e21171 Background: The RAS is known for regulation of blood pressure. However, an activated RAS also supports tumor growth, in particular by its effector peptide Ang II. Elevated Ang II levels were found in plasma and malignant effusions of cancer patients (Samonigg et al. ASCO 2010). We have developed a sensitive LC-MS method to quantify plasma levels of all relevant peptides of the RAS. Utilization of this method for analysis of plasma of cancer patients, resulting in a "RAS peptide fingerprint" gives insight into the activation pattern of the RAS and may be utilized as guidance for novel therapies that re-balance an activated RAS, thereby reverting a tumor growth-promoting environment.

METHODS: A sensitive method based on LC-MS was developed to quantify Ang peptides and metabolites in plasma in a single run. Plasma was obtained from various patients with solid cancers in advanced stage and levels of Ang I, Ang II, Ang III, Ang IV, Ang1-9, Ang1-7, Ang2-7, Ang3-7 and Ang1-5 assessed. Respective results found in 21 healthy volunteers served as comparison.

RESULTS: In all analysed cancer patients (n%%%equ%%) an activated RAS was seen. Substantially elevated Ang peptide plasma levels were found (in pg/ml): Ang I: mean 1.900, range 90-12.000 (mean healthy 17); Ang II: mean 350, range 5-2.100 (mean healthy 8); Ang1-9: mean 22, range 3-160 (mean healthy 3) Ang1-7: mean 45, range 5-250 (mean healthy 3); Ang1-5: mean 23, range 2-120 (mean healthy 2).

CONCLUSIONS: Ang peptide levels in cancer patients were massively elevated when compared to healthy controls (up to 100-fold). Highly elevated levels were found for the effector peptide Ang II and its precursor Ang I, indicating overactivity of Renin and ACE. Degradation products of Ang II such as Ang1-7 and Ang1-5 were also elevated. Interestingly, the activation of the RAS did not have obvious impact on blood pressure. Based on these results, a novel therapeutic modality against cancer may consist in re-balancing an activated RAS. In this regard, treatment of cancer patients with recombinant human ACE2 (which efficiently degrades Ang II to Ang1-7 and is in clinical development against diseases with an imbalanced RAS) may be considered.

CONCLUSION: As shown by the significant influence of metastatic sites, some P die from their advanced systemic disease situation before they would experience cerebral progression, in part explaining the influence of systemic treatment. In other individuals however, intensified local treatment and systemic treatment appear to influence both cTTP and OS significantly, implicating a direct influence of systemic therapy on BM. This might result from an impaired blood brain barrier around metastatic sites, making sufficient tissue concentrations of cytotoxic agents possible. No significant financial relationships to disclose.

TREATMENT: Rx 375 mg/m(2) IV at day 1; concomitant therapy: Rasburicase, steroids only for anaphylaxis, intrathecal (IT) triple drug at days 1, 3 for CNS pts only. Begin of chemotherapy at day 5. Response evaluation: product of 2 perpendicular diameters of 1 - 3 index lesions/% blasts in BM/PB within 24 h prior to Rx and at day 5: responder (RP): at least 1 lesion with at least objective effect (decrease of ≥25%) and no progress (increase of ≥25 %) at other sites. Study plan: Simon 2-stage phase II with α and β = 5%. Response rate (RR) for poor activity was set to 45%, for good activity 65%. 33 pts entered the first stage, final evaluation after 79 pts.