title: Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in Colorectal Cancer.
abstract: VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future.
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK; Centre d'Immunologie Pierre Fabre, 5 Avenue Napoléon III, 74160 Saint-Julien-en-Genevois, France.
authors.forename: Aurélien J C
authors.initials: AJ
authors.lastname: Pommier
authors.affiliation: Cancer Research Technology, Angel Building, St. John Street, London EC1V 4AD, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Farren
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Bhavika
authors.initials: B
authors.lastname: Patel
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Wappett
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Filippos
authors.initials: F
authors.lastname: Michopoulos
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Smith
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Kendrew
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Frith
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Huby
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Eberlein
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Campbell
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Womack
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Robertson
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Shethah
authors.initials: S
authors.lastname: Morgan
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Critchlow
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. Electronic address: simon.t.barry@astrazeneca.com.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D015992:Body Mass Index; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D020738:Leptin / Q000494:pharmacology* / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000097:blood / Q000188:drug therapy; D051379:Mice; D008820:Mice, Obese; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D059467:Transcriptome; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D020738:Leptin; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C500926:cediranib; D007211:Indoles