Protein-protein interaction and interference of carcinogenesis by supramolecular modifications.

Protein-protein interactions (PPIs) are essential in normal biological processes, but they can become disrupted or imbalanced in cancer. Various technological advancements have led to an increase in the number of PPI inhibitors, which target hubs in cancer cell's protein networks. However, it remains difficult to develop PPI inhibitors with desired potency and specificity. Supramolecular chemistry has only lately become recognized as a promising method to modify protein activities. In this review, we highlight recent advances in the use of supramolecular modification approaches in cancer therapy. We make special note of efforts to apply supramolecular modifications, such as molecular tweezers, to targeting the nuclear export signal (NES), which can be used to attenuate signaling processes in carcinogenesis. Finally, we discuss the strengths and weaknesses of using supramolecular approaches to targeting PPIs.

RAGE Signaling in Melanoma Tumors.

Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with very poor prognosis. Emerging evidences suggest that the receptor for advance glycation end products (RAGE) plays a key role in melanoma progression through its activation in both cancer and stromal cells. In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated. Here, we provide a review of the current role of RAGE in melanoma and conclude that targeting RAGE in melanoma could be an approach to improve the outcomes of melanoma patients.

Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy.

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.

Of immune checkpoint maladies and remedies: The throwing of jabs in the oncogenic ring of PDAC.

The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells, the enhancement of Tregs-mediated trogocytosis that contribute delayed maturation of antigen presenting cell (APC), and the high Tregs/CD+8 ratio that maintained low threshold of CD+8 cells in the tumor microenvironment (TME); all represent the nuances in the immune evasive strategies of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most aggressive type of pancreatic cancers characterized by poor prognosis and extremely low survivability. Over the years, fraternity of scientists have developed therapeutic agents that can bolster the capacity of the antitumor immunity, usually via the inhibition of immune checkpoints. While this immune checkpoint inhibition therapy represents one major jab from immunity to PDAC, this cancer remains highly resistant due to the acme of desmoplasia in its TME. In this review, we discuss the mechanisms of various checkpoint receptors/ligands axes that are relevant to the fitness of PDAC in its oncogenic ring. These checkpoints include PD-1, CTLA-4, ICOS, TIM-3, TIGIT, BTLA, BTN3A, and VISTA. In addition, we provided evidences that are relevant to the understanding of immune checkpoint inhibition, with extensive outline of immune checkpoint inhibitors that are critical to the treatment of PDAC. Finally, we discuss recently known intricacies of PDAC-mediated immunosuppression, and current advances in treatment options. Having realized that the overall scenario between PDAC and antitumor immunity is like the throwing of jabs in a ring, we therefore discuss future directions and prospect that can knock out PDAC in favor of immunity and humanity.