Drug Repositioning for Rare Diseases

A recent Findacure meeting focused on the importance and progression of drug repositioning in rare diseases. Dr Bruce Bloom, Dr Mike Briggs and Dr Farid Khan, discussed ongoing repositioning work, methods to identify new drugs and targets and the need for collaborations to drive new research and trials. Cures Within Reach are launching a new interactive platform CureAccelerator to help form such collaborations. The session’s presentations are available here.

There are over 6000 rare diseases1 recognised worldwide, and as the development of a new drug is thought to take between 10-15 years2 and cost approximately $1.2 billion USD3, the limited market appeal of rare disease or orphan drugs reduces investment incentive.  The Orphan Drug Act of 1983 was passed in the US to increase incentive and, to date, 486 orphan drugs have been approved4. The remaining 90-95% of rare diseases do not have any specific treatments.

An alternative approach is to reposition (or repurpose) some of the 4000 existing drugs approved for human use worldwide (Huang et al., 2011). Existing early phase safety and efficacy data for these drugs means repositioning studies can be cheaper, safer and faster than conventional drug development.

BHD is a rare disease for which no preventative treatments are available and Clinicaltrials.gov lists only three trials for BHD. Two long running studies at the National Cancer Institute are looking at the clinical, genetic and molecular basis of BHD and all heritable urologic disorders, and a third, funded by the Myrovlytis Trust, assessed the use of topical rapamycin to treat fibrofolliculomas (discussed here).

Rapamycin, an mTOR inhibitor, is a repositioned drug: first licenced as an immunosuppressant it is now used as a treatment for a range of diseases including cancers including advanced kidney cancer in BHD patients. The role of mTOR activity in fibrofolliculoma pathology is less understood. This could explain why the clinical trial did not find evidence of topical rapamycin as an effective treatment for BHD fibrofolliculomas (Gijezan et al., 2014).

FLCN loss also disrupts other pathways including HIF signalling; increased HIF signalling is seen in FLCN-null cell lines (Preston et al., 2011) as a result of altered AMPK activity, and could be a driving force in the development of renal tumours. HIF-1 hyperactivity is also seen in sporadic renal tumours which lead to the development of HIF-1 inhibitors (Onnis et al., 2009, Welsh et al., 2013). If BHD pathologies are linked to aberrant HIF-1 activity these drugs may be able to provide the basis for new treatments.

A drug screen, funded by the Myrovlytis Trust, using a BHD-kidney cell line (Yang et al., 2008) identified Mithramycin, an antineoplastic antibiotic, as selectively toxic to FLCN null cells (Lu et al., 2011). Used to treat testicular cancer, leukaemia and Paget’s disease, Mithramycin could potentially, after further research, be a viable drug for repositioning trials in BHD.

The pathology of BHD fibrofolliculomas and pulmonary cysts is less well understood than FLCN-associated renal tumours. This potentially limits the development of new treatments based on aberrant biological pathways or activity. Further research into the mechanisms through which a reduction in FLCN leads to these phenotypes will hopefully enable new drug targets to be identified.

Drug screens, incidental findings, bioscience research and computational biology can all provide insights into potential new treatments for specific diseases or pathways. Greater understanding of the pathways affected in BHD and their roles in pathology will enable researchers to identify more likely drug targets. Repositioning of known drugs could then prove useful in discovering safe and effective treatments for BHD and other rare disease patients in a shorter time span than conventional methods.

  • Gijezen LM, Vernooij M, Martens H, Oduber CE, Henquet CJ, Starink TM, Prins MH, Menko FH, Nelemans PJ, van Steensel MA. Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: a double-blind placebo-controlled randomized split-face trial. PLoS One. 2014 Jun 9;9(6):e99071. PubMed PMID: 24910976.
  • Huang, R., Southall, N., Wang, Y., Yasgar, A., Shinn, P., Jadhav, A., … Austin, C. P. (2011). The NCGC Pharmaceutical Collection: A comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics.Science Translational Medicine3(80). PMID: 21525397
  • Lu X, Wei W, Fenton J, Nahorski MS, Rabai E, Reiman A, Seabra L, Nagy Z, Latif F, Maher ER. Therapeutic targeting the loss of the birt-hogg-dube suppressor gene. Mol Cancer Ther. 2011 Jan;10(1):80-9. PubMed PMID: 21220493.
  • Onnis B, Rapisarda A, Melillo G. Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med. 2009 Sep;13(9A):2780-6. PubMed PMID: 19674190.
  • Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, Tee AR. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene. 2011 Mar 10;30(10):1159-73. PubMed PMID: 21057536.
  • Welsh SJ, Dale AG, Lombardo CM, Valentine H, de la Fuente M, Schatzlein A, Neidle S. Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule. Sci Rep. 2013 Sep 30;3:2799. PubMed PMID: 24165797.
  • Yang Y, Padilla-Nash HM, Vira MA, Abu-Asab MS, Val D, Worrell R, Tsokos M, Merino MJ, Pavlovich CP, Ried T, Linehan WM, Vocke CD. The UOK 257 cell line: a novel model for studies of the human Birt-Hogg-Dubé gene pathway. Cancer Genet Cytogenet. 2008 Jan 15;180(2):100-9. PubMed PMID: 18206534.


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