sta-9090 and Adenocarcinoma

This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination.. Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS).. Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191).. Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Docetaxel; Female; HSP90 Heat-Shock Proteins; Humans; L-Lactate Dehydrogenase; Lung Neoplasms; Male; Middle Aged; Proportional Hazards Models; Proto-Oncogene Proteins p21(ras); Taxoids; Treatment Outcome; Triazoles

Despite the common usage of radiotherapy for the treatment of NSCLC, outcomes for these cancers when treated with ionizing radiation (IR) are still unsatisfactory. A better understanding of the mechanisms underlying resistance to IR is needed to design approaches to eliminate the radioresistant cells and prevent tumor recurrence and metastases. Using multiple fractions of IR we generated radioresistant cells from T2821 and T2851 human lung adenocarcinoma cells. The radioresistant phenotypes present in T2821/R and T2851/R cells include multiple changes in DNA repair genes and proteins expression, upregulation of EMT markers, alterations of cell cycle distribution, upregulation of PI3K/AKT signaling and elevated production of growth factors, cytokines, important for lung cancer progression, such as IL-6, PDGFB and SDF-1 (CXCL12). In addition to being radioresistant these cells were also found to be resistant to cisplatin.HSP90 is a molecular chaperone involved in stabilization and function of multiple client proteins implicated in NSCLC cell survival and radioresistance. We examined the effect of ganetespib, a novel HSP90 inhibitor, on T2821/R and T2851/R cell survival, migration and radioresistance. Our data indicates that ganetespib has cytotoxic activity against parental T2821 and T2851 cells and radioresistant T2821/R and T2851/R lung tumor cells. Ganetespib does not affect proliferation of normal human lung fibroblasts. Combining IR with ganetespib completely abrogates clonogenic survival of radioresistant cells.Our data show that HSP90 inhibition can potentiate the effect of radiotherapy and eliminate radioresistant and cisplatin -resistant residual cells, thus it may aid in reducing NSCLC tumor recurrence after fractionated radiotherapy.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Phenotype; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Time Factors; Triazoles

Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1α and STAT-3 are clients of the heat shock protein 90 (HSP90). We hypothesized that ganetespib, a potent HSP90 inhibitor, would disrupt angiogenesis in colorectal cancer (CRC) through inhibition of HIF-1α and STAT-3. CRC cell lines (HCT116 and HT29) were used in all the experiments. Egg CAM and HUVEC assays revealed decreased angiogenesis in ganetespib treated cell lines. Ganetespib inhibited matrigel plug vascularization and tumor growth of xenografts. Significant inhibition of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, HIF-1α and STAT-3 expression was observed in both cell lines treated ganetespib. HIF-1α overexpression resulted in the increase VEGF and STAT-3 expression and this was inhibited by ganetespib. HIF-1α knockdown inhibited VEGF and STAT-3 expression. STAT-3 knockdown inhibited VEGF but not HIF-1α expression. HSP90, STAT-3 and VEGF expression was significantly higher in CRC compared to adjacent normal tissue. Significant downregulation of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, STAT-3 and HIF-1α mRNA was observed in the post ganetespib treatment tumor samples from patients with rectal cancer. These results collectively suggest that inhibition of HSP90 is a promising antiangiogenic strategy in CRC. HSP90 angiogenic effects are mediated through HIF-1α and STAT-3.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Collagen; Colorectal Neoplasms; Down-Regulation; Drug Combinations; Female; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; HSP90 Heat-Shock Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Laminin; Mice, Nude; Platelet-Derived Growth Factor; Proteoglycans; Rectal Neoplasms; Ribonuclease, Pancreatic; RNA, Messenger; Specific Pathogen-Free Organisms; STAT3 Transcription Factor; Transforming Growth Factor beta1; Triazoles; Vascular Endothelial Growth Factor A; Vesicular Transport Proteins; Xenograft Model Antitumor Assays

A randomized phase II clinical trial demonstrated that combining the second-generation heat shock protein 90 inhibitor ganetespib with docetaxel can boost overall survival in patients with advanced lung adenocarcinoma who started therapy more than six months after diagnosis.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Neoplasm Staging; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Triazoles; Xenograft Model Antitumor Assays