Virginia Metrangolo

Name: Virginia Metrangolo

Nationality: Italian

Academic Background: M.Sc. Medical biotechnology and Nanobiotechnology, University of Salento (Lecce), Italy

Project Title: Toward the development of dual mechanistic antibody-drug conjugates for targeting the urokinase receptor in pancreatic cancer

Project Background/ (why should audience care about my research)? Pancreatic cancer is one of the most lethal malignancies, with a 5-year survival rate of only 6%, limited treatment options and a continuously rising incidence rate. This poor prognosis is mainly attributed to the highly aggressive nature of the disease which typically metastasize to adjacent organ at early stages. As a result, only about 25% of patients are surgical candidates at the time of diagnosis, while most of them (80-90%) present with metastatic unresectable disease and must be treated with systemic chemotherapy regimens, which are still largely ineffective in improving patient survival. One of the main factors contributing to chemotherapy failure in pancreatic cancer is the tumor microenvironment (TME) surrounding the neoplastic mass which is strongly immunosuppressive and remarkably characterized by the so called “desmoplastic reaction”. This consists in a dense deposition of “extracellular matrix” (ECM) by specialized cells within the TME called cancer-associated fibroblast. The extracellular matrix is a complex three-dimensional network of non-cellular components released by resident cells within a tissue, where it provides structural support and integrity. It has a tissue-specific composition arising though a dynamic, constant remodeling process occurring during tissue development. It also actively contributes to the function of the tissue it-self and regulates important cellular processes (e.g. growth, differentiation, migration and tissue repair) by promoting cell-to-cell communication. As such, the extracellular matrix also plays an essential role in cancer providing a structural and biochemical “niche” for tumor growth and progression. As a result, most solid tumors are associated to increased ECM deposition with pancreatic cancer providing a representative extreme example. Due to its ability to act as a biophysical barrier to therapeutic agents, the excessive ECM deposition occurring in pancreatic cancer has been recognized as one of the major contributor to therapy resistance. Overall, this scenario underscores an urgent unmet need for novel more effective treatment options with higher specificity for relevant pancreatic tumor-driving targets. An attractive targeted approach that has not yet been explored in pancreatic cancer treatment involves the use of antibody-drug conjugates or ADCs. This emerging class of anticancer therapeutics consists of tumor-selective antibodies that like “magic bullets” provide selective delivery of highly potent cytotoxic drugs to antigen-expressing cells within the tumor, with the benefit of enhanced selectivity and efficacy, and reduced off-target systemic toxicity compared to conventional chemotherapy. One of the crucial factors in the design and development of effective ADCs is the target choice as it substantially contributes to their anti-tumor activity and tolerability. An ideal ADC target must be selectively and homogeneously expressed at high density on the cell surface of tumor cells, with limited or no expression in normal tissues to minimize off-target side-effects. Typical ADCs targets are cell surface receptors with tumor-promoting roles and able to internalize extracellular cargos, thereby allowing ADCs intracellular uptake and toxin release within the targeted cells.

Project Aim: The aim of the present project is the preclinical development and testing of a novel targeted therapeutic strategy for pancreatic cancer. This will be based on antibody drug conjugates targeting a receptor called urokinase receptor or uPAR which has been recognized as an attractive therapeutic target for aggressive tumors due to its central role in tumor invasion and metastasis. Consistently, it is strongly upregulated in most cancers where it is frequently associated to poor patient survival and outcome. This is also the case of pancreatic cancer, where uPAR appears to be heterogeneously expressed by both cancer and stromal cells in the tumor microenvironment. For this reason, in my project, we will try to implement a dual mode of action strategy to achieve efficient tumor eradication: one hand, uPAR-positive cells (either cancer or stromal cells) will be directly targeted by our anti-uPAR ADCs; on the other hand, the ADCs properties will be adjusted to achieve efficient killing of adjacent cancer cells in a target independent manner. This phenomenon is known as “bystander effect” as it implies toxin diffusion from the ADC-targeted cells into surrounding or “bystander” cancer cells which may or may not express the target antigen, leading to cell death.

Expected Outcome:  In addition to advance the challenging field of pancreatic cancer therapy and provide novel insights into ADCs based anti-cancer therapeutics, this project is also expected to further validate the therapeutic relevance of targeting the urokinase receptor for the treatment of aggressive cancers, like pancreatic cancer. Also, the possibility to target uPAR-positive tumor-associated cells which play a critical role in pancreatic cancer progression and resistance to therapy, may lead to enhanced antitumor activity, and enable combinatorial approaches with conventional therapies or immunotherapy approaches with the potential to improve patient clinical outcome and survival.

Contact:  virginia.metrangolo@bric.ku.dk