imetelstat and Prostatic-Neoplasms

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

Prostate cancer is the most common malignancy in men, and patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. Most cancer therapies target the bulk tumor cells, but may leave intact a small population of tumor-initiating cells (TICs), which are believed to be responsible for the subsequent relapse and metastasis. Using specific surface markers (CD44, integrin alpha(2)beta(1) and CD133), Hoechst 33342 dye exclusion, and holoclone formation, we isolated TICs from a panel of prostate cancer cell lines (DU145, C4-2 and LNCaP). We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. These findings suggest that telomerase inhibition therapy may be able to efficiently target the prostate TICs in addition to the bulk tumor cells, providing new opportunities for combination therapies.

Topics: Cell Line, Tumor; Humans; Indoles; Male; Neoplastic Stem Cells; Niacinamide; Oligonucleotides; Prostatic Neoplasms; Proto-Oncogene Proteins c-kit; Spheroids, Cellular; Telomerase; Telomere