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Several studies have reported the health-beneficial effects of dietary phytochemicals, namely polyphenols, to prevent various diseases, including cancer. Polyphenols, like (-)-epigallocatechin-3-gallate (EGCG) from green tea, curcumin from turmeric, and ellagic acid from pomegranate are known to act by modulating antioxidant, anti-inflammatory and apoptotic signal transduction pathways in the tumor milieu. The evolving literature underscores the role of epigenetic regulation of genes associated with cancer by these polyphenols, primarily via non-coding RNAs (ncRNAs), such as microRNAs (miRNA) and long noncoding RNA (lncRNA). However, there is little clarity on the exact role(s) played by these ncRNAs and their interactions with other ncRNAs, or with their protein targets, in response to modulation by these dietary polyphenols. Here, we review ncRNA interactions and functional networks of the complex ncRNA interactome with their targets in preclinical studies along with the role of epigenetics as well as key aspects of pharmacokinetics and phytochemistry of dietary polyphenols. We also summarize the current state of clinical trials with these dietary polyphenols. Taken together, this synthetic review provides insights into the molecular aspects underlying the anticancer chemopreventive effects of dietary polyphenols as well as summarizes data on novel biomarkers modulated by these polyphenols for preventive or therapeutic purposes in various types of cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplasia which contributes to poor prognosis by hindering tumor entry of immune cells and therapeutics. This leads to PDAC being difficult to treat with gemcitabine, a current standard-of-care, with only a 22% 12-month survival rate. Therapeutic modalities are needed to tackle the PDAC tumor microenvironment (TME). An alternative target is polyamine metabolism which is required for tumor growth, survival, metastasis, and also for modulating generation, survival, and activity of immune cells. Myeloid-derived suppressor cells (MDSCs) are immune cells that have a key role in PDAC metastasis, invasion, progression, and in impeding anti-tumor immune response to therapeutics in PDAC. MDSCs include monocyte-like (M-MDSC) and neutrophil-like (PMN-MDSC) cells. Previous studies have shown that polyamine blockade therapy (PBT), consisting of difluoromethylornithine (DFMO) to block polyamine biosynthesis and a polyamine transport inhibitor (Trimer44NMe), elicits anti-tumor immune response, improved survival, and a decrease in MDSCs in other tumor types. This is of interest given our previous findings that PBT improved survival of PDAC-bearing mice. Here, we tested PBT in altering PDAC-stimulated MDSC survival and whether it shifts their immunosuppressive phenotype. Studies were conducted using CD11b+ bone marrow cells that were differentiated into MDSCs via GM-CSF and tumor-conditioned media from PDAC cells derived from a genetic mouse model for pancreatic cancer (KPC-mice). Bulk RNA-sequencing was conducted on MDSCs treated with PBT, gemcitabine or combination. MDSCs exhibited widespread downregulation of expression in the gemcitabine and combination treatment, but PBT alone exhibited more targeted downregulation. Specifically, Gene Ontology (GO) analysis revealed a decrease in genes associated with immune cell migration and chemotaxis, and KEGG analysis showed downregulation of inflammatory pathways. These findings indicate that PBT may modify MDSCs from their tumor-associated immunosuppressive and pro-inflammatory behavior. MDSC subtype-specific markers were investigated by flow cytometry. Results show subsets of immune cells, such as PMN-MDSCs, are reduced upon PBT treatment alone or in combination with gemcitabine, thereby highlighting the dependence of this subtype on polyamine metabolism. In conclusion, PBT alters the expression of MDSC immunomodulatory genes, decreases MDSC survival and supports the use of PBT for treatment of PDAC in combination with other immunomodulatory therapeutics. Citation Format: Joseph A. Goode, Sai Preethi Nakkina, Manav Gandhi, Otto Phanstiel, Deborah A. Altomare. Polyamine blockade therapy: A strategy to block immunosuppression in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4503.

Malignant mesothelioma (MM) is a cancer of the mesothelial lining of the pleura, peritoneum, pericardium and testes. The most common form is asbestos-linked MM that is etiologically linked to repeated asbestos exposure with a long latency period, although non-asbestos MM has also been reported. Late diagnosis, poor survival rates, lack of diagnostic and prognostic markers act as major impediments in the clinical management of MM. Despite advances in immune checkpoint inhibition and CAR T-cell-based therapies, MM which is of different histologic subtypes remains challenging to treat. We review microRNAs (miRNAs) and the miRNA interactome implicated in MM which can be useful as circulating miRNA biomarkers for early diagnosis of MM and as biomarkers for prognostication in MM. Further, we underscore the relevance of the NRF2/MAPK signal transduction pathway that has been implicated in MM which may be useful as druggable targets or as biomarkers of predictive response. In addition, since MM is driven partly by inflammation, we elucidate chemopreventive phytochemicals that are beneficial in MM, either via crosstalk with the NRF2/MAPK pathway or via concerted anticancer mechanisms, and may be of benefit as adjuvants in chemotherapy. Taken together, a multifactorial approach comprising identification of miRNA target hubs and NRF2/MAPK biomarkers along with appropriately designed clinical trials may enable early detection and faster intervention in MM translating into better patient outcomes for this aggressive cancer.