Repurposing Drugs for Cancer Therapy (2016)
Repurposing is a recognized strategy in drug discovery and development where a drug already approved for human use, is screened for new effects and new targets. Repurposing is potentially fruitful because we already know that these drugs are introduced to and distributed in the organism with acceptable and known side effects.
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It is also often the聽case that 鈥渘ew substances鈥� which are聽promising in cell culture, and even in聽animal models, fail the requirements for聽absorption, distribution, acceptable side聽effects and efficiency when they are later聽tested in the human body.
Based on 1578 FDA-approved (Food聽and Drug Administration, USA) drugs聽and drugs in late clinical development,聽the number of druggable molecules is聽estimated to 667 among more than 21.000 genes and 1.5 million proteins and聽isoforms expressed. If an optimal use of聽these drugs could be exploited across聽a wider range of diseases, this would聽expand the therapeutic toolbox considerably.聽There are several examples of useful聽repurposing internationally and in our聽groups.
Thalidomide presents one interesting聽example. This drug was developed as聽an anti-emetic and sleeping pill in the聽late 1950s, resulting in catastrophic聽occurrence of birth defects when used聽during pregnancy. Promoted by patient聽advocacy groups, thalidomide was tested聽nearly 50 years later with effect against聽multiple myeloma and stimulated聽research into thalidomide analogs. One聽such analog, lenalidomide, was particular聽effective in myelodysplasia lacking one聽copy of the 5q chromosome and provided聽an example of so-called synthetic lethality聽with 5q deletion. Cereblon, an E3 ubiquitin聽ligase, was identified as the molecular聽target of lenalidomide.
In a different approach, our group tested聽the anti-leukemic effect of the old anticonvulsant聽and mood stabilizing agent聽valproic acid in combination with alltrans聽retinoic acid and theophylline in聽acute myeloid leukemia, aiming for a聽combined effect that resulted in increased聽differentiation and programmed cell聽death of tumor cells. Novel low-toxic聽combinations with valproic acid are in聽development for evaluation in clinical聽trials.
Our research group employed a fluorescent聽reporter to screen FDA-approved聽drug panels for compounds that could聽inhibit WNT/尾-catenin signaling, a聽pathway that is commonly aberrantly聽activated in cancer. Several small molecular聽candidate compounds were found to聽inhibit activated 尾-catenin signaling and聽were next characterized using a method聽called DARTS. This is a method to identify聽the molecular target of the compound. The聽compound axitinib, previously approved聽as a VEGFR inhibitor against kidney聽cancer, was found to bind and stabilize聽the E3 ubiquitin ligase SHPRH, leading聽to subsequent degradation of activated聽尾-catenin in the cell nucleus. Further聽testing revealed that axitinib could selectively聽inhibit WNT/尾-catenin signals in聽both zebrafish and mouse models with聽reduced tumor development in the mice.聽Repurposing is not, however, straightforward.聽Careful design of the screening聽and evaluation assays is important. Small聽molecule substances might have more聽than one molecular target in the cells. The聽drug concentration required to achieve a聽desired pharmacological effect can vary聽strongly between targets. Consequently, if聽a substantially higher drug concentration聽is required for a new pharmacological聽effect, a new preclinical evaluation will聽be necessary in addition to a new clinical聽evaluation of toxicity and side effects.聽At one end of the spectrum, repurposing聽has the potential to bring old drugs聽rapidly into new use. At the other end of聽the spectrum, repurposing could serve to聽discover leading compounds that could聽be chemically modified in order to聽increase target affinity and reduce necessary聽dosing and toxicity.
The major challenge of cancer therapy聽today is therapeutic effect in metastatic聽cancer and surgically non-resectable聽tumors. A deeper understanding of聽tumor cell clonal evolution has followed聽increasing understanding of disease聽heterogeneity. Therapy of advanced聽cancer urgently needs a greater toolbox.聽Repurposing may be one important strategy聽to increase the number of therapy聽responders in cancer.
Repurposing may need regulatory steps聽to move forward, securing approved聽indications, safety data and allowing聽insurance reimbursement. An effective聽moderate cost clinical development plan聽may be needed to collect sufficient documentation聽to allow approval of old drugs聽for new indications.