A serum metabolomic fingerprint of bevacizumab and temsirolimus combination as first-line treatment of metastatic renal cell carcinoma.

Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE

Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.

Angiogenesis Inhibitors/*therapeutic use ; Antineoplastic Agents/*therapeutic use ; Bevacizumab/*therapeutic use ; Carcinoma, Renal Cell/*drug therapy ; Kidney Neoplasms/*drug therapy ; Serum/*metabolism ; Sirolimus/*analogs & derivatives; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Renal Cell/blood ; Carcinoma, Renal Cell/metabolism ; Female ; Humans ; Indoles/therapeutic use ; Interferon-alpha/metabolism ; Kidney Neoplasms/blood ; Kidney Neoplasms/metabolism ; Male ; Metabolome/physiology ; Middle Aged ; Pyrroles/therapeutic use ; Sirolimus/therapeutic use ; Sunitinib ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism

Background: Renal cell carcinoma is one of the most chemoresistant cancers, and its metastatic form requires administration of targeted therapies based on angiogenesis or mTOR inhibitors. Understanding how these treatments impact the human metabolism is essential to predict the host response and adjust personalised therapies. We present a metabolomic investigation of serum samples from patients with metastatic RCC (mRCC) to identify metabolic signatures associated with targeted therapies.
Methods: Pre-treatment and serial on-treatment sera were available for 121 patients participating in the French clinical trial TORAVA, in which 171 randomised patients with mRCC received a bevacizumab and temsirolimus combination (experimental arm A) or a standard treatment: either sunitinib (B) or interferon-α+bevacizumab (C). Metabolic profiles were obtained using nuclear magnetic resonance spectroscopy and compared on-treatment or between treatments.
Results: Multivariate statistical modelling discriminates serum profiles before and after several weeks of treatment for arms A and C. The combination A causes faster changes in patient metabolism than treatment C, detectable after only 2 weeks of treatment. Metabolites related to the discrimination include lipids and carbohydrates, consistently with the known RCC metabolism and side effects of the drugs involved. Comparison of the metabolic profiles for the three arms shows that temsirolimus, an mTOR inhibitor, is responsible for the faster host metabolism modification observed in the experimental arm.
Conclusions: In mRCC, metabolomics shows a faster host metabolism modification induced by a mTOR inhibitor as compared with standard treatments. These results should be confirmed in larger cohorts and other cancer types.

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0 (Angiogenesis Inhibitors)
0 (Antineoplastic Agents)
0 (Indoles)
0 (Interferon-alpha)
0 (Pyrroles)
2S9ZZM9Q9V (Bevacizumab)
624KN6GM2T (temsirolimus)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
V99T50803M (Sunitinib)
W36ZG6FT64 (Sirolimus)

Date Created: 20150916 Date Completed: 20160128 Latest Revision: 20240324

20240324

PMC4647878

10.1038/bjc.2015.322

26372698