Carbidopa (Lodosyn) is an FDA-approved drug for treating Parkinson's disease (PD). PD patients receive Carbidopa along with L-DOPA. Our interest in this compound arose due to the recent association studies showing that PD patients have lower incidence of most cancers including pancreatic cancer, notable exception being melanoma. Interestingly, L-DOPA is not responsible for the lower cancer incidence. That prompted us to ponder with the idea that maybe Carbidopa is the one that is responsible for the lower incidence of cancer in patients with PD. Carbidopa is structurally similar to phenylhydrazine (a phenyl ring and a hydrazine moiety), a potent IDO1 inhibitor. IDO1 is a drug target for antitumor immunotherapy. Pancreatic cancer is known to have the highest IDO1 expression. We were thrilled with the idea that if Carbidopa is an IDO1 inhibitor, it would uncover a hitherto unknown potential of the drug in cancer treatment as an immunotherapy agent. Being already an FDA-approved drug, clinical trials can be started right away to evaluate its anticancer efficacy. Also, recently we have discovered an amino acid transporter that is very selective for tryptophan, induced in DCs upon interferon gamma (IFN-?) stimulation. The most exciting thing about this transporter is its simultaneous induction along with IDO1, suggesting that it might be responsible for supplying tryptophan to IDO1. Could Carbidopa also inhibit this transporter, which works in tandem with IDO1? With these ideas in mind, we initiated the current project. Preliminary studies have already provided strong support to our hypothesis that Carbidopa could be used as an immunotherapy agent for the treatment of cancer. The goal of the current project is to evaluate the merits of this hypothesis further. We have two specific aims in the project.
Aim 1 : Demonstrate the inhibition of the TrpT/IDO1 functional complex by Carbidopa in antigen-presenting cells in vitro;
Aim 2 : Demonstrate the functional relevance of Carbidopa-induced inhibition of the TrpT/IDO1 functional complex in antigen-presenting cells to T cell proliferation and its potential for immunotherapy of pancreatic cancer.
For Aim 1, we will use dendritic and monocytic cell lines to evaluate the inhibitory effects of Carbidopa on the activities of IDO1 and the tryptophan-selective transporter TrpT.
For Aim 2, we will use an in vitro assay to demonstrate that Carbidopa-induced inhibition of the in antigen-presenting cells does indeed promote T cell proliferation and then use an in vivo assay to evaluate the potential of Carbidopa as an immunotherapy agent for the treatment of pancreatic cancer, alone as a single agent as well as in combination with gemcitabine, using a syngeneic orthotopic transplantation model of pancreatic cancer in immunocompetent mice. TrpT/IDO1functional complex
The goal of the project is to demonstrate that Carbidopa, an FDA-approved drug for Parkinson's disease can be used as a potential immunotherapy agent to treat pancreatic cancer by inhibiting IDO1 as well as the tryptophan-selective transporter (TrpT). This will be achieved by utilizing both cell culture as well as animal models.