Ildiko Csiki

Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer : A phase II trial of celecoxib and docetaxel

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in prostaglandin (PG) synthesis and is overexpressed in 70% to 90% of non–small cell lung cancers (NSCLC). Preclinical studies suggest inhibition of COX-2 can enhance the cytotoxic effect of docetaxel. To test this concept clinically, we administered celecoxib (400 mg p.o. twice daily) plus docetaxel (75 mg/m2 every 3 weeks) to a cohort of patients with recurrent, previously treated NSCLC. Patients first received single agent celecoxib for 5 to 10 days to ascertain the effectiveness of COX-2 inhibition, which was determined by measuring pre- and post-celecoxib levels of urinary 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E2 (PGE2). We enrolled 56 patients (35 men, 21 women; median age, 61 years). All patients had received at least one prior chemotherapy regimen. The overall response rate was 11% and median survival was 6 months, similar to that observed with docetaxel alone. Pre-celecoxib urinary PGE-M decreased from a mean level of 27.2 to 12.2 ng/mg Cr after 5 to 10 days of celecoxib (P = 0.001). When grouped by quartile, patients with the greatest proportional decline in urinary PGE-M levels experienced a longer survival compared to those with no change or an increase in PGE-M (14.8 versus 6.3 versus 5.0 months). Our data suggest that combining celecoxib with docetaxel using the doses and schedule employed does not improve survival in unselected patients with recurrent, previously treated NSCLC. However, in light of the apparent survival prolongation in the subset with a marked decline in urinary PGE-M levels, further investigation of strategies designed to decrease PGE2 synthesis in NSCLC seems warranted.

Thioredoxin-1 Modulates Transcription of Cyclooxygenase-2 via Hypoxia-Inducible Factor-1α in Non–Small Cell Lung Cancer

Hypoxic induction of gene expression occurs mainly via the hypoxia-inducible factor-1 (HIF-1) transcription factor and is a critical step in tumor growth. Cyclooxygenase-2 (COX-2) is commonly overexpressed in non-small cell lung cancer (NSCLC). In this study, we sought to determine the role of HIF-1 in the induction of COX-2 expression during hypoxia. Through sequence comparison of hypoxia-responsive genes, COX-2 promoter deletion analysis, and site-directed mutagenesis, we identified a hypoxia-responsive element within the COX-2 promoter that interacts with HIF-1alpha and underlies the mechanism of hypoxic activation of COX-2 in lung cancer cells. Proteomic analysis of NSCLC identified thioredoxin-1 as a redox protein overexpressed in NSCLC correlated with poor prognosis. We also show that thioredoxin-1 stabilizes HIF-1alpha to induce hypoxia-responsive genes under normoxic conditions. Our results identify two new mechanisms for regulation of COX-2 expression in NSCLC.

Regulated cell death pathways: New twists in modulation of BCL2 family function

A number of cell death pathways have been recognized. Though apoptosis and autophagy have been well characterized, programmed necrosis has recently received attention and may provide clinical alternatives to suppress resistant tumors. Necrosis is primarily characterized by large-scale permeabilization, swelling, and rupture of cell membranes and the release of pro-inflammatory cytokines. Traditionally, necrosis in cancer cells has been indicative of poor prognoses, as chronic inflammation was found to encourage tumor growth. Yet, many antitumor effects associated with necrosis have been discovered in certain settings, such as the formation of an effective antitumor immune response. In this way, finding ways to attenuate the pro-tumor effects of necrosis while engaging the antitumor pathways via drugs, radiation, and sensitization may prove valuable as a clinical focus for the future. We hypothesize that the use of Bcl-2 inhibitors may enhance necrotic death characterized by inflammation and antitumor immunity. In this article, we briefly review apoptosis and autophagy and reason how necrosis may be a suitable alternative therapeutic endpoint. We then highlight novel inhibitors of Bcl-2 that may provide clinical application of our hypothesis in the future. [Mol Cancer Ther 2009;8(6):1421–9]

A Phase II Study of Celecoxib in Combination with Paclitaxel, Carboplatin, and Radiotherapy for Patients with Inoperable Stage IIIA/B Non–Small Cell Lung Cancer

Purpose: Cyclooxygenase (COX)-2 up-regulation plays an important role in the pathogenesis of lung cancer. Selective COX-2 inhibitors have promoted chemosensitivity and radiosensitivity of tumor cells in preclinical trials. Experimental Design: In a single-institution phase II study, we sought to determine the effectiveness of concurrent chemoradiation given with celecoxib and examined biomarkers to predict response to COX-2 inhibition. Results: Seventeen patients with stage IIIA or IIIB non–small cell lung cancer (NSCLC) were enrolled in the study. All received 400 mg celecoxib twice daily continuously while on trial in addition to concurrent chemoradiation therapy with paclitaxel and carboplatin. Celecoxib was continued until disease progression. The overall objective response rate was 42.9%, and the median overall survival time was 203 days. In contrast to nonresponders, those patients with complete and partial responses had a significant decrease in the level of urinary 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E2, after 1 week of celecoxib administration. Patients with very high levels of PGE-M before initiation of therapy also responded poorly to therapy. Serum vascular endothelial growth factor levels did not predict response or survival. Conclusion: The trial was terminated because it did not meet the predetermined goal of 80% overall response rate. In unselected patients, the addition of celecoxib to concurrent chemoradiotherapy with inoperable stage IIIA/B NSCLC does not improve survival. Urinary PGE-M is a promising biomarker for predicting response to COX-2 inhibition in NSCLC.

Did Targeted Therapy Fail Cyclooxygenase Too

There are considerable preclinical and clinical data showing that cyclooxygenase-2 (COX-2) plays an important role in the pathogenesis of non–small-cell lung cancers (NSCLC). COX-2 is one of two isoforms of COX that catalyzes the conversion of arachidonic acid to prostaglandin (PG) G2, which is then reduced to an unstable endoperoxide intermediate, PGH2. 3 Specific PG synthases in turn metabolize PGH2 to at least five structurally related bioactive lipid molecules, including PGE2, PGD2, PGF2 , PGI2, and thromboxane A2 (TxA2). 3

Anti-Vascular Endothelial Growth Factor Treatment in Combination with Chemotherapy Delays Hematopoietic Recovery Due to Decreased Proliferation of Bone Marrow Hematopoietic Progenitor Cells

Introduction: Targeting of cancer by chemotherapy in combination with anti-vascular endothelial growth factor (VEGF) therapy has demonstrated not only the clinical efficacy but also a higher risk of serious hematologic complications including neutropenia. The purpose of the study was to elucidate the molecular mechanisms responsible for the development of neutropenia during the combination treatment. Methods: Mouse model and in vitro studies were undertaken to determine the effect of interference with VEGF signaling by VEGF-specific agents or a multitargeted VEGF receptor (VEGFR) tyrosine kinase inhibitor on proliferation of hematopoietic progenitor cell (HPC) and repopulation of the hematopoietic compartment after myeloablation. Results: The studies demonstrated that blockage of VEGFR1 or VEGFR2 signaling decreased HPC proliferation and impaired repopulation of the hematopoietic compartment after myelosuppression by slowing the progression of HPC through the cell cycle. The combination of cytotoxic drugs and VEGFR tyrosine kinase inhibitor had an additive inhibitory effect and decreased proliferation of HPC significantly stronger than either agent alone. Conclusions: Signaling through both VEGFR1 and VEGFR2 is required for normal reconstitution of the hematopoietic compartment after cytotoxic chemotherapy.

Urine PGE-M as a marker of intratumoral cyclooxygenase-2 activity in non-small cell lung cancer (NSCLC)

9527 Background: Prostaglandin E2 (PGE2) is implicated in the pathogenesis of NSCLC. PGE2 levels are elevated in NSCLC often in association with overexpression of cyclooxygenase-2 (COX2). The most accurate method to assess PG production in vivo in humans is via quantification of urinary metabolites. We hypothesized that urine levels of 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of PGE2, could be a useful marker of tumor COX2 activity & PGE2 production. METHODS PGE-M levels were determined in urine specimens derived from a previously reported phase II trial employing celecoxib & docetaxel in recurrent NSCLC (Proc. ASCO 22:640, 2003). We employed liquid chromatography electrospray ionization MS using selected reaction monitoring. PGE-M was chemically synthesized & converted to a [2H6] methyloxime isomer for use as an internal standard. After purification, endogenous PGE-M was analyzed as a methyloxime derivative. Assay precision is ± 5%; accuracy is 92%. RESULTS Pts=57; RR=10.5%; MST=228 days. Urinary PGE-M levels = 11.3 ± 5.7 (mean±2 SD, n=10) & 6.4 ± 3.8 ng/mg creatinine (mean±2 SD, n=10) in normal men & women. In men & women with recurrent NSCLC, PGE-M levels were elevated 2-fold (p<0.01) & 3.1-fold above normal mean (p<0.005). PGE-M levels fell by a mean of 51% (p<0.001) & 43% (P<0.001) respectively in men & women following 5-7 days of celecoxib (400 mg p.o. bid). These data suggest that a large proportion of the PGE2 overproduction is COX2 derived. In a multivariate model accounting for sex, race, smoking history & histology we correlated PGE-M changes with clinical parameters & found a strong association with survival. Pts experiencing a reduction in urine PGE-M levels after celecoxib administration were much less likely to die than those who did not (P<0.005). CONCLUSION Changes in urinary PGE-M levels following short course celecoxib may be a useful predictor of intratumoral COX2 inhibition. (Grant support: CA68485; P5090949). [Table: see text].