNA binding, contains a potent transactivation domain, and has been implicated as both a transcriptional activator and a repressor. Transcription of the human hsp70 gene is stimulated by adenovirus El a protein. This El a transactivation of the hsp70 promoter is mediated by CCAAT binding factor (CBF). It is demonstrated here that p53 both represses transcription from the human hsp70 promoter and also interacts with CBF. Thus, the repression of the hsp70 promoter by p53 may be mediated by direct protein-protein interaction with CBF. These results suggest that proteinprotein interaction between p53 and specific transcription factors may be an additional mechanism by which p53 regulates gene expression.

Journal of Clinical Oncology, Jun 1, 2023

9509 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed... more 9509 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from the first 75 pts enrolled into the registration-directed (R-D) cohort in anti–PD-1–failed melanoma (target enrollment N = 125) from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts must have locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) on 2 assessments ≥28 days apart while on ≥8 consecutive weeks of anti–PD-1 ± anti–CTLA-4 therapy, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy must have had PD confirmed by biopsy while on adjuvant therapy. RP1 is initially given intratumorally at 106 PFU/mL and then every 2 weeks (Q2W) at 107 PFU/mL for ≤8 total cycles (≤10 mL/dose) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then receive nivo alone (240 mg Q2W or 480 mg Q4W IV) for ≤2 years, with the option to reinitiate RP1 if specified criteria are met. Results: A total of 91 pts are included in this analysis (initial melanoma cohort, 16 pts; R-D cohort, 75 pts; data cut: Dec 30, 2022). The overall objective response rate (ORR) was 37.4% (initial cohort, 37.5%; R-D cohort, 37.3%) and 18.7% of pts achieved complete response (CR; Table). The response rates seen were also encouraging when evaluated by prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions in most responding patients, including in pts with bulky and visceral disease. The majority of responses were observed in pts with PD-L1–negative tumors at baseline (17 of 52 pts with PD-L1–negative tumors responded, compared to 15 of 26 pts with PD-L1–positive tumors, and 2 of 13 pts for whom PD-L1 status was unknown). 85.3% of responses were ongoing 3.7–36.6 months from initiating therapy. Most treatment-related adverse events (TRAEs) were Grade 1–2 with the most common (>20%) being fatigue, chills, pyrexia, and nausea. Conclusions: The initial data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated, with mostly on-target TRAEs. Additional and updated data will be presented. Clinical trial information: NCT03767348 . [Table: see text]