pazopanib 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

Pazopanib was not effective in altering the premetastatic niche in the neoadjuvant setting.Pazopanib was safe and well tolerated without any new safety signals.. Vascular endothelial growth factor receptor 1 (VEGFR1) expressing myeloid-derived suppressor cells (VEGFR1+ MDSCs) potentially foster metastases by establishing a premetastatic niche. In a preclinical study, VEGFR1+ clustering in lymph nodes (LNs) independently predicted time to biochemical recurrence (TTBR) in localized prostate cancer [1]. The hypothesis was that neoadjuvant pazopanib therapy will decrease VEGFR1+ clusters in pelvic lymph nodes and improve outcomes.. This is a phase II trial (NCT01832259) of neoadjuvant pazopanib 800 mg versus placebo daily for 4 weeks in high-risk localized prostate cancer. The primary endpoint was a decrease in VEGFR1+ MDSC clustering assessed by immunohistochemistry (IHC) analysis. Secondary endpoints were safety, feasibility, and TTBR.. Thirty patients were randomized to pazopanib versus placebo, with 15 patients randomized to each arm. Demographic and disease characteristics were similar in both arms. There was no difference in the VEGFR1+ clustering between the treatment arms (p = .345). Neoadjuvant therapy with pazopanib was well tolerated, and surgical complications were similar in both arms.. Neoadjuvant pazopanib therapy did not alter the premetastatic niche; however, treatment targeting vascular endothelial growth factor (VEGF) in the preoperative period was safe and feasible, which may open up the avenue to investigate novel combinatorial regimens, including a VEGF inhibitor in combination with immune checkpoint inhibitor in this setting.

Topics: Humans; Indazoles; Male; Prostatectomy; Prostatic Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Vascular Endothelial Growth Factor A

Intermittent androgen suppression (IAS) is an increasingly popular treatment option for castrate-sensitive prostate cancer. On the basis of previous data with anti-angiogenic strategies, we hypothesized that pan-inhibition of the vascular endothelial growth factor receptor using pazopanib during the IAS off period would result in prolonged time to PSA failure.. Men with biochemically recurrent prostate cancer, whose PSA was <0.5 ng ml(-1) after 6 months of androgen deprivation therapy were randomized to pazopanib 800 mg daily or observation. The planned primary outcome was time to PSA progression >4.0 ng ml(-1).. Thirty-seven patients were randomized. Of 18 patients randomized to pazopanib, at the time of study closure, 4 had progressive disease, 1 remained on treatment and 13 (72%) electively disenrolled, the most common reason being patient request due to grade 1/2 toxicity (8 patients). Two additional patients were removed from treatment due to adverse events. Of 19 patients randomized to observation, at the time of study closure, 4 had progressive disease, 7 remained under protocol-defined observation and 8 (42%) had disenrolled, most commonly due to non-compliance with protocol visits (3 patients). Because of high dropout rates in both arms, the study was halted.. IAS is a treatment approach that may facilitate investigation of novel agents in the hormone-sensitive state. This trial attempted to investigate the role of antiangiogenic therapy in this setting, but encountered several barriers, including toxicities and patient non-compliance, which can make implementation of such a study difficult. Future investigative efforts in this arena should carefully consider drug toxicity and employ a design that maximizes patient convenience to reduce the dropout rate.

Topics: Antineoplastic Agents; Chicago; Diarrhea; Early Termination of Clinical Trials; Fatigue; Humans; Indazoles; Male; Orchiectomy; Patient Compliance; Prostatic Neoplasms; Pyrimidines; Sulfonamides; Treatment Outcome; United States; United States Department of Defense; Universities

Topics: Antineoplastic Agents; Combined Modality Therapy; Gamma Rays; Humans; Indazoles; Leiomyosarcoma; Male; Middle Aged; Prostate; Prostatic Neoplasms; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

To determine if cellular interleukin-6 production predicts response to tyrosine kinase inhibitors (TKIs). As clinical experience using TKIs in patients with castration-resistant prostate cancer (CRPC) matures, Phase II trials show a heterogeneous response to sunitinib in CRPC patients. Change in serum prostate-specific antigen (PSA) level has proven unreliable for prediction of CRPC response to TKIs. Interleukin-6 (IL-6), a critical mediator of prostate cancer pathogenesis, has been shown to rise in patients with disease progression. As such, we investigated whether cellular IL-6 production can predict TKI response in both in vitro and in vivo models.. IL-6 mRNA levels and protein expression were examined by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Apoptosis was examined using the terminal dUTP nick-end labeling assay. For in vivo studies, a CRPC xenograft model in C.B17/Icr-scid mice was used.. PC-3 and DU-145 CRPC cell lines exhibited a heterogeneous response to sunitinib and pazopanib. Dose-dependent reduction of IL-6 was observed in TKI-sensitive DU-145 cells. In contrast, the TKI-resistant PC-3 cells failed to suppress IL-6 secretion. Instead, in the presence of tumor necrosis factor-alpha, IL-6 rose significantly upon administration of TKIs. Findings of in vitro experiments were confirmed in an in vivo mouse model of CRPC.. Sensitivity of CRPC cells to TKIs is heterogeneous. These findings are consistent with results of recently published Phase II clinical trials using sunitinib in patients with CRPC. A substantial rise in IL-6 occurs both in vitro and in vivo in the presence of TKIs in resistant PC-3 cells but not in TKI-sensitive DU-145 cells. These findings suggest that IL-6 may represent a biomarker for TKI resistance in patients with CRPC.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Indazoles; Indoles; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Neoplasm Transplantation; Prostatic Neoplasms; Pyrimidines; Pyrroles; Receptor Protein-Tyrosine Kinases; RNA, Messenger; Sulfonamides; Sunitinib

Topics: Aged; Antibiotics, Antineoplastic; Blood Glucose; Diabetes Mellitus, Type 2; Epirubicin; Humans; Hypoglycemic Agents; Indazoles; Male; Prostatic Neoplasms; Pyrimidines; Sulfonamides