Potential for personalised medicine in kidney cancer

Precision medicine, or personalised medicine, describes the use of therapies that are specifically chosen for the patient based on the molecular characteristics of their disease. It is an emergent field in healthcare, made possible by recent advances in molecular and genetic diagnostic technology. Genetic disorders are particularly amenable to precision medicine, as it is now possible to sequence patient or tumour DNA to identify mutations, and choose an appropriate treatment in a reasonably short time frame. This approach is expected to improve patient outcomes, and to reduce the number of patients given ineffective or unnecessary treatments.

At the recent Crick Symposium on Rare Diseases, Professor Timothy Aitman from Imperial College London described a number of cases where precision medicine had been used to successfully treat patients with rare diseases.

As discussed recently, the ΔF508 mutation disrupts the folding of the CFTR protein and causes roughly 70% of Cystic Fibrosis cases (Serohijos et al., 2008). Vertex Pharmaceuticals developed Lumacaftor, which targets this specific mutation by correct defects in the CFTR folding. Lumcaftor improves the respiratory function and reduces the number of hospital admissions of CF patients with this mutation (Ren et al., 2013).

Historically cancers are classified by which tissue they originate from rather than their underlying biological characteristics, which is now known to be a false paradigm. Lung cancer prognosis is poor, particularly in advanced disease (Mountain, 2000). However, there has been some success with personalised medicine approaches, with increased progression free survival of up to a year using targeted therapies (Reungwetwattana and Dy, 2013).  For example, the 10-12% of lung cancers that are EGFR positive can be treated with the EGFR inhibitors Erlotinib, Gefetinib and Afatinib, and crizotinib can be used to treat the 3-6% of lung cancers carrying an EML4-ALK translocation (Reungwetwattana and Dy, 2013).

Kidney cancers are also likely to be amenable to personalised therapy as there are a many causative genes with strong genotype-phenotype correlation, and there are several existing therapies including interferon, tyrosine kinase inhibitors (TKIs), VEGF inhibitors, and mTOR inhibitors (Junker et al., 2013). The current standard of care to treat metastatic RCC is to predominantly use anti-angiogenic therapies and only use mTOR inhibitors as a first line therapy in cases of clear cell carcinoma with poor prognosis (Escudier et al., 2012). However, there is some evidence to suggest that mTOR inhibitors may prove more effective as first-line treatments BHD kidney tumours than TKIs (Nakamura et al., 2013). There are currently two clinical trials testing the effects of new immunotherapies (RAD001 and AGS-16C3F) on the different histological subtypes of renal cell carcinoma. Further subtype analyses on existing treatments would improve the management and prognosis of kidney cancer.

While there are a number of success stories in genomics and precision medicine, it is not an option available to the vast majority of patients at the moment. Precision medicine is labour intensive, usually only available as part of a clinical trial or research project, and sometimes even when a patient’s genetic mutation is known, there is not always an available therapy.

However, advances in technology and large scale sequencing projects, have driven the price of sequencing down considerably, and we have now entered the era of the $1000 genome. As more patients have genome sequencing performed as part of their care, it will be possible to correlate genotypes with disease symptoms more accurately. Furthermore, as more drugs are developed to target specific genetic mutations or biological pathways, doctors will also have more treatment options available to them. Together, this will allow for the refinement of precision medicines, further improving patient outcomes and perhaps eventually making this healthcare approach the rule rather than the exception.

 

  • Escudier B, Eisen T, Porta C, Patard JJ, Khoo V, Algaba F, Mulders P, Kataja V, & ESMO Guidelines Working Group (2012). Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 23 Suppl 7 PMID: 22997456
  • Junker K, Ficarra V, Kwon ED, Leibovich BC, Thompson RH, & Oosterwijk E (2013). Potential role of genetic markers in the management of kidney cancer. European urology, 63 (2), 333-40 PMID: 23040205
  • Mountain CF (2000). The international system for staging lung cancer. Seminars in surgical oncology, 18 (2), 106-15 PMID: 10657912
  • Nakamura M, Yao M, Sano F, Sakata R, Tatenuma T, Makiyama K, Nakaigawa N, & Kubota Y (2013). [A case of metastatic renal cell carcinoma associated with Birt-Hogg-Dubé syndrome treated with molecular-targeting agents]. Hinyokika kiyo. Acta urologica Japonica, 59 (8), 503-6 PMID: 23995526
  • Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, Hoffman BJ, & Cyr DM (2013). VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Molecular biology of the cell, 24 (19), 3016-24 PMID: 23924900
  • Reungwetwattana T, & Dy GK (2013). Targeted therapies in development for non-small cell lung cancer. Journal of carcinogenesis, 12 PMID: 24574860
  • Serohijos AW, Hegedus T, Aleksandrov AA, He L, Cui L, Dokholyan NV, & Riordan JR (2008). Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proceedings of the National Academy of Sciences of the United States of America, 105 (9), 3256-61 PMID: 18305154

 

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