imetelstat and Gastrointestinal-Stromal-Tumors

Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.

Topics: Antineoplastic Agents; Benzamides; Benzenesulfonates; Disease Progression; Drug Resistance, Neoplasm; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Mutation; Neoplasm Proteins; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperazines; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Pyrimidines; Pyrroles; Receptor, Platelet-Derived Growth Factor alpha; Sorafenib; Staurosporine; Sunitinib; Thiazoles

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal cancer of teh gastrointestinal tract. They are characterized by the expression of KIT. Therapeutically, metastatic GISTs are effectively treated by imatinib, a tyrosine kinase inhibitor (TKI) with activity against KIT and platelet-derived growth factor receptor. Gastrointestinal stromal tumors refractory to standard therapy with imatinib are a clinical challenge. This has lead to the clinical testing of a variety of agents used alone or in combination with other TKIs. Sunitinib, a multitargeted TKI, is the first drug available fort eh treatment of these patients. Additional trials are ongoing, evaluating the efficacy of the novel KIT TKIs AMG 706 and AMN 107 (nilotinib). RAD001, PKC412, and bavacizumab are being tested in conjunction with imatinib. Lastly, the heat-shock protein-90 inhibitor IPI-540 is also in phase I evaluation in imatinib-refractory patients with GIST. The future management of GIST is likely to be altered by the availability of more agents and by better biologic understanding of the patient populations each agent best treats.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bevacizumab; Clinical Trials as Topic; Dasatinib; Drug Resistance, Neoplasm; Everolimus; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Immunosuppressive Agents; Indoles; Niacinamide; Oligonucleotides; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrimidines; Pyrroles; Sirolimus; Staurosporine; Sunitinib; Thiazoles

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, and it is characterized by the occurrence, in > 90 % of cases, of a gain of function mutation in the c-kit proto-oncogene. STI-571 (imatinib mesylate), a selective KIT tyrosine kinase inhibitor, has changed the natural history of this disease, since it has shown high effectiveness in metastatic GIST, and it is currently under investigation also in the adjuvant and neoadjuvant setting. Mechanisms of resistance to imatinib mesylate include both de novo, and, more frequently, acquired resistance, which may occur after several months of drug administration and possibly depends, in most cases, upon an acquired second mutation. In order to overcome imatinib mesylate resistance, the addition of other drugs may be considered in patients who have less than an optimal response to imatinib mesylate monotherapy. Investigational agents that are being studied in this setting include the mammalian target of rapamycin (mTOR) inhibitor RAD 001 and the protein kinase C inhibitor PKC412. In addition, other KIT tyrosine kinase inhibitors with anti-VEGF receptor inhibitory activity, such as SU11248, PTK787/ZK787 and AMG 706, are currently being explored as second line monotherapy for imatinib mesylate-resistant GIST. Finally, another new drug, ecteinascidin (ET-743), that blocks cell cycle progression in G2/M phase through a p53-independent apoptotic mechanism, has shown important preclinical and clinical activity against a number of human solid tumors, including GIST.

Topics: Antineoplastic Agents; Benzamides; Chemotherapy, Adjuvant; Dioxoles; Drug Resistance, Neoplasm; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Neoadjuvant Therapy; Niacinamide; Oligonucleotides; Phthalazines; Piperazines; Proto-Oncogene Mas; Pyridines; Pyrimidines; Pyrroles; Sunitinib; Tetrahydroisoquinolines; Trabectedin

This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST).. Patients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by (18)FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety.. In the patients evaluable for response (N = 102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease ≥24 weeks; 38% had disease progression. Higher objective response rates were observed per (18)FDG-PET (N = 91) (30%) and Choi criteria (41%). The median PFS was 16 weeks (95% CI = 14-24 weeks); the median TTP was 17 weeks (95% CI = 15-24 weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing.. In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Male; Middle Aged; Niacinamide; Oligonucleotides; Piperazines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Treatment Outcome

Motesanib (AMG 706) is a multitargeted anticancer agent with an inhibitory action on the human vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and the cellular stem-cell factor receptor (KIT). The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate.. All patients had experienced progression or relapse while undergoing with imatinib as 400 mg/day or higher. The patients were administered 125 mg of motesanib once daily. The primary endpoint was overall response. Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumor, and safety was assessed according to the Common Terminology Criteria for Adverse Events (version 3).. Of 35 enrolled and treated patients, no patient showed a complete response, and one patient showed a partial response (PR). Seven had stable disease (SD) for at least 24 months, two of whom continued to have SD for more than 2 years. The median progression-free survival time was 16.1 weeks. Motesanib was well tolerated; commonly reported treatment-related adverse events were hypertension, diarrhea, and fatigue. Anemia was the only hematological toxicity that was reported.. One patient showed PR, and seven patients showed SD more than 24 weeks. Motesanib was found to be safe and well tolerated. The observed toxicities were consistent with Phase I study findings.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Benzamides; Drug Resistance, Neoplasm; Drug Tolerance; Female; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Japan; Male; Middle Aged; Niacinamide; Oligonucleotides; Piperazines; Pyrimidines; Radiography; Treatment Outcome

Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).. This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.. Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC50 = 18 nM) and exon 11 (V560 D, IC50 = 5 nM; Delta552-559, IC50 = 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC50 = 77 nM; V560D/T670I, IC50 = 277 nM; Y823 D, IC50 = 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC50 > 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC50 values in good agreement with those observed in the autophosphorylation assays.. In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.

Topics: Animals; Blotting, Western; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Female; Gastrointestinal Stromal Tumors; Humans; Indoles; Mice; Mice, Inbred C57BL; Mutation; Niacinamide; Oligonucleotides; Phosphorylation; Proto-Oncogene Proteins c-kit

Topics: Base Sequence; Benzamides; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Middle Aged; Niacinamide; Oligonucleotides; Piperazines; Point Mutation; Proto-Oncogene Proteins c-kit; Pyrimidines