Abstract PL06-03: Urokinase plasminogen activator system: A multifunctional drug target.
Authors: Harbeck Nadia 
Published: June 2012

The plasminogen activator system with its components uPA (urokinase-type plasminogen activator), its type 1 inhibitor PAI-1, and the uPA-receptor (uPAR), plays a key role in tumor invasion and metastasis. Elevated levels of one or several of these factors have been associated with tumor aggressiveness and poor disease outcome in a variety of solid tumors such as breast cancer, gynaecological (i.e. ovarian, endometrial or cervical cancer) and urological (i.e prostate, kidney, bladder) malignancies, GI cancers (e.g. stomach, colorectal, pancreas), and many other solid tumors.

In primary breast cancer, uPA and PAI-1 have achieved the highest level of evidence (LOE I) for their prognostic impact based on a meta-analysis in more than 8,000 patients as well as the prospective randomised Chemo N0 trial with 10-year follow-up. Low levels of uPA and PAI 1, as measured by ELISA in tumor tissue extracts, are associated with such good outcome that these patients may be spared adjuvant chemotherapy as recommended by international guidelines (AGO, ASCO). Patients with high levels of either or both factors derive enhanced benefit from adjuvant chemotherapy. Two additional prospective clinical trials (NNBC-3, Plan B) using the uPA/PAI-1 assay have been completed in early breast cancer, randomizing about 7,000 patients.

Next to its value as a prognostic or predictive cancer biomarker, uPA is obviously also an interesting drug target given its clinical relevance in many solid tumors. Two small synthetic uPA inhibitors (WX-UK-1, WX-671) have successfully completed phase I evaluation. Two phase II trials with the oral compound WX-671 have recently been completed in pancreatic and breast cancer. In locally advanced, inoperable, non-metastatic pancreatic cancer (n=75), a randomised open label trial compared two different WX-671 doses together with gemcitabine vs. gemcitabine alone. Compared to chemotherapy alone, the combination of gemcitabine plus 400 mg WX-671 daily led to an increase in response (3.8 vs. 12.9%), 1 year PFS (16.2 vs. 26.9%) and 1 year OS (33.9 vs. 50.6%) rates. No specific toxicities were observed. In first line metastatic breast cancer, oral WX-671 (200 mg daily) or placebo were administered together with capecitabine (1000mg/m2 BID d1–14 q21) in more than 100 patients. This trial is currently collecting follow-up results. An uPA-derived peptide (Å6) is also being explored as a cancer therapeutic. No safety issue were reported from phase I evaluation. First phase II evidence showed an increase in TTP compared to placebo in ovarian cancer patients; results of a second trial (GOG 170N) are still pending.

Taken together, uPA/PAI-1 has a validated clinical utility as prognostic markers in early breast cancer. Given its key role in tumor progression, the uPA system remains an interesting drug target. Early clinical trials interfering with this system have shown good tolerability of the compounds and some very promising clinical data which now need to be validated

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL06-03.