Polyamine blockade promotes antitumor immunity

Abstract

The levels of polyamines are elevated in neoplastic lesions as compared with normal tissues, and cancer cells tend to manifest a robust dependence on these compounds for proliferation and survival. We have recently demonstrated that a novel approach to polyamine depletion suppresses tumor growth in a T cell-dependent manner, highlighting a poorly appreciated role of polyamines as strong modulators of antitumor immune responses.

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

“…In summary, numerous reports in the literature describe roles for polyamines in PDAC growth, its microenvironment, desmoplasia and the immune response. Combination therapies, which reduce polyamine levels, have been shown to slow tumor growth and enhance the immune response . Lastly, this area is ripe for drug discovery and future success in designing efficient polyamine‐targeting therapies could have broad applications in many human diseases, which rely on polyamines for growth and intercellular communication …”

“…Since polyamines can be both biosynthesized and imported into cancer cells, a combination therapy of a polyamine biosynthesis inhibitor ( e.g ., DFMO) and a polyamine transport inhibitor (PTI) is required for efficient, sustained intracellular polyamine depletion. Polyamine depletion is expected to have dramatic consequences for the tumor, stroma and the overall immune response …”

“…Polyamine depletion is expected to have dramatic consequences for the tumor, stroma and the overall immune response. 10,11 A combination therapy of both biosynthesis and transport inhibitors is needed because DFMO treated cells are readily rescued by uptake of exogenous polyamines. While inhibitors of polyamine biosynthesis like DFMO are well known, efficient inhibitors of polyamine transport are less established and can vary in design.…”

“…Prior research has suggested that pancreatic cancers are addicted to polyamine growth factors and that inhibition of polyamine metabolism may constitute a viable treatment for these cancers . Polyamines play key roles in processes associated with tumor growth, spread and survival including translation, transcription, chromatin remodeling, autophagy, metastasis, tumorigenesis, immune privilege and formation of eIF5A . Because the native polyamines (putrescine, spermidine and spermine, Fig.…”

Dietary Polyamines and Diseases: Reducing Polyamine Intake Can Be Beneficial In Cancer Treatment

“…A polyamine blocker therapy applied to explore the role of tumor-associated polyamines as immunosuppressive metabolites in oncogenesis and tumor progression and resulted that the applied therapy did not only block tumor growth but also promoted anticancer immune responses [79]. In prostate cancer patients it was shown that the reduction of dietary polyamine intake and partial intestinal decontamination was beneficial for patient quality of life and pain control [80].…”