IMPDH inhibitors for anti-tumor therapy in tuberous sclerosis complex

Structured AbstractPurposemTORC1 is a master regulator of anabolic cell growth and proliferation that is activated in the majority of human tumors. We recently demonstrated that elevated mTORC1 activity in cells and tumors can confer dependence on IMPDH, the rate-limiting enzyme in de novo guanylate nucleotide synthesis, to support increased ribosome biogenesis and cell viability. Pharmacological agents that inhibit IMPDH, such as mizoribine and mycophenolic acid (CellCept), are in wide clinical use as immunosuppressants. However, whether these agents can be repurposed for anti-tumor therapy requires further investigation in preclinical models, including direct comparisons to identify the best candidate(s) for advancement.Experimental DesignDistinct IMPDH inhibitors were tested on cell and mouse tumor models of tuberous sclerosis complex (TSC), a genetic tumor syndrome featuring widespread lesions with uncontrolled mTORC1 activity. Growth and viability were assessed in cells and tumors lacking the TSC2 tumor suppressor, together with drug pharmacokinetics and pharmacodynamics, target inhibition, and effects on tumor, tissue, and plasma metabolic biomarkers.ResultsMizoribine, used throughout Asia, exhibited greater selectivity in specifically targeting TSC2-deficient cells with active mTORC1 compared to the FDA-approved IMPDH inhibitors mycophenolic acid or ribavirin, or approved inhibitors of other nucleotide synthesis enzymes. In distinct tumor models, mizoribine demonstrated robust anti-tumor efficacy that is superior to mycophenolic acid, despite similar immunosuppressive effects.ConclusionsThese results provide pre-clinical rationale for repurposing mizoribine as an anti-tumor agent in tumors with active mTORC1, such as in TSC. Our findings also suggest that IMPDH inhibitors should be revisited in cancer models where MMF has shown modest efficacy.Statement of translational relevanceIMPDH inhibitors have been used clinically for decades as safe and effective immunosuppressants. Recent studies in pre-clinical tumor models establish IMPDH as a viable target for anti-tumor therapy, but the relative efficacies of approved IMPDH inhibitors in tumors have not been directly compared. Our data demonstrate a clear advantage of the IMPDH inhibitor mizoribine, used clinically throughout Asia, over the FDA-approved IMPDH inhibitor mycophenolate mofetil (or CellCept, a prodrug of mycophenolic acid) in mouse models of tuberous sclerosis complex (TSC) exhibiting mTORC1-driven tumor growth. While these IMPDH inhibitors elicit similar immunosuppressive effects, mizoribine has far superior anti-tumor activity in these models, indicating the potential for repurposing this drug for TSC and perhaps cancer treatment. We also identify the purine synthesis intermediate AICAR as an in vivo metabolic biomarker specific for effective inhibition of IMPDH with mizoribine, which can be readily detected in blood plasma shortly after mizoribine administration.

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story

The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely a secondary manifestation of increased cell proliferation. Suggestive of a direct causative effect includes evidence that, in some cancer types, the rate-limiting enzyme in de novo GTP biosynthesis, inosine monophosphate dehydrogenase (IMPDH), is upregulated and that the IMPDH inhibitor, mycophenolic acid (MPA), possesses anti-tumor activity. However, historically, enthusiasm for employing IMPDH inhibitors in cancer treatment has been mitigated by their adverse effects at high treatment doses and variable response. Recent advances in our understanding of the mechanistic role of IMPDH in tumorigenesis and cancer progression, as well as the development of IMPDH inhibitors with selective actions on GTP synthesis, have prompted a reappraisal of targeting this enzyme for anti-cancer treatment. In this review, we summarize the history of IMPDH inhibitors, the development of new inhibitors as anti-cancer drugs, and future directions and strategies to overcome existing challenges.