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Huang Y, Hou R, Lam FS, Jia Y, Zhou Y, He X, Li G, Xiong F, Cao Y, Wang D, Li X. Agonist Discovery for Membrane Proteins on Live Cells by Using DNA-encoded Libraries. J Am Chem Soc 2024; 146:24638-24653. [PMID: 39171830 DOI: 10.1021/jacs.4c08624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Identifying biologically active ligands for membrane proteins is an important task in chemical biology. We report an approach to directly identify small molecule agonists against membrane proteins by selecting DNA-encoded libraries (DELs) on live cells. This method connects extracellular ligand binding with intracellular biochemical transformation, thereby biasing the selection toward agonist identification. We have demonstrated the methodology with three membrane proteins: epidermal growth factor receptor (EGFR), thrombopoietin receptor (TPOR), and insulin receptor (INSR). A ∼30 million and a 1.033 billion-compound DEL were selected against these targets, and novel agonists with subnanomolar affinity and low micromolar cellular activities have been discovered. The INSR agonists activated the receptor by possibly binding to an allosteric site, exhibited clear synergistic effects with insulin, and activated the downstream signaling pathways. Notably, the agonists did not activate the insulin-like growth factor 1 receptor (IGF-1R), a highly homologous receptor whose activation may lead to tumor progression. Collectively, this work has developed an approach toward "functional" DEL selections on the cell surface and may provide a widely applicable method for agonist discovery for membrane proteins.
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Affiliation(s)
- Yiran Huang
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, China
| | - Rui Hou
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units 1503-1511, 15/F., Building 17W, Hong Kong SAR 999077, China
| | - Fong Sang Lam
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, China
| | - Yunxuan Jia
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, China
| | - Yu Zhou
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units 1503-1511, 15/F., Building 17W, Hong Kong SAR 999077, China
| | - Xun He
- Shenzhen NewDEL Biotech Co., Ltd., Shenzhen 518110, China
| | - Gang Li
- Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518000, China
| | - Feng Xiong
- Shenzhen NewDEL Biotech Co., Ltd., Shenzhen 518110, China
| | - Yan Cao
- School of Pharmacy, Naval Medical University, Shanghai 200433, China
| | - Dongyao Wang
- School of Pharmacy, Naval Medical University, Shanghai 200433, China
| | - Xiaoyu Li
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units 1503-1511, 15/F., Building 17W, Hong Kong SAR 999077, China
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Monteiro M, Zhang X, Yee D. Insulin promotes growth in breast cancer cells through the type I IGF receptor in insulin receptor deficient cells. Exp Cell Res 2024; 434:113862. [PMID: 38036052 PMCID: PMC10842809 DOI: 10.1016/j.yexcr.2023.113862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/14/2023] [Accepted: 11/21/2023] [Indexed: 12/02/2023]
Abstract
Breast cancer is the most common cancer in women. The upregulation of insulin-like growth factor (IGF) system observed in certain types of breast cancers was linked to growth, metastasis, and survival resulting in multiple strategies designed to target the type I IGF receptor (IGF-1R) in breast cancer. These attempts failed to prove beneficial and it has been suggested that insulin receptor (IR) could also play an important role in breast cancer biology. To better understand the IR's role in breast cancer cells, the receptor was deleted from MCF-7L cells using CRISPR technology, and fluorescence-assisted cell sorting was used to obtain clone 35 (CL35). It was found that CL35 activated signaling pathways upon insulin stimulation despite the absence of IR expression. We hypothesized that CL35 used a surrogate receptor for sustained growth and development. IGF-1R was able to activate insulin signaling and growth in CL35. Thus, insulin may play a central role in regulating breast cancer growth due to its ability to activate all the receptors of the IGF family. These findings argue that dual targeting of IR and IGF-IR may be required to inhibit breast cancer growth.
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Affiliation(s)
- Marvis Monteiro
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA; Purdue University, Heine Pharmacy Building, 575 Stadium Mall Drive, West Lafayette, IN, 47907-2091, USA
| | - Xihong Zhang
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Douglas Yee
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
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Stueven NA, Beauvais DM, Hu R, Kimple RJ, Rapraeger AC. Inhibiting IGF1R-mediated Survival Signaling in Head and Neck Cancer with the Peptidomimetic SSTN IGF1R. CANCER RESEARCH COMMUNICATIONS 2023; 3:97-108. [PMID: 36968227 PMCID: PMC10035507 DOI: 10.1158/2767-9764.crc-22-0274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/26/2022] [Accepted: 01/03/2023] [Indexed: 01/07/2023]
Abstract
Previous studies have shown that the type I IGFR (IGF1R) suppresses apoptosis when it is autoactivated by coupling its extracellular domain to a matrix adhesion receptor complex consisting of syndecan-1 (Sdc1) and αvβ3 or αvβ5 integrin. We now report that head and neck squamous cell carcinoma (HNSCC) relies on this receptor complex. Disruption of the complex in HNSCC cells in vitro with a peptide mimetic of the organizer site in Sdc1 (called SSTNIGF1R) inactivates IGF1R, even in the presence of IGF1, and relieves the suppression of apoptosis signal-regulating kinase-1 (ASK1), dramatically reducing tumor cell survival. Normal epithelial cells do not assemble this receptor complex, require IGF1 to activate the IGF1R, and are refractory to SSTNIGF1R. In vivo, SSTNIGF1R reduced the growth of patient-derived HNSCC tumors in immunodeficient mice by 85%-95%. IGF1R's assimilation into the matrix receptor complex, which is detected in these tumors using the proximity ligation assay (PLA), is quantitatively disrupted by SSTNIGF1R, coinciding with ASK1 activation. PLA also detects the IGF1R-containing receptor complex in the archival sections of tonsil carcinomas, whereas the adjacent benign epithelium is negative. Likewise, PLA screening of oropharyngeal and adenoid cystic tumor microarrays demonstrated that over 95% of the tumors contained this unique receptor complex with no detectable expression in benign tissue. These findings suggest that HNSCC upregulates and is highly dependent on IGF1R signaling via this adhesion receptor complex. Targeting this mechanism with novel therapeutics, including highly specific SSTNIGF1R, is likely to offer promising outcomes for patients with carcinoma. Significance A newly developed biomarker reveals upregulation of an antiapoptotic IGF1R-integrin-syndecan receptor complex in head and neck cancer and documents disruption of the complex in patient-derived tumor xenografts (PDX) treated with the inhibitor SSTNIGF1R. A corresponding blockade in PDX growth in the presence of this inhibitor demonstrates that therapies designed to target this mechanism will likely offer promising outcomes for patients with head and neck cancer.
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Affiliation(s)
- Noah A. Stueven
- Department of Human Oncology, University of Wisconsin–Madison, Madison, Wisconsin
| | | | - Rong Hu
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, Wisconsin
| | - Randall J. Kimple
- Department of Human Oncology, University of Wisconsin–Madison, Madison, Wisconsin
| | - Alan C. Rapraeger
- Department of Human Oncology, University of Wisconsin–Madison, Madison, Wisconsin
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IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma. Cancers (Basel) 2021; 13:cancers13225863. [PMID: 34831014 PMCID: PMC8616282 DOI: 10.3390/cancers13225863] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary Melanoma accounts for only 4% of skin cancer, but is the major cause of skin cancer related deaths. The use of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), two FDA approved drugs to treat patients with BRAFV600E melanoma, is limited in the clinic due to the development of resistance. The IGF family of receptors is known to play a crucial role in cancer progression. In our in vitro screening, we identified that the activation of Insulin-like growth factor 1 receptor (IGF1R) and Insulin Receptor (IR) mediates resistance to dabrafenib and trametinib. Patients with high levels of IGF1R and IR have worse survival outcomes compared to patients with low levels of these receptors. We demonstrate that combining dabrafenib and trametinib with an IGF1R/IR inhibitor, BMS-754807, in vitro and in vivo, is efficacious and inhibits proliferation and tumor growth. This research opens up avenues for the development of novel and potent IGF1R/IR inhibitors for patients with BRAF-mutant melanoma. Abstract The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.
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Rapraeger AC. Syndecans and Their Synstatins: Targeting an Organizer of Receptor Tyrosine Kinase Signaling at the Cell-Matrix Interface. Front Oncol 2021; 11:775349. [PMID: 34778093 PMCID: PMC8578902 DOI: 10.3389/fonc.2021.775349] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/27/2021] [Indexed: 01/11/2023] Open
Abstract
Receptor tyrosine kinases (RTKs) and integrin matrix receptors have well-established roles in tumor cell proliferation, invasion and survival, often functioning in a coordinated fashion at sites of cell-matrix adhesion. Central to this coordination are syndecans, another class of matrix receptor, that organize RTKs and integrins into functional units, relying on docking motifs in the syndecan extracellular domains to capture and localize RTKs (e.g., EGFR, IGF-1R, VEGFR2, HER2) and integrins (e.g., αvβ3, αvβ5, α4β1, α3β1, α6β4) to sites of adhesion. Peptide mimetics of the docking motifs in the syndecans, called “synstatins”, prevent assembly of these receptor complexes, block their signaling activities and are highly effective against tumor cell invasion and survival and angiogenesis. This review describes our current understanding of these four syndecan-coupled mechanisms and their inhibitory synstatins (SSTNIGF1R, SSTNVEGFR2, SSTNVLA-4, SSTNEGFR and SSTNHER2).
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Affiliation(s)
- Alan C Rapraeger
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
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Yee D, Isaacs C, Wolf DM, Yau C, Haluska P, Giridhar KV, Forero-Torres A, Jo Chien A, Wallace AM, Pusztai L, Albain KS, Ellis ED, Beckwith H, Haley BB, Elias AD, Boughey JC, Kemmer K, Yung RL, Pohlmann PR, Tripathy D, Clark AS, Han HS, Nanda R, Khan QJ, Edmiston KK, Petricoin EF, Stringer-Reasor E, Falkson CI, Majure M, Mukhtar RA, Helsten TL, Moulder SL, Robinson PA, Wulfkuhle JD, Brown-Swigart L, Buxton M, Clennell JL, Paoloni M, Sanil A, Berry S, Asare SM, Wilson A, Hirst GL, Singhrao R, Asare AL, Matthews JB, Hylton NM, DeMichele A, Melisko M, Perlmutter J, Rugo HS, Fraser Symmans W, Van't Veer LJ, Berry DA, Esserman LJ. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer. NPJ Breast Cancer 2021; 7:131. [PMID: 34611148 PMCID: PMC8492731 DOI: 10.1038/s41523-021-00337-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.
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Affiliation(s)
- Douglas Yee
- Masonic Cancer Center, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN, 55455, USA.
| | - Claudine Isaacs
- Georgetown University, 3800 Reservoir Rd, NW, Washington, DC, 20007, USA
| | - Denise M Wolf
- University of California San Francisco Department of Laboratory Medicine, 2340 Sutter Street, S433, San Francisco, CA, 94115, USA
| | - Christina Yau
- University of California San Francisco Department of Laboratory Medicine, 2340 Sutter Street, S433, San Francisco, CA, 94115, USA
| | - Paul Haluska
- Mayo Clinic Rochester c/o Merck Corporation, 126 E. Lincoln Ave Rahway, New Jersey, 07065, USA
| | - Karthik V Giridhar
- Mayo Clinic Division of Medical Oncology, 200 1st St SW, Rochester, MN, 55905, USA
| | - Andres Forero-Torres
- University of Alabama at Birmingham c/o Seattle Genetics, 21823 30th Drive S.E., Bothell, WA, 98021, USA
| | - A Jo Chien
- University of California San Francisco Division of Hematology-Oncology, 550 16th Street, San Francisco, CA, 94158, USA
| | - Anne M Wallace
- University of California San Diego Department of Surgery, 3855 Health Sciences Dr, M/C 0698, La Jolla, CA, 92093, USA
| | - Lajos Pusztai
- Yale University Medical Onciology, 111 Goose Lane, Fl 2, Guilford, CT, 06437, USA
| | - Kathy S Albain
- Loyola University Chicago Stritch School of Medicine Cardinal Bernardin Cancer Center, 2160 South First Ave, Maywood, IL, 60153, USA
| | - Erin D Ellis
- Swedish Cancer Institute Medical Oncology, 1221 Madison Street, Seattle, WA, 98104, USA
| | - Heather Beckwith
- Masonic Cancer Center, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN, 55455, USA
| | - Barbara B Haley
- UT Southwestern Medical Center Division of Hematology-Oncology, 5323 Harry Hines Blvd, Bldg E6.222D, Dallas, TX, 75390-9155, USA
| | - Anthony D Elias
- University of Colorado Anschutz Medical Center Division of Medical Oncology, 1665 Aurora Ct., Rm. 3200, MS F700, Aurora, CO, 80045, USA
| | - Judy C Boughey
- Mayo Clinic Division of Medical Oncology, 200 1st St SW, Rochester, MN, 55905, USA
| | - Kathleen Kemmer
- OHSU Knight Cancer Institute South Waterfront Center for Health and Healing, 3303 SW Bond Ave Building 1, Suite 7, Portland, OR, 97239, USA
| | - Rachel L Yung
- University of Washington Seattle Cancer Care Alliance, 825 Eastlake Ave East, Seattle, WA, 98109-1023, USA
| | - Paula R Pohlmann
- Georgetown University, 3800 Reservoir Rd, NW, Washington, DC, 20007, USA
| | - Debu Tripathy
- MD Anderson Cancer Center, 1515 Holcombe, Houston, Texas, 77030, USA
| | - Amy S Clark
- University of Pennsylvania Division of Hematology-Oncology 3 Perelman Center, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA
| | - Hyo S Han
- Moffit Cancer Center, 2902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Rita Nanda
- University of Chicago Section of Hematology/Oncology, 5841S. Maryland Avenue, MC 2115, Chicago, IL, 60437, USA
| | - Qamar J Khan
- University of Kansas Division of Oncology, 2330 Shawnee Mission Pkwy, Ste 210, Westwood, KS, 66205, USA
| | - Kristen K Edmiston
- Inova Medical Group, 3580 Joseph Siewick Dr 101, Fairfax, VA, 22033-1764, USA
| | - Emanuel F Petricoin
- George Mason University Institute for Advanced Biomedical Research, 10920 George Mason Circle Room 2008, MS1A9, Manassas, Virginia, 20110, USA
| | - Erica Stringer-Reasor
- University of Alabama at Birmingham Hematology/Oncology, 1802 Sixth Avenue South 2510, Birmingham, AL, 35294-3300, USA
| | - Carla I Falkson
- Wilmot Cancer Institute Pluta Cancer Center, 125 Red Creek Drive, Rochester, NY, 14623, USA
| | - Melanie Majure
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Rita A Mukhtar
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Teresa L Helsten
- University of California San Diego Division of Hematology-Oncology, 9400 Campus Point Dr, La Jolla, CA, 92037, USA
| | - Stacy L Moulder
- MD Anderson Cancer Center, 1515 Holcombe, Houston, Texas, 77030, USA
| | - Patricia A Robinson
- Loyola University Chicago Stritch School of Medicine Cardinal Bernardin Cancer Center, 2160 South First Ave, Maywood, IL, 60153, USA
| | - Julia D Wulfkuhle
- George Mason University Institute for Advanced Biomedical Research, 10920 George Mason Circle Room 2008, MS1A9, Manassas, Virginia, 20110, USA
| | - Lamorna Brown-Swigart
- University of California San Francisco Department of Laboratory Medicine, 2340 Sutter Street, S433, San Francisco, CA, 94115, USA
| | - Meredith Buxton
- University of California San Francisco c/o Global Coalition for Adaptive Research, 1661 Massachusetts Ave, Lexington, MA, 02420, USA
| | - Julia L Clennell
- University of California San Francisco c/o IQVIA, 135 Main St 21 floor, San Francisco, CA, 94105, USA
| | | | - Ashish Sanil
- Berry Consultants, LLC 3345 Bee Cave Rd Suite 201, Austin, TX, 78746, USA
| | - Scott Berry
- Berry Consultants, LLC 3345 Bee Cave Rd Suite 201, Austin, TX, 78746, USA
| | - Smita M Asare
- Quantum Leap Healthcare Collaborative, 3450 California St, San Francisco, CA, 94143, USA
| | - Amy Wilson
- Quantum Leap Healthcare Collaborative, 3450 California St, San Francisco, CA, 94143, USA
| | - Gillian L Hirst
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Ruby Singhrao
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Adam L Asare
- Quantum Leap Healthcare Collaborative, 3450 California St, San Francisco, CA, 94143, USA
| | - Jeffrey B Matthews
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Nola M Hylton
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Angela DeMichele
- University of Pennsylvania Division of Hematology-Oncology 3 Perelman Center, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA
| | - Michelle Melisko
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Jane Perlmutter
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - Hope S Rugo
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
| | - W Fraser Symmans
- MD Anderson Cancer Center, 1515 Holcombe, Houston, Texas, 77030, USA
| | - Laura J Van't Veer
- University of California San Francisco Department of Laboratory Medicine, 2340 Sutter Street, S433, San Francisco, CA, 94115, USA
| | - Donald A Berry
- Quantum Leap Healthcare Collaborative, 3450 California St, San Francisco, CA, 94143, USA
| | - Laura J Esserman
- University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA
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Adachi Y, Nojima M, Mori M, Himori R, Kubo T, Akutsu N, Lin Y, Kurozawa Y, Wakai K, Tamakoshi A. Insulin-Like Growth Factor 2 and Incidence of Liver Cancer in a Nested Case-Control Study. Cancer Epidemiol Biomarkers Prev 2021; 30:2130-2135. [PMID: 34497090 DOI: 10.1158/1055-9965.epi-21-0481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/18/2021] [Accepted: 08/25/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Insulin-like growth factor (IGF)2 is a potent mitogen. To elucidate the relationship between IGF2 and risk of tumorigenesis, we analyzed associations between serum levels of IGF2 and incidence of liver cancer in a prospective case-control study nested in the Japan Collaborative Cohort study. METHODS A baseline survey was conducted from 1988 using blood samples from 39,242 subjects. Those who had been diagnosed with liver cancer by 1997 were regarded as cases. For each case, we randomly selected two or three controls matched for sex, age, and residential area. Conditional logistic regression was used to estimate ORs for cancer incidence associated with IGF2. RESULTS This analysis included 86 cases and 294 controls. Low IGF2 was associated with risk of future liver cancer (P trend <0.001). After controlling for alcohol intake, body mass index, smoking, hepatitis viral infection, IGF1, and IGF-binding protein-3, participants with low IGF2 displayed a higher risk of liver cancer (P trend < 0.001). Individuals in quintiles 2 to 5 showed lower risk compared with quintile 1 (OR range, 0.05-0.16). In both sexes and in both nonelderly and elderly groups, subjects in the lowest quintiles showed higher risks of liver cancer. Limiting subjects to those followed for 3 years, low IGF2 was associated with cancer risk (P trend < 0.001). CONCLUSIONS Our findings suggest that low serum IGF2 level, especially below 460 ng/mL, is related to future risk of liver cancer. IMPACT Our findings highlight this important biomarker for further analysis in large prospective cohorts and pooled investigation with other cohorts.
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Affiliation(s)
- Yasushi Adachi
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Japan. .,Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masanori Nojima
- The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan
| | - Mitsuru Mori
- Hokkaido Chitose College of Rehabilitation, Chitose, Japan
| | - Ryogo Himori
- Department of Public Health, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Toshiyuki Kubo
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Noriyuki Akutsu
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Youichi Kurozawa
- Division of Health Administration and Promotion, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University, Graduate School of Medicine, Nagoya, Japan
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Icard P, Loi M, Wu Z, Ginguay A, Lincet H, Robin E, Coquerel A, Berzan D, Fournel L, Alifano M. Metabolic Strategies for Inhibiting Cancer Development. Adv Nutr 2021; 12:1461-1480. [PMID: 33530098 PMCID: PMC8321873 DOI: 10.1093/advances/nmaa174] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/14/2020] [Accepted: 12/14/2020] [Indexed: 12/11/2022] Open
Abstract
The tumor microenvironment is a complex mix of cancerous and noncancerous cells (especially immune cells and fibroblasts) with distinct metabolisms. These cells interact with each other and are influenced by the metabolic disorders of the host. In this review, we discuss how metabolic pathways that sustain biosynthesis in cancer cells could be targeted to increase the effectiveness of cancer therapies by limiting the nutrient uptake of the cell, inactivating metabolic enzymes (key regulatory ones or those linked to cell cycle progression), and inhibiting ATP production to induce cell death. Furthermore, we describe how the microenvironment could be targeted to activate the immune response by redirecting nutrients toward cytotoxic immune cells or inhibiting the release of waste products by cancer cells that stimulate immunosuppressive cells. We also examine metabolic disorders in the host that could be targeted to inhibit cancer development. To create future personalized therapies for targeting each cancer tumor, novel techniques must be developed, such as new tracers for positron emission tomography/computed tomography scan and immunohistochemical markers to characterize the metabolic phenotype of cancer cells and their microenvironment. Pending personalized strategies that specifically target all metabolic components of cancer development in a patient, simple metabolic interventions could be tested in clinical trials in combination with standard cancer therapies, such as short cycles of fasting or the administration of sodium citrate or weakly toxic compounds (such as curcumin, metformin, lipoic acid) that target autophagy and biosynthetic or signaling pathways.
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Affiliation(s)
- Philippe Icard
- Université Caen Normandie, Medical School, CHU de Caen, Caen, France
- Normandie Université, UNICAEN, INSERM U1086, Interdisciplinary Research Unit for Cancer Prevention and Treatment, Centre de Lutte Contre le Cancer Centre François Baclesse, Caen, France
- Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris-Descartes University, Paris, France
| | - Mauro Loi
- Radiotherapy Department, Humanitas Cancer Center, Rozzano, Milan, Italy
| | - Zherui Wu
- School of Medicine, Shenzhen University, Shenzhen, Guangdong, China
- INSERM UMR-S 1124, Cellular Homeostasis and Cancer, Paris-Descartes University, Paris, France
| | - Antonin Ginguay
- Service de Biochimie, Hôpital Cochin, Hôpitaux Universitaires Paris-Centre, AP-HP, Paris, France
- EA4466 Laboratoire de Biologie de la Nutrition, Faculté de Pharmacie de Paris, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France
| | - Hubert Lincet
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon (CRCL), France
- ISPB, Faculté de Pharmacie, Université Lyon 1, Lyon, France
| | - Edouard Robin
- Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris-Descartes University, Paris, France
| | - Antoine Coquerel
- INSERM U1075, Comete “Mobilités: Attention, Orientation, Chronobiologie”, Université Caen, Caen, France
| | - Diana Berzan
- Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris-Descartes University, Paris, France
| | - Ludovic Fournel
- Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris-Descartes University, Paris, France
- INSERM UMR-S 1124, Cellular Homeostasis and Cancer, Paris-Descartes University, Paris, France
| | - Marco Alifano
- Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris-Descartes University, Paris, France
- INSERM U1138, Integrative Cancer Immunology, Paris, France
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9
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Disrupting Insulin and IGF Receptor Function in Cancer. Int J Mol Sci 2021; 22:ijms22020555. [PMID: 33429867 PMCID: PMC7827299 DOI: 10.3390/ijms22020555] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 12/29/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023] Open
Abstract
The insulin and insulin-like growth factor (IGF) system plays an important role in regulating normal cell proliferation and survival. However, the IGF system is also implicated in many malignancies, including breast cancer. Preclinical studies indicate several IGF blocking approaches, such as monoclonal antibodies and tyrosine kinase inhibitors, have promising therapeutic potential for treating diseases. Uniformly, phase III clinical trials have not shown the benefit of blocking IGF signaling compared to standard of care arms. Clinical and laboratory data argue that targeting Type I IGF receptor (IGF1R) alone may be insufficient to disrupt this pathway as the insulin receptor (IR) may also be a relevant cancer target. Here, we review the well-studied role of the IGF system in regulating malignancies, the limitations on the current strategies of blocking the IGF system in cancer, and the potential future directions for targeting the IGF system.
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10
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Lee HJ, Pham PC, Pei H, Lim B, Hyun SY, Baek B, Kim B, Kim Y, Kim MH, Kang NW, Min HY, Kim DD, Lee J, Lee HY. Development of the phenylpyrazolo[3,4- d]pyrimidine-based, insulin-like growth factor receptor/Src/AXL-targeting small molecule kinase inhibitor. Am J Cancer Res 2021; 11:1918-1936. [PMID: 33408789 PMCID: PMC7778606 DOI: 10.7150/thno.48865] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022] Open
Abstract
Rationale: The type I insulin-like growth factor receptor (IGF-1R) signaling pathway plays key roles in the development and progression of numerous types of human cancers, and Src and AXL have been found to confer resistance to anti-IGF-1R therapies. Hence, co-targeting Src and AXL may be an effective strategy to overcome resistance to anti-IGF-1R therapies. However, pharmacologic targeting of these three kinases may result in enhanced toxicity. Therefore, the development of novel multitarget anticancer drugs that block IGF-1R, Src, and AXL is urgently needed. Methods: We synthesized a series of phenylpyrazolo[3,4-d]pyrimidine (PP)-based compounds, wherein the PP module was conjugated with 2,4-bis-arylamino-1,3-pyrimidines (I2) via a copper(I)-catalyzed alkyne-azide cycloaddition reaction. To develop IGF-1R/Src/AXL-targeting small molecule kinase inhibitors, we selected LL6 as an active compound and evaluated its antitumor and antimetastatic effects in vitro and in vivo using the MTT assay, colony formation assays, migration assay, flow cytometric analysis, a tumor xenograft model, the KrasG12D/+-driven spontaneous lung tumorigenesis model, and a spontaneous metastasis model using Lewis lung carcinoma (LLC) allografts. We also determined the toxicity of LL6 in vitro and in vivo. Results: LL6 induced apoptosis and suppressed viability and colony-forming capacities of various non-small cell lung cancer (NSCLC) cell lines and their sublines with drug resistance. LL6 also suppressed the migration of NSCLC cells at nontoxic doses. Administration of LL6 in mice significantly suppressed the growth of NSCLC xenograft tumors and metastasis of LLC allograft tumors with outstanding toxicity profiles. Furthermore, the multiplicity, volume, and load of lung tumors in KrasG12D/+ transgenic mice were substantially reduced by the LL6 treatment. Conclusions: Our results show the potential of LL6 as a novel IGF-1R/Src/AXL-targeting small molecule kinase inhibitor, providing a new avenue for anticancer therapies.
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11
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Adachi Y, Nojima M, Mori M, Himori R, Kubo T, Yamano HO, Lin Y, Wakai K, Tamakoshi A. Insulin-like Growth Factor-1, Insulin-like Growth Factor Binding Protein-3 and the Incidence of Malignant Neoplasms in a Nested Case–Control Study. Cancer Prev Res (Phila) 2020; 13:385-394. [PMID: 31996369 DOI: 10.1158/1940-6207.capr-19-0375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 11/07/2019] [Accepted: 01/23/2020] [Indexed: 12/24/2022]
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12
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Adachi Y, Nojima M, Mori M, Kubo T, Yamano HO, Lin Y, Wakai K, Tamakoshi A. Circulating insulin-like growth factor binding protein-3 and risk of gastrointestinal malignant tumors. J Gastroenterol Hepatol 2019; 34:2104-2111. [PMID: 31158304 DOI: 10.1111/jgh.14753] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 05/21/2019] [Accepted: 05/27/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIM Insulin-like growth factor-1 (IGF1) is a potent mitogen and is inhibited by IGF-binding protein-3 (IGFBP3). High serum IGF1 and low IGFBP3 are associated with increased risk of several carcinomas. Here, we assessed the relationship of these peptides with the risk of gastrointestinal malignancies, in a prospective case-control study nested in the Japan Collaborative Cohort Study. METHODS The analysis involved 916 cases who had been diagnosed as gastrointestinal malignancies (C15-25) and 2306 controls. To estimate odds ratios for incidence of malignancies associated with these levels, a conditional logistic model was used. RESULTS Both higher total and free IGFBP3 were associated with a decreased risk of tumor (P for trend < 0.001 and = 0.003, respectively). People in the second to fifth quintiles had lower risk compared to the first quintile (odds ratios ranged 0.532-0.650 and 0.582-0.725, respectively). After adjustment for IGF1, body mass index, drinking, and smoking, total IGFBP3 was inversely correlated with cancer risk (P for trend = 0.031). After adjustment, free IGFBP3 was inversely associated with the risk (P for trend = 0.007). Although total IGF1 was inversely correlated with tumor risk, it was not after controlling for IGFBP3 (P for trend = 0.007 and 0.589, respectively). Free IGF1 was not associated with the risk (P for trend = 0.361). Limiting subjects to those followed for over 3 years reinforced the inverted relationships of total and free IGFBP3 with risk for tumors (P for trend = 0.005 and 0.008, respectively). CONCLUSION Both total and free IGFBP3 may be inversely associated with the incidence of gastrointestinal malignancies.
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Affiliation(s)
- Yasushi Adachi
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Sapporo Medical University, Sapporo, Japan
| | - Masanori Nojima
- The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan
| | - Mitsuru Mori
- Hokkaido Chitose College of Rehabilitation, Chitose, Japan
| | - Toshiyuki Kubo
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Sapporo Medical University, Sapporo, Japan
| | - Hiro-O Yamano
- Department of Gastroenterology and Hepatology, Sapporo Medical University, Sapporo, Japan
| | - Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University, Graduate School of Medicine, Nagoya, Japan
| | - Akiko Tamakoshi
- Department of Public Health, Hokkaido University Faculty of Medicine, Sapporo, Japan
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Insulin Receptor Substrate Suppression by the Tyrphostin NT157 Inhibits Responses to Insulin-Like Growth Factor-I and Insulin in Breast Cancer Cells. Discov Oncol 2018; 9:371-382. [PMID: 30229539 DOI: 10.1007/s12672-018-0343-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 06/25/2018] [Indexed: 12/11/2022] Open
Abstract
Insulin and insulin-like growth factor (IGF) signaling systems regulate breast cancer growth, progression, and metastasis. The insulin receptor substrates 1 and 2 (IRS1/2) transduce signaling from the type I IGF receptor (IGF-IR) and insulin receptor (InR) to mediate the biological effects of receptor activation. In breast cancer, IRS-1 plays a critical role in cancer cell proliferation while IRS-2 is associated with motility and metastasis. NT157, a small-molecule tyrphostin, downregulates IRS proteins in several model systems. In breast cancer cells, NT157 treatment suppressed IRS protein expression in a dose-dependent manner. Exposure to NT157 inhibited the activation of downstream signaling mediated by the IRS proteins. NT157 induced a MAPK-dependent serine phosphorylation of IRS proteins which resulted in disassociation between IRS proteins and their receptors resulting in IRS degradation. In estrogen receptor-α-positive (ERα+) breast cancer cells (MCF-7 and T47D), NT157 also resulted in cytoplasmic ERα downregulation likely because of disruption of an IRS-1-IGF-IR/InR/ERα complex. NT157 decreased S phase fraction, monolayer, and anchorage-independent growth after IGF/insulin treatment in ERα+ breast cancer cells. NT157 downregulation of IRS protein expression also sensitized ERα+ breast cancer cells to rapamycin. Moreover, NT157 inhibited the growth of tamoxifen-resistant ERα+ breast cancer cells. Given that both IGF-IR and InR play a role in cancer biology, targeting of IRS adaptor proteins may be a more effective strategy to inhibit the function of these receptors.
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Abstract
Early preclinical and population data suggested a role for the type I insulin-like growth factor receptor (IGF1R) in the regulation of breast cancer growth and survival. To target this pathway, multiple monoclonal antibodies and tyrosine kinase inhibitors were developed and tested in clinical trials. While some of the early clinical trials suggested a benefit for these drugs, none of the attempts showed improved outcomes when compared to conventional therapy. This failure of the IGF1R inhibitors was pronounced in breast cancer; multiple trials testing IGF1R inhibition in estrogen receptor-positive breast cancer were conducted, none showed benefit. This review will evaluate the rationale for IGF1R inhibition, discuss results of the clinical trials and suggest a path forward.
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Affiliation(s)
- Douglas Yee
- Masonic Cancer CenterUniversity of Minnesota, Minneapolis, Minnesota, USA
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15
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Adachi Y, Nojima M, Mori M, Yamashita K, Yamano HO, Nakase H, Endo T, Wakai K, Sakata K, Tamakoshi A. Insulin-like growth factor-1, IGF binding protein-3, and the risk of esophageal cancer in a nested case-control study. World J Gastroenterol 2017; 23:3488-3495. [PMID: 28596684 PMCID: PMC5442084 DOI: 10.3748/wjg.v23.i19.3488] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/25/2017] [Accepted: 04/21/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the relationship between serum levels of insulin-like growth factor-1 (IGF1)/IGF-binding protein-3 (IGFBP3) and the risk of esophageal carcinoma.
METHODS We assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective, nested case-control study of participants from the Japan Collaborative Cohort Study. A baseline survey was conducted from 1988 to 1990. Of the 110585 enrolled participants, 35% donated blood samples. Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies. A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels.
RESULTS Thirty-one cases and 86 controls were eligible for the present assessment. The molar ratio of IGF1/IGFBP3, which represents the free and active form of IGF1, was not correlated with the risk of esophageal carcinoma. A higher molar difference between IGFBP3 and IGF1, which estimates the free form of IGFBP3, was associated with a decreased risk of esophageal carcinoma (P = 0.0146), and people in the highest tertile had the lowest risk (OR = 0.107, 95%CI: 0.017-0.669). After adjustment for body mass index, tobacco use, and alcohol intake, the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma (P = 0.0150).
CONCLUSION The free form of IGFBP3, which is estimated by this molar difference, may be inversely associated with esophageal cancer incidence.
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Björner S, Rosendahl AH, Simonsson M, Markkula A, Jirström K, Borgquist S, Rose C, Ingvar C, Jernström H. Body Mass Index Influences the Prognostic Impact of Combined Nuclear Insulin Receptor and Estrogen Receptor Expression in Primary Breast Cancer. Front Endocrinol (Lausanne) 2017; 8:332. [PMID: 29234306 PMCID: PMC5712344 DOI: 10.3389/fendo.2017.00332] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 11/09/2017] [Indexed: 01/03/2023] Open
Abstract
The prognostic importance of tumor-specific nuclear insulin receptor (InsR) expression in breast cancer is unclear, while membrane and cytoplasmic localization of InsR is better characterized. The insulin signaling network is influenced by obesity and may interact with the estrogen receptor α (ERα) signaling. The purpose was to investigate the interplay between nuclear InsR, ER, body mass index (BMI), and prognosis. Tumor-specific expression of nuclear InsR was evaluated by immunohistochemistry in tissue microarrays from 900 patients with primary invasive breast cancer without preoperative treatment, included in a population-based cohort in Sweden (2002-2012) in relation to prognosis. Patients were followed for up to 11 years during which 107 recurrences were observed. Nuclear InsR+ expression was present in 214 patients (23.8%) and increased with longer time between surgery and staining (P < 0.001). There were significant effect modifications by ER status and BMI in relation to clinical outcomes. Nuclear InsR+ conferred higher recurrence-risk in patients with ER+ tumors, but lower risk in patients with ER- tumors (Pinteraction = 0.003). Normal-weight patients with nuclear InsR+ tumors had higher recurrence-risk, while overweight or obese patients had half the recurrence-risk compared to patients with nuclear InsR- tumors (Pinteraction = 0.007). Normal-weight patients with a nuclear InsR-/ER+ tumor had the lowest risk for recurrence compared to all other nuclear InsR/ER combinations [HRadj 0.50, 95% confidence interval (CI): 0.25-0.97], while overweight or obese patients with nuclear InsR-/ER- tumors had the worst prognosis (HRadj 7.75, 95% CI: 2.04-29.48). Nuclear InsR was more prognostic than ER among chemotherapy-treated patients. In summary, nuclear InsR may have prognostic impact among normal-weight patients with ER+ tumors and in overweight or obese patients with ER- tumors. Normal-weight patients with nuclear InsR-/ER+ tumors may benefit from less treatment than normal-weight patients with other nuclear InsR/ER combinations. Overweight or obese patients with nuclear InsR-/ER- tumors may benefit from more tailored treatment or weight management.
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Affiliation(s)
- Sofie Björner
- Faculty of Medicine, Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
| | - Ann H. Rosendahl
- Faculty of Medicine, Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
| | - Maria Simonsson
- Faculty of Medicine, Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
| | - Andrea Markkula
- Faculty of Medicine, Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
| | - Karin Jirström
- Faculty of Medicine, Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
| | - Signe Borgquist
- Faculty of Medicine, Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
- Clinical Trial Unit, Forum South, Skåne University Hospital, Lund, Sweden
| | - Carsten Rose
- CREATE Health and Department of Immunotechnology, Lund University, Lund, Sweden
| | - Christian Ingvar
- Department of Clinical Sciences Lund, Surgery, Lund University, Skåne University Hospital, Lund, Sweden
| | - Helena Jernström
- Faculty of Medicine, Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
- *Correspondence: Helena Jernström,
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17
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Adachi Y, Nojima M, Mori M, Matsunaga Y, Akutsu N, Sasaki S, Endo T, Kurozawa Y, Wakai K, Tamakoshi A. Insulin-like growth factor-related components and the risk of liver cancer in a nested case-control study. Tumour Biol 2016; 37:15125-15132. [PMID: 27662841 DOI: 10.1007/s13277-016-5360-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 09/07/2016] [Indexed: 12/16/2022] Open
Abstract
Insulin-like growth factor-1 (IGF1) is a potent mitogen. IGF-binding protein-3 (IGFBP3) binds and inhibits IGF1. High circulating IGF1 levels and low IGFBP3 levels are associated with increased risk of several cancers. We examined relationships between serum levels of these factors and hepatoma risk in a case-control study nested in a prospective cohort study (the Japan Collaborative Cohort Study (JACC Study)). A baseline survey was conducted from 1988 to 1990, and 39,242 subjects donated blood samples. Participants diagnosed with hepatoma by 1997 were considered cases for nested case-control studies. Ninety-one cases and 263 sex- and age-matched controls were analyzed. A conditional logistic model was used to estimate odds ratios (ORs) for the incidence of hepatoma associated with serum IGF1 and IGFBP3 levels. Neither IGF1 nor the molar ratio of IGF1/IGFBP3 was correlated with hepatoma risk. After adjustment for hepatitis viral infection, body mass index, smoking, and alcohol intake, a higher molar difference of (IGFBP3 - IGF1) was associated with a decreased hepatoma risk more than IGFBP3 alone (p for trend <0.001 and = 0.003, respectively). People in the highest quartile had a lower risk (OR = 0.098; 95 % confidence interval = 0.026-0.368). In subgroup analyses of males and females, the molar difference was associated with a decreased hepatoma risk (p for trend <0.05). In non-elderly individuals, the difference was inversely correlated with the incidence of hepatoma (p for trend <0.01). The molar difference of (IGFBP3 - IGF1) may be inversely associated with the incidence of hepatoma.
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Affiliation(s)
- Yasushi Adachi
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Japan. .,Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan.
| | - Masanori Nojima
- The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan
| | - Mitsuru Mori
- Department of Public Health, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Yasutaka Matsunaga
- Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Noriyuki Akutsu
- Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Shigeru Sasaki
- Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Takao Endo
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Japan
| | - Youichi Kurozawa
- Division of Health Administration and Promotion, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Akiko Tamakoshi
- Department of Public Health, Hokkaido University School of Medicine, Sapporo, Japan
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18
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Frago S, Nicholls RD, Strickland M, Hughes J, Williams C, Garner L, Surakhy M, Maclean R, Rezgui D, Prince SN, Zaccheo OJ, Ebner D, Sanegre S, Yu S, Buffa FM, Crump MP, Hassan AB. Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist. Proc Natl Acad Sci U S A 2016; 113:E2766-75. [PMID: 27140600 PMCID: PMC4878476 DOI: 10.1073/pnas.1513023113] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Among the 15 extracellular domains of the mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the koff value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer.
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Affiliation(s)
- Susana Frago
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Ryan D Nicholls
- Department of Organic and Biological Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
| | - Madeleine Strickland
- Department of Organic and Biological Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
| | - Jennifer Hughes
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Christopher Williams
- Department of Organic and Biological Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
| | - Lee Garner
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Mirvat Surakhy
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Rory Maclean
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Dellel Rezgui
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Stuart N Prince
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Oliver J Zaccheo
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Daniel Ebner
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom
| | - Sabina Sanegre
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Sheng Yu
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - Francesca M Buffa
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - Matthew P Crump
- Department of Organic and Biological Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom;
| | - Andrew Bassim Hassan
- Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom;
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19
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de Lint K, Poell JB, Soueidan H, Jastrzebski K, Vidal Rodriguez J, Lieftink C, Wessels LF, Beijersbergen RL. Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R. Mol Cancer Ther 2016; 15:1545-56. [DOI: 10.1158/1535-7163.mct-15-0865] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 03/26/2016] [Indexed: 11/16/2022]
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20
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Stauffer F, Cowan-Jacob SW, Scheufler C, Furet P. Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors. Bioorg Med Chem Lett 2016; 26:2065-7. [PMID: 26951750 DOI: 10.1016/j.bmcl.2016.02.074] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 02/22/2016] [Accepted: 02/24/2016] [Indexed: 11/17/2022]
Abstract
We report structure-guided modifications of the benzyloxy substituent of the Insulin-like Growth Factor-1 Receptor (IGF-1R) inhibitor NVP-AEW541. This chemical group has been shown to confer selectivity against other protein kinases but at the expense of a metabolism liability. X-ray crystallography has revealed that the benzyloxy moiety interacts with a lysine cation of the IGF-1R kinase domain via its ether function and its aromatic π-system and is nicely embedded in an induced hydrophobic pocket. We show that 1,4-diethers displaying an adequate hydrophobic and constrained shape are advantageous benzyloxy replacements. A single digit nanomolar inhibitor (compound 20, IC50=8.9 nM) was identified following this approach.
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Affiliation(s)
- Frédéric Stauffer
- Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland.
| | - Sandra W Cowan-Jacob
- Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland
| | - Clemens Scheufler
- Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland
| | - Pascal Furet
- Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland
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21
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Roland CL, May CD, Watson KL, Al Sannaa GA, Dineen SP, Feig R, Landers S, Ingram DR, Wang WL, Guadagnolo BA, Feig B, Hunt KK, Cormier JN, Lazar AJ, Torres KE. Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma. Ann Surg Oncol 2016; 23:2220-8. [PMID: 26847678 DOI: 10.1245/s10434-016-5115-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Indexed: 11/18/2022]
Abstract
BACKGROUND Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. METHODS A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome. RESULTS At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age <61 years, tumor size <10 cm, margin-negative resection, and sporadic-tumor status. At the protein level, loss of cyclin D1 (p = 0.06), pEGFR (p = 0.023), pIGF-1R (p = 0.022), and PTEN (p < 0.001) and overexpression of AXL (p = 0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA, and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS), whereas RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R. DISCUSSION Loss of cyclin D1, overexpression of AXL, and loss of PTEN are associated with poor cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and also could explain the aggressive phenotype seen in RA-UPS compared with the sporadic lesions.
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Affiliation(s)
- Christina L Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Caitlin D May
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,The University of Texas Health Science Center at Houston - Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Kelsey L Watson
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ghadah A Al Sannaa
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sean P Dineen
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rachel Feig
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sharon Landers
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Davis R Ingram
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei-Lien Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - B Ashleigh Guadagnolo
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Barry Feig
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kelly K Hunt
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Janice N Cormier
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander J Lazar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keila E Torres
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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22
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Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int 2015; 35:2203-17. [PMID: 26123841 DOI: 10.1111/liv.12903] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 06/09/2015] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and is one of the leading causes of cancer-related death. The risk factors for HCC include cirrhosis, chronic viral hepatitis, heavy alcohol intake and metabolic diseases such as obesity, type 2 diabetes and metabolic syndrome. Insulin resistance is a common denominator of all of these conditions and is tethered to hyperinsulinaemia. Here, we give an overview of the recent advances linking hyperinsulinaemia to HCC development and progression. In particular, we summarise the underlying causes of hyperinsulinaemia in the setting of chronic liver diseases. We present epidemiological evidence linking metabolic diseases to HCC risk and HCC-related mortality, as well as the pathogenic cellular and molecular mechanisms explaining this relation. A better understanding of the mechanisms by which insulin participates in HCC biology might ultimately provide novel opportunities for prevention and treatment.
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Affiliation(s)
- Hamza Chettouh
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Marie Lequoy
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,Service d'Hépatologie, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Laetitia Fartoux
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,Service d'Hépatologie, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Corinne Vigouroux
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,Laboratoire Commun de Biologie et Génétique Moléculaires AP-HP, Hôpital Saint-Antoine, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France
| | - Christèle Desbois-Mouthon
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
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23
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Chapman JAW, Costantino JP, Dong B, Margolese RG, Pritchard KI, Shepherd LE, Gelmon KA, Wolmark N, Pollak MN. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29. Breast Cancer Res Treat 2015; 153:353-60. [PMID: 26276354 DOI: 10.1007/s10549-015-3547-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 08/11/2015] [Indexed: 11/25/2022]
Abstract
NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97% of patients were ≥50 years; for B-29, 62%. MA.14 patients were 53% lymph node negative (LN-) while B-29 were 100% LN-; 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while B-29 had 53% concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100%. MA.14 patients experienced 5-year DFS of 80% with TAM, 76% with TAM + OCT; B-29 patients had 5-year DFS of 88% for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81-1.20; p = 0.69): for MA.14, HR = 0.94 (0.73-1.20; p = 0.50); for B-29, HR = 1.09 (0.80-1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81-1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin-IGF-I receptor family with less toxic therapeutics.
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Affiliation(s)
- Judith-Anne W Chapman
- NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON, K7L 3N6, Canada,
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