Pancreatic ductal adenocarcinoma (PDA) accounts for more than 90% of pancreatic cancer cases, and it is one of the most aggressive malignancies with a 5-year survival rate of 6%. The high mortality rate caused by PDA is primarily from the lack of early diagnosis – it is often asymptomatic in early stages – and a poor response to conventional chemotherapy and radiotherapy. One of the major immune cell types present in the PDA microenvironment is a subset of macrophages commonly termed tumor-associated macrophages (TAM). TAMs originate, in part, from circulating monocytes upon activation by CCL2, a chemotactic chemokine secreted and then recruited to the tumor microenvironment by cytokines expressed by PDA cells.
TAMs consist primarily of polarized M2 macrophages which promote tumor growth by secreting immunosuppressive factors that block effector T-cell activation. TAMs express scavenger receptors such as CD206 which facilitate tumor angiogenesis and migration. CD206 is a member of the large C-type lectin receptor family and not found on other TAM population like undifferentiated M0 or M1-like macrophages. CD206high expression and infiltration with CD206high macrophages has been associated with poor clinical outcomes in pancreatic cancer and other solid organ cancers. Current anti-macrophage therapy generally inhibits activation or the recruitment of macrophages (CCL2/CCR2), which lacks specificity towards M2-like macrophages, agonism of M1 signaling via CD40 ligation, or blockade of the CD47-SIRP ‘do-not-eat’ cancer phagocytosis checkpoint.
Researchers at the National Cancer Institute (NCI) have discovered a small molecule that binds to CD206 and induces M2-to-M1 reprogramming, cancer cell phagocytosis and M2 cell death. The anti-CD206 small molecule was identified through structure-based pharmacophore modeling and in silico screening of the anti-cancer peptide, RP-182 (NIH Reference Number: E-242-2015.) The activity of this CD206 small molecule modulator was confirmed in vitro and in vivo across a number of different solid organ cancer models. In addition to its reprogramming function to a M1 mechanism, a selective reduced cell viability was observed in human CD206high M2-like macrophages derived from healthy volunteers compared with M1 control macrophages. This new small molecule immunomodulator will be the first-in-class that will have application in selectively targeting M2 macrophages – a pro-tumor immune cell population – and the reprogramming of M2 macrophages towards a M1 phenotype (anti-tumor cell population) for the treatment of pancreatic cancer. The small molecule candidate has high oral bioavailability, a large therapeutic window, favorable pharmacokinetics, and limited off-target effects.
The NCI is seeking licensing partners and/or collaborators to perform IND enabling studies to translate the anti-CD206 small molecule into a therapeutic for CD206 expressing cancers.