Small molecule XIAP inhibitors enhance TRAIL-Lnduced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma

Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-Iinked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAIL-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. © 2009 American Association for Cancer Research

p16 Expression Differentiates High-Risk Gastrointestinal Stromal Tumor and Predicts Poor Outcome1

Gastrointestinal stromal tumors (GISTs) are characterized by alterations in genes involved in cell cycle regulation. Although p16 (INK4A) have been extensively investigated in GISTs, there are still discrepancies regarding its prognostic value. Therefore, we evaluated the clinical occurrence, diagnostic and prognostic value of p16 staining in GIST. One hundred one patients (54 women and 47 men) with a mean age of 64.1 years (range, 17–94 years) were surgically treated for a GIST within a 10-year period. Of these patients, 28 (28%) were affected by metastases (mean follow-up, 4.5 years). In 36 patients (36%), GIST occurred coincidentally with other malignancies. Expression of c-kit was confirmed in 97 GIST patients (96%). In patients with high-risk GIST, the expression of p16 expression was highly predictive for poor prognosis, i.e., the development of recurrence or metastases (P = .006) and poor survival (P = .004). In addition, the expression of p16 was highly predictive for reduction of the survival in patients who were affected by metastases or recurrence (P = .041). The disease-specific and disease-free 1-, 3-, and 5-year survival rate was 96%, 90%, and 85% and 81%, 77%, and 72%, respectively. Primary tumor state, tumor size, and high-risk classification were confirmed as relevant predictors for unfavorable prognosis in GIST (P < .001). Our results indicate that in high-risk GIST and in patients with recurrence or metastases, the expression of p16 is highly predictive for poor outcome. Thus, in addition to high-risk classification, p16 expression might be an indicator for “very high risk GIST.