First-in-class small molecule therapeutics targeting phospholipase D (PLD) demonstrate promise as potent and selective inhibitors for viral diseases and oncology. Vanderbilt researchers have developed small molecule selective inhibitors of phospholipase D isoforms 1 and 2, as well as molecules that inhibit both isoforms. These molecules have shown efficacy in models of influenza infection, glioblastoma, and breast cancer. Genetic and chemical inhibition of PLD 1 and 2 exhibit negligible side effects, and these molecules have shown minimal off target toxicity and excellent DMPK profiles.
Phospholipase D is a membrane protein that catalyzes the conversion of phosphatidylcholine to phosphatidic acid, a signaling molecule that affects diverse downstream processes. Many of these processes, including control of the cell cycle, proliferation, and intracellular trafficking, result in disease when dysfunctional. PLD inhibitors may find utility in the following areas:
Influenza/Viral Infections: Encapsulated viruses, such as influenza, require PLD activity for: i) entry into, ii) replication within, and iii) egress from host cells. Endocytosis and endosomal trafficking of influenza virus is an essential component of infection. Chemical inhibition of PLD2 slows this process significantly, allowing time for a robust antiviral immune response. A549 cells treated with a PLD2 inhibitor show a significant decrease in viral titer after infection with influenza virus compared to control. Additionally, PLD1 is implicated in viral egress. Inhibition of this step in the infection process would prevent spread of the virus to uninfected cells. Tandem inhibition of both PLD isozymes may enable an effective multi-pronged approach to treating influenza infections. Whereas currently available small molecule treatments target viral proteins, PLD inhibition represents a novel approach to treatment of influenza and viral infections as it targets host factors involved in infection.
Cancer: PLD1 and 2 are involved in regulating processes essential to cancer cell survival, proliferation, and metastasis. PLD signaling is upstream of many important oncogenes, which cannot be directly inhibited due to toxicity. The Akt pathway is one such example. Vanderbilt researchers have demonstrated that PLD2 inhibition also indirectly inhibits Akt-mediated regulation of autophagy in glioblastoma cells, leading to cell death. In contrast to direct inhibition of Akt, which results in numerous deleterious effects, inhibition through PLD is innocuous. PLD inhibitors developed at Vanderbilt show excellent CNS penetrance allowing access to the tumor. This represents a novel mode of treatment for glioblastoma multiforme, a cancer with limited treatment options and high mortality. In addition, Vanderbilt researchers have demonstrated small molecule inhibition of PLD decreases invasiveness in models of breast cancer. Ongoing research may demonstrate utility in treating other cancers.
Potential Market Size
The broad therapeutic scope of PLD inhibitors indicates a potentially significant market size. Cancer: Cancer will affect 1 in 2 men and 1 in 3 women in America. Breast cancer is the most diagnosed cancer in American women with ~230,000 new diagnoses expected in 2014 (NCI). Glioblastoma mutliforme (GBM) is a more rare cancer with ~12,000 new diagnoses each year, however, it is very difficult to treat and approximately 10% of patients will survive beyond five years after treatment. The current drug of choice to treat GBM, Temodar, had sales of $304 million in the US in 2013. Influenza: The CDC estimates that 5-20% of the population will be infected with influenza each season resulting in approximately 200,000 hospitalizations per year. Sales for Tamiflu, the primary drug used to treat influenza infection, were $456 million in the US ($677 million worldwide) in 2013 and is predicted have stable sales for the next several years.
Intellectual Property Status
Vanderbilt holds patent applications for composition of novel chemical series for PLD1-selective, PLD2-selective and dual PLD inhibitors, as well as method of use for these inhibitors.