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Sarcoma Biology & 'Omics

(P 349) THE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR-ASSOCIATED PROTEIN (UPARAP) IS AN ATTRACTIVE TARGET FOR THE DEVELOPMENT OF ANTIBODY DRUG CONJUGATES FOR TREATMENT OF MESENCHYMAL MALIGNANCIES

Location: The Liffey, Level 1
Objective: Urokinase plasminogen activator receptor-associated protein (uPARAP) is an endocytic receptor expressed at low levels on selected mesenchymal cell types, which internalizes fragments of collagen and transfers them to the lysosome for degradation. Besides its physiological role, uPARAP is considered a critical modulator of the tumor microenvironment. The aim of the study was to explore the molecular epidemiology of uPARAP in sarcoma tissue to validate this receptor as potential target for the development of antibody drug conjugates (ADCs) in this indication.

Methods: uPARAP expression was assessed by immunohistochemistry in soft tissue and bone sarcoma specific tissue microarrays with specimens from more than 400 individual donors. Expression was scored by a dedicated sarcoma pathologist based on staining intensity (score 0-3) and percentage of uPARAP-positive tumor cells. Tumors were grouped into high, low and negative uPARAP expressing subgroups.

Results: uPARAP was found to be strongly over-expressed in a high percentage of cases of common STS, with variations in terms of incidence and level of expression between histological subtypes. High uPARAP expression (intensity score 2 or 3 and >50% positive tumor cells) was found in bone sarcoma (93% of cases), fibrosarcoma (86%), dermatofibrosarcoma protuberans (85%), synovial (82%), pleomorphic lipo- (67%), dedifferentiated lipo- (65%), myxofibro- (59%), leiomyo- (49%), and myxoid / round cell liposarcoma (25%). Work is ongoing in additional sarcoma subtypes.

Conclusion: Based on protein expression uPARAP is an attractive emerging therapeutic target for the development of uPARAP-binding ADCs in a broad range of mesenchymal malignancies. In addition, expression of uPARAP in STS may serve as a potential marker for patient selection in early clinical studies with uPARAP-targeting ADCs.