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Oncotarget Apr 2017Prognostic studies of insulin-like growth factor-1 receptor(IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R... (Review)
Review
BACKGROUND
Prognostic studies of insulin-like growth factor-1 receptor(IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R signalling was crucial in cancer cells growth. However, the conclusion of later clinical trials revealed a dim future for IGF-1R inhibitors to treat cancer. We conducted this analysis to figure out how IGF-1R inhibitors acted in clinical cancer therapy.
MATERIAL AND METHODS
We searched up-to-date studies about the single agent of IGF-1R inhibitors or combination with other therapies in solid tumor. Five IGF-1R anti-agents were involved. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS).
RESULT
17studies were enrolled. The results was not significant in overall survival (I2=37.1%, P=0.080, HR=1.08, 95% CI=0.97-1.21) and in progression-free survival (I2=0.0%, P=0.637, HR=1.05, 95% CI=0.98-1.12). OS for dalotuzumab, breast cancer, colorectal cancer, and PFS for prostate cancer even indicated harmful effects.
CONCLUSION
So far, anti-IGF-1R mono-antibodies did not make significant differences in solid tumor prognosis. On the contrary, pessimistic effects were shown in the dalotuzumab, breast cancer, colorectal cancer and prostate cancer subgroups. Further studies of IGF-1R anti-agents were needed, but unwarranted in unselected patients by predictive biomarkers.
Topics: Aged; Humans; Middle Aged; Neoplasms; Prognosis; Receptor, IGF Type 1; Survival Analysis
PubMed: 28427155
DOI: 10.18632/oncotarget.15704 -
Experimental Hematology & Oncology 2014We investigated the safety and antitumor activity of dalotuzumab, a selective anti-insulin growth factor 1 receptor monoclonal antibody (IGF1R MoAb), plus erlotinib in a...
Activity of dalotuzumab, a selective anti-IGF1R antibody, in combination with erlotinib in unselected patients with Non-small-cell lung cancer: a phase I/II randomized trial.
BACKGROUND
We investigated the safety and antitumor activity of dalotuzumab, a selective anti-insulin growth factor 1 receptor monoclonal antibody (IGF1R MoAb), plus erlotinib in a sequential phase I/II trial in unselected patients with refractory advanced non-small-cell lung cancer (NSCLC).The phase I trial determined the recommended dose and safety of erlotinib plus dalotuzumab at 5 mg/kg or 10 mg/kg weekly in 20 patients. The phase II trial compared outcomes to erlotinib alone and erlotinib plus dalotuzumab at the mg/kg established in the phase I trial.
RESULTS
Erlotinib at 150 mg plus dalotuzumab at 10 mg/kg was safe. The phase II trial included 37 patients in the erlotinib arm and 38 patients in the erlotinib plus dalotuzumab arm. Progression-free survival was 1.6 versus 2.5 months, overall survival was 10.2 and 6.6 months, and the objective response rate was 7.9% and 2.7%, respectively, with no significant differences between the two arms. Grade 3-5 adverse events occurred in 11 (28.9%) versus 13 (35.1%) patients, respectively. The most frequent adverse events were asthenia (36.8% vs. 37.8%), dehydration (5.3% vs. 2.7%), diarrhea (71% vs. 81.1%), hyperglycemia (13.1% vs.18.9%), and skin-related toxicities (92.1% vs. 86.4%).
CONCLUSION
The addition of dalotuzumab to erlotinib did not improve efficacy outcome in patients with refractory advanced NSCLC.
PubMed: 25414803
DOI: 10.1186/2162-3619-3-26 -
Clinical Cancer Research : An Official... Jan 2015Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR... (Clinical Trial)
Clinical Trial
PURPOSE
Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.
EXPERIMENTAL DESIGN
In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.
RESULTS
Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER(+)/high-proliferative breast cancer showed antitumor activity.
CONCLUSIONS
Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER(+)/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).
Topics: Adult; Aged; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Humans; Middle Aged; Receptor, IGF Type 1; Receptors, Somatomedin; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays
PubMed: 25320355
DOI: 10.1158/1078-0432.CCR-14-0940 -
Breast Cancer Research and Treatment Oct 2017To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.
METHODS
This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS).
RESULTS
Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81-1.72; P = 0.565). Grade 3-5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.
CONCLUSIONS
R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.
Topics: Adult; Aged; Aged, 80 and over; Androstadienes; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Middle Aged; Neoplasm Staging; Retreatment; Sirolimus; Treatment Outcome
PubMed: 28681171
DOI: 10.1007/s10549-017-4375-5 -
Molecular Endocrinology (Baltimore, Md.) Nov 2015Preclinical studies in the 1980s defined a role for IGF signaling in the development and sustainability of the malignant process. Subsequently, antibody, tyrosine... (Review)
Review
Preclinical studies in the 1980s defined a role for IGF signaling in the development and sustainability of the malignant process. Subsequently, antibody, tyrosine kinase, and ligand inhibitors of the IGF receptor were manufactured. In the past decade, numerous clinical trials have tested the efficacy of IGF receptor inhibitors in the treatment of advanced tumors. Early-phase trials in heavily pretreated populations showed promise with complete or partial responses in a few patients and stable disease in many more. Unfortunately, the results of the early-phase trials did not pan out to later-phase trials. The lack of use of biomarkers to define subsets of patients that may benefit from IGF receptor blockade and compensatory signaling via other growth factor receptors such as the insulin, GH, and epidermal growth factor receptors may have played a role in the lack of efficacy of IGF receptor inhibition in phase III trials. Although these trials failed to show benefit, the trials have revealed previously unknown knowledge regarding the complex nature of IGF signaling. The knowledge obtained from these trials will be useful in designing future trials studying inhibitors of growth factor signaling.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Humans; Insulin-Like Growth Factor I; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Receptor, IGF Type 1; Receptors, Somatomedin; Signal Transduction
PubMed: 26366975
DOI: 10.1210/me.2015-1157 -
Breast Cancer Research and Treatment Jun 2017Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%).
METHODS
This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS).
RESULTS
Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.
CONCLUSIONS
The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.
Topics: Adult; Aged; Androstadienes; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Disease-Free Survival; Female; Humans; Middle Aged; Protein Kinase Inhibitors; Receptors, Estrogen; Sirolimus; Stomatitis
PubMed: 28324268
DOI: 10.1007/s10549-017-4199-3 -
British Journal of Cancer Nov 2014Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus... (Randomized Controlled Trial)
Randomized Controlled Trial
A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.
BACKGROUND
Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.
METHODS
A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.
RESULTS
A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.
CONCLUSIONS
Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzene Derivatives; Biomarkers, Tumor; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cohort Studies; Female; Follow-Up Studies; Heterocyclic Compounds, 3-Ring; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; Prognosis; Propionates; Proto-Oncogene Proteins c-akt; Randomized Controlled Trials as Topic; Receptor, IGF Type 1; Receptors, Notch; Sirolimus; Sulfones; TOR Serine-Threonine Kinases; Tissue Distribution
PubMed: 25290091
DOI: 10.1038/bjc.2014.497 -
Clinical Cancer Research : An Official... Oct 2015The IGF1R signaling pathway is a complex and tightly regulated network that is critical for cell proliferation, growth, and survival. IGF1R is a potential therapeutic... (Review)
Review
The IGF1R signaling pathway is a complex and tightly regulated network that is critical for cell proliferation, growth, and survival. IGF1R is a potential therapeutic target for patients with many different malignancies. This brief review summarizes the results of clinical trials targeting the IGF1R pathway in patients with breast cancer, sarcoma, and non-small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF1R pathway targeting strategies, including monoclonal antibodies to IGF1 and IGF2 (MEDI-573 and BI 836845) and a small-molecule tyrosine kinase inhibitor of IGF1R (linsitinib). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF1R-directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Humans; Male; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Receptor, IGF Type 1; Signal Transduction; Translational Research, Biomedical; Treatment Outcome
PubMed: 26429980
DOI: 10.1158/1078-0432.CCR-14-2518 -
BMC Cancer Oct 2016Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth...
BACKGROUND
Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option.
METHODS
Using hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; "MK-0646"; anti-IGF-1R antibody), ridaforolimus (RIDA; "MK-8669"; mTORC1 small molecule inhibitor) and letrozole ("LET", aromatase inhibitor).
RESULTS
With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach.
CONCLUSION
These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Proliferation; Drug Synergism; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Hormone-Dependent; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptor, IGF Type 1; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 27765027
DOI: 10.1186/s12885-016-2847-3 -
Journal of the National Cancer Institute Dec 2016Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical...
BACKGROUND
Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical responses in a subset of Ewing sarcoma (ES) patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to the IGF-1R/mTOR blockade are still undefined.
METHODS
To elucidate predominant mechanism(s) of acquired drug resistance while identifying synergistic drug combinations that improve clinical efficacy, we generated more than 18 ES cell lines resistant to IGF-1R- or mTOR-targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Reverse-phase protein lysate arrays (RPPAs) revealed proteomic changes linked to IGF-1R/mTOR resistance, and selected proteins were validated in cell-based assays, xenografts, and within human clinical samples. All statistical tests were two-sided.
RESULTS
Novel mechanisms of resistance (MOR) emerged after dalotuzumab-, NVP-ADW-742-, and OSI-906-based targeting of IGF-1R. MOR to dalotuzumab included upregulation of IRS1, PI3K, and STAT3, as well as p38 MAPK, which was also induced by OSI-906. pEIF4E(Ser209), a key regulator of Cap-dependent translation, was induced in ridaforolimus-resistant ES cell lines. Unique drug combinations targeting IGF-1R and PI3K-alpha or Mnk and mTOR were synergistic in vivo and vitro (P < .001) as assessed respectively by Mantel-Cox and isobologram testing.
CONCLUSIONS
We discovered new druggable targets expressed by chemoresistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets, in concert with IGF-1R or mTOR blockade, should improve clinical outcomes.
Topics: Adenosine Triphosphatases; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cation Transport Proteins; Cell Line, Tumor; Copper-Transporting ATPases; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imidazoles; Insulin Receptor Substrate Proteins; Male; Mice; Mice, SCID; Neoplasm Transplantation; Nucleocytoplasmic Transport Proteins; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Array Analysis; Pyrazines; Pyrimidines; Pyrroles; Receptor, IGF Type 1; Receptors, Somatomedin; STAT3 Transcription Factor; Sarcoma, Ewing; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation; p38 Mitogen-Activated Protein Kinases
PubMed: 27576731
DOI: 10.1093/jnci/djw182