Targeting cellular senescense in pancreatic cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Cellular senescence is a stress response that imposes a growth arrest on cancer and nonmalignant cells during cancer progression and/or therapy. Although senescence is known to play a tumor suppressive role, studies have also demonstrated the tumor-prompting functions of senescent cells in the tumor microenvironment (TME). Recent evidence suggests that the malignant behavior of pancreatic ductal adenocarcinoma (PDAC) is influenced by a senescent cell-associated, strongly immunosuppressive TME. Cancer associated fibroblasts are responsible for a desmoplastic reaction surrounding tumor glands in PDAC. Pro-fibrotic senescent fibroblasts thicken and stiffen the extracellular matrix; such desmoplastic stiffening impedes immune infiltration and drug delivery. By secreting a plethora of proinflammatory growth factors collectively termed the senescence- associated secretory phenotype (“SASP”), senescent cells can promote cancer progression and metastasis. Moreover, the SASP molecules are shown to drive therapy resistance and mediate the adverse effects of cancer therapies. Hence, we hypothesize that depletion of senescent and pro-fibrotic cells in PDAC could lead to the remodeling of tumor microenvironment and antitumor activity. In this project we propose to determine the biological effects of a senescent cell targetd antibody, SIWA318, and determine its activity in improving the efficacy of standard of care chemotherapy or immune checkpoint inhibitors (ICIs) in preclinical models for PDAC. To achieve this goal, we will conduct studies with the following specific aims: 1) to determine the biological effects of SIWA318 treatment on TME in mouse models for PDAC and 2) to determine the antitumor activity and biological effects of SIWA318 in combination with standard of care agents or an ICI in mouse models for PDAC. The overall goal of this project is to develop a senescent cell targeted new therapeutic that improves the efficacy of current standard care agents or ICIs in PDAC. If successful, it will lead to novel therapies for patients with PDAC and validate the approach of targeting senescence cells for cancer treatment, opening the door for more effective therapies for other cancer types.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is the third leading cause of cancer-related deaths in the United States, with a 5-year survival rate of about 13%. We seek to develop a novel antibody therapy that targets senescent cells within pancreatic tumors to enhance the activity of current standard of care therapy and an immune checkpoint inhibitor. The results generated from this project will validate the approach of targeting senescent cells in pancreatic cancer and have the potential to directly benefit patients by improving the treatment of their disease.