Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Cancer-associated cachexia is a debilitated syndrome that has a dramatic impact on the quality of life and outcome of patients. Cancer cachexia occurs with a remarkably high incidence in pancreatic ductal adenocarcinoma (PDAC) patients. Cancer cachexia is characterized by the progressive depletion of muscle skeletal mass, which often culminates in general organ dysfunction and patient death. Therefore, a deeper understanding of the underlying mechanisms of cancer cachexia would ultimately lead to the identification of innovative therapeutics to improve the management of muscle wasting in cancer patients. Our recent studies have shown that pancreas-specific ablation of the Tgif1 gene in a KrasG12D background led to a dramatic acceleration of PDAC in mice. Quite intriguingly, despite having this severe PDAC phenotype, these mice do not display any prominent sign of cancer cachexia, such as progressive weight loss and decreased muscle mass and function. This contrasts with our previous study using two different mouse models of human PDAC, KPC (KrasG12D and heterozygous deletion of Trp53) and KICLuc (KrasG12D and homozygous deletion of p16Ink4a), which consistently manifest severe cancer cachexia during PDAC progression. These findings hint at the possibility that TGIF1 might function in PDAC cells to initiate events that culminate in muscle cachexia. In efforts to probe this possibility, we generated a new mouse model that allows for conditional overexpression of Tgif1, and found that enforcing TGIF1 expression in the pancreatic epithelium was sufficient to induce muscle cachexia. Subsequent mechanistic experiments revealed an ability of TGIF1 to induce expression of FN14, which functions as a transmembrane receptor in cancer cells to drive inflammation leading to muscle cachexia. Enforced TGIF1 expression also induced the expression of the membrane-bound form of transforming growth factor alpha (TGFa), whose overexpression in the pancreas also drives an inflammatory phenotype similar to what we observed in mice with conditional overexpression of TGIF1. Inspired by these intriguing findings, we created a new bispecific antibody (Bis-14a) to simultaneously neutralize the pro-cachectic activities of FN14 and TGFa. This tremendous progress prompted us to design a variety of innovative genetic and antibody-based pharmacological approaches to provide irrefutable proof-of-principle that targeting FN14 and TGFa downstream of TGIF1 could offer innovative therapeutic strategies to curb cancer cachexia. Overarching specific aims are: Specific Aim 1: Expand role and translational potential of TGIF1 in PDAC-driven muscle cachexia Specific Aim 2) Explore the mechanisms by which TGIF1 facilitates PDAC-driven muscle cachexia Specific Aim 3) Test the therapeutic efficacy of monoclonal and bispecific antibodies targeting FN14 and TGFa signaling in PDAC-mediated muscle cachexia As such, completion of this highly innovative proposal will likely culminate in a paradigm shift in our understanding and treatment of this lethal wasting syndrome.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).