1144O - Osteopontin (OPN) predicts the efficacy of anti-angiogenic therapy with multikinase inhibitors (MKIs) in advanced neuroendocrine tumors (NETs): Underlying molecular mechanisms

Background

Angiogenesis plays an important role in NET development and progression. Axitinib significantly improved overall response rate and progression free survival (PFS) in advanced extra-pancreatic NETs (EP-NETs). However, the magnitude of the benefit was limited. We have recently described a 3-gene signature (SPP1, REXO1L2P and ATXN7) predictive of response to axitinib in NET patients (A. Lens et al, ENETS 2023). Here, we validate the signature in plasma samples and characterize the resistance mechanisms to MKIs driven by SPP1 gene encoding for OPN in NET cell lines.

Methods

Signature discovery was performed using gene expression data from 126 patients with NETs included in the AXINET randomized double-blind placebo-controlled phase 3 trial, that assessed axitinib in EP-NETs. OPN predictive capacity was validated by ELISA in plasma samples from 193 patients from the AXINET trial and in an external cohort of 51 patients treated with MKIs or somatostatin analogs (SSAs). Finally, OPN was overexpressed in NET cell lines and functional assays were performed in vitro.

Results

We identified a 3-gene signature (ATXN7, REXO1L2P, SPP1) that significantly predicted PFS (HR=0.31; p=0.0003) in axitinib-treated patients. Moreover, low OPN plasma levels were associated with improved PFS (HR=0.41; p=0.0016). The signature was validated in an external cohort of 51 tumor samples from patients treated with MKIs at our institution (HR=0.00014; p=0.05). On the contrary, neither the tumor signature nor OPN plasma levels were associated with PFS in placebo/SSA-treated patients. Pathway analysis identified enrichment of epithelial-mesenchymal transition (EMT), hypoxia, and PI3K-AKT in low signature patients. OPN overexpression significantly increased proliferation, clonogenicity and migration of NET cell lines through the PI3K-Akt pathway. Functional assays with conditional knockout cell lines are ongoing as well as in vivo studies.

Conclusions

We have validated the 3-gene signature and OPN as predictive biomarkers of antiangiogenic MKIs efficacy in NET patients. Moreover. OPN promotes resistance to MKI by enhancing proliferation and migration capacities of NET cells.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Instituto de Investigación Sanitaria Hospital 12 de Octubre.

Funding

Pfizer.

Disclosure

E. Grande: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, Ipsen, Janssen, Lilly, Merck KGa, Pfizer, Roche, Dr. Reddy's, Adium; Financial Interests, Personal, Advisory Board: Astellas, Bayer, MSD, Novartis, Sanofi-Genzyme; Financial Interests, Institutional, Advisory Board: Caris Life Sciences, ONCODNA (Biosequence); Financial Interests, Institutional, Research Grant, Independent research grant: Astellas, AstraZeneca, Lexicon, MTEM/Threshold, Nanostring Technologies, Pfizer, Roche, Merck; Financial Interests, Institutional, Coordinating PI, Independent research grant: Ipsen; Non-Financial Interests, Other, Ad Board Member: ENETS; Non-Financial Interests, Member of Board of Directors: GETNE, GUARD Consortium, Grupo centro de Tumores Genitourinarios. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Astellas, Bayer, BMS, Boehringer Ingelheim, Esteve, Hutchmed, Ipsen, Midatech Pharma, MSD, Novartis, PharmaMar, Servier, Takeda; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Chair elect: European Neuroendocrine Tumor Society (ENETS); Non-Financial Interests, Leadership Role, Past presidente, Member of the Executive Committee: Grupo Español de Tumores Neuroendocrinos (GETNE); Other, Honoraria received by spouse for advisory board or invited speaker roles: Abbie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. All other authors have declared no conflicts of interest.