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Oncoimmunology Jan 2013During the past 20 years, dozens-if not hundreds-of monoclonal antibodies have been developed and characterized for their capacity to mediate antineoplastic effects,...
During the past 20 years, dozens-if not hundreds-of monoclonal antibodies have been developed and characterized for their capacity to mediate antineoplastic effects, either as they activate/enhance tumor-specific immune responses, either as they interrupt cancer cell-intrinsic signal transduction cascades, either as they specifically delivery toxins to malignant cells or as they block the tumor-stroma interaction. Such an intense research effort has lead to the approval by FDA of no less than 14 distinct molecules for use in humans affected by hematological or solid malignancies. In the inaugural issue of , we briefly described the scientific rationale behind the use of monoclonal antibodies in cancer therapy and discussed recent, ongoing clinical studies investigating the safety and efficacy of this approach in patients. Here, we summarize the latest developments in this exciting area of clinical research, focusing on high impact studies that have been published during the last 15 months and clinical trials launched in the same period to investigate the therapeutic profile of promising, yet hitherto investigational, monoclonal antibodies.
PubMed: 23482847
DOI: 10.4161/onci.22789 -
Cancer Research Jul 2012The role of the insulin-like growth factor (IGF) system in breast cancer is well defined, and inhibitors of this pathway are currently in clinical trials. The majority...
The role of the insulin-like growth factor (IGF) system in breast cancer is well defined, and inhibitors of this pathway are currently in clinical trials. The majority of anti-IGF1R clinical trials are in estrogen receptor-positive patients who have progressed on prior endocrine therapy; early reports show no benefit for addition of IGF1R inhibitors to endocrine therapy in this setting. In this study, we examined the effectiveness of IGF1R inhibitors in vitro by generating tamoxifen-resistant (TamR) cells. We found that TamR cells had diminished levels of IGF1R with unchanged levels of insulin receptor (IR), and failed to respond to IGF-I-induced Akt activation, proliferation, and anchorage-independent growth while retaining responsiveness to both insulin and IGF-II. The IGF1R antibody dalotuzumab inhibited IGF-I-mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells, but had no effect on TamR cells. An IGF1R tyrosine kinase inhibitor, AEW541, with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells. Interestingly, AEW541 also inhibited insulin- and IGF-II-stimulated effects in TamR cells. Tamoxifen-treated xenografts also had reduced levels of IGF1R, and dalotuzumab did not enhance the effect of tamoxifen. We conclude that cells selected for tamoxifen resistance in vitro have downregulated IGF1R making antibodies directed against this receptor ineffective. Inhibition of IR may be necessary to manage tamoxifen-resistant breast cancer.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Adhesion; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Real-Time Polymerase Chain Reaction; Receptor, IGF Type 1; Signal Transduction; Tamoxifen
PubMed: 22573715
DOI: 10.1158/0008-5472.CAN-12-0684 -
Cancer Oct 2012Neuroendocrine tumor (NET) cell lines frequently express both insulin-like growth factor (IGF) ligand and the cognate IGF-1 receptor (IGF-1R) and, as such, potentially...
BACKGROUND
Neuroendocrine tumor (NET) cell lines frequently express both insulin-like growth factor (IGF) ligand and the cognate IGF-1 receptor (IGF-1R) and, as such, potentially depend on the activation of IGF-1R and its downstream effectors for growth and survival. Preclinical studies suggest that somatostatin analogs and mammalian target of rapamycin (mTOR) inhibitors exhibit antitumor activity against NETs through inhibition of IGF-1-dependent signaling, suggesting that IGF-1R inhibition may be a promising therapeutic approach to NETs. Therefore, the authors of this report evaluated the safety and efficacy of MK-0646, a fully human monoclonal antibody (MoAb) that binds to the IGF-1R, as monotherapy in patients with metastatic, well-differentiated NETs.
METHODS
A phase 2 study was performed in which patients received intravenous MK-0646 10 mg/kg once weekly over 1 hour. Archived pretreatment tumor tissue was obtained and genotyped for v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-3-kinase, catalytic, alpha polypeptide (PIK3CA); and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, and immunohistochemistry was performed to measure the expression IGF-1R.
RESULTS
Twenty-five patients received treatment (40% women; median age, 61 years; age range, 37-83 years), including 15 patients with carcinoid tumors and 10 patients with pancreatic NETs. No partial or complete responses were observed. The median progression-free survival was 4.2 months in the pancreatic NET cohort (range, 0.7-6.7 months) and 2.7 months in the carcinoid cohort (range, 2-3 months). Serious adverse events that were potentially related to MK-0646 included grade 3/4 hyperglycemia in 8 of 25 patients (32%), grade 2 hypersensitivity reaction in 1 of 24 patients (4%), and grade 3 lipase elevation in 1 of 25 patients (4%).
CONCLUSIONS
Despite a compelling preclinical rationale, MK-0646 was inactive as a single agent in well-differentiated NETs. Further studies of MK-0646 as a monotherapy in unselected NETs are unwarranted.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoid Tumor; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Genotype; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Receptor, IGF Type 1; Treatment Failure
PubMed: 22437754
DOI: 10.1002/cncr.27459 -
Clinical Cancer Research : An Official... Dec 2011Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically...
PURPOSE
Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically altered pathways with the purpose of scanning possible therapeutic targets.
EXPERIMENTAL DESIGN
We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. Immunohistochemistry (IHC) and cell biology detection and validation were carried out on human MPNST tissues and cell lines.
RESULTS
Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes. At the pathway level, we identified a significant enrichment of copy number-altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself. To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using IHC. Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using siRNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and mitogen-activated protein kinase pathways.
CONCLUSION
These integrated genomic and molecular studies provide evidence that the IGF1R pathway is a potential therapeutic target for patients with MPNST.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blotting, Western; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemoradiotherapy; Cohort Studies; Comparative Genomic Hybridization; Extracellular Signal-Regulated MAP Kinases; Female; Genomics; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Nerve Sheath Neoplasms; Peripheral Nervous System Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA Interference; Receptor, IGF Type 1; Signal Transduction
PubMed: 22042973
DOI: 10.1158/1078-0432.CCR-11-1707 -
PloS One 2011A correlation between components of the insulin-like growth factor (IGF) system and endometrial cancer risk has been shown in recent studies. The antitumor action of...
A correlation between components of the insulin-like growth factor (IGF) system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR) signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa) and uterine serous papillary (Type II, USPC-2) endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Insulin-Like Growth Factor I; Models, Biological; Signal Transduction; Uterus; Vorinostat
PubMed: 21931726
DOI: 10.1371/journal.pone.0024468 -
MAbs 2011This overview of 25 monoclonal antibody (mAb) and 5 Fc fusion protein therapeutics provides brief descriptions of the candidates, recently published clinical study...
This overview of 25 monoclonal antibody (mAb) and 5 Fc fusion protein therapeutics provides brief descriptions of the candidates, recently published clinical study results and on-going Phase 3 studies. In alphanumeric order, the 2011 therapeutic antibodies to watch list comprises AIN-457, bapineuzumab, brentuximab vedotin, briakinumab, dalotuzumab, epratuzumab, farletuzumab, girentuximab (WX-G250), naptumomab estafenatox, necitumumab, obinutuzumab, otelixizumab, pagibaximab, pertuzumab, ramucirumab, REGN88, reslizumab, solanezumab, T1h , teplizumab, trastuzumab emtansine, tremelimumab, vedolizumab, zalutumumab and zanolimumab. In alphanumeric order, the 2011 Fc fusion protein therapeutics to watch list comprises aflibercept, AMG-386, atacicept, Factor VIII and Factor IX-Fc. Commercially-sponsored mAb and Fc fusion therapeutics that have progressed only as far as Phase 2/3 or 3 were included. Candidates undergoing regulatory review or products that have been approved may also be in Phase 3 studies, but these were excluded. Due to the large body of primary literature about the candidates, only selected references are given and results from recent publications and articles that were relevant to Phase 3 studies are emphasized. Current as of September 2010, the information presented here will serve as a baseline against which future progress in the development of antibody-based therapeutics can be measured.
Topics: Antibodies, Monoclonal; Clinical Trials, Phase III as Topic; Humans; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 21051951
DOI: 10.4161/mabs.3.1.13895