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ISSUE 1 FEBRUARY
Letters to the Editor

Janus kinase inhibitors – holistically seeing two faces

  • John A Loudon, Paul Kubler, d4bb942bb920ddcf

The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. When letters are published, they are usually accompanied in the same issue by their responses or comments. The Committee screens out discourteous, inaccurate or libellous statements. The letters are sub-edited before publication. Authors are required to declare any conflicts of interest. The Committee's decision on publication is final.

Letter to the Editor

Editor, - I was interested to read the recent article on Janus kinase inhibitors by Paul Kubler (Aust Prescr 2014;37:154-7). In addition to being pro-cancer, the Janus kinase-Signal Transducer and Activation of Transcription (JAK-STAT) pathway is part of a central physiological pro-survival mechanism.1 Thus pharmacological targeting of this signalling cascade may pose potential threats, for example to cardiac integrity.2 Targeting JAK-STAT will also potentially challenge neuroprotection.3 Conversely, activation of JAK-STAT is proposed as a tangible approach to managing heart disease.4

The message is that there is a clinically highly relevant ‘crossroads’ between physiology and cancer, thus maintaining the truly holistic viewpoint. Therefore treatments aimed at targeting cancer necessarily target normal tissues and in turn define burgeoning fields within cancer-related therapy such as cardio-oncology. Activating a pro-survival pathway such as JAK-STAT therapeutically to manage heart disease removes a barrier in the multiple-step process of oncogenesis. Targeting the JAK-STAT pathway is in a sense ‘non-specifically specific’. The target may be a defined one, but the target itself is universally expressed.

Future developments in therapeutics must be designed to be ‘specifically specific’ to the disease target to be effective, yet with little fear of resultant adverse reaction.

John A Loudon
Dental practitioner
Baulkham Hills NSW


 

Author's comment

Paul Kubler, the author of the article, comments: It is not surprising that therapies targeting the JAK-STAT pathway have the potential for diverse applications, as over 500 kinases have been identified in the human kinome. Janus kinases belong to the tyrosine kinase family, of which there are at least 90 recognised members.

Although there is a large volume of published data about the JAK-STAT pathway, it is mostly pre-clinical. Currently, very few drugs targeting Janus kinase signalling have been approved by regulatory authorities and are in clinical use. The focus of the article was on those mechanisms which have current clinical applications.

The statement of whether specifically targeting selective errors of the immune system (that is being specifically specific) versus inhibiting multiple cytokines (that is being non-specifically specific) is a better way of improving effectiveness and reducing adverse effects, is a vexed question with no clear answer. The clinical data in the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus do not consistently support this hypothesis. The patho-aetiology of many autoimmune diseases is characterised by multiple abnormalities of the immune system with cascading effects over time and alternative pathways of disease perpetuation after onset, hence I would suggest specifically specific therapies are less likely to be effective from a biological plausibility perspective as the disease progresses. If we could identify and treat disease in a pre-clinical phase, specifically specific therapies have the potential to be more effective. However, the answer to this is unknown.

 

References

  1. Loudon JA. A novel prosurvival model for cancer under environmental challenge: the \u2018heart-felt\u2019 message for therapeutic intervention. Oncol Res 2011;19:407-43.
  2. Fischer P, Hilfiker-Kleiner D. Role of gp130-mediated signalling pathways in the heart and its impacton potential therapeutic aspects. Br J Pharmacol 2008;153:S414-27.
  3. Oliva AA Jr, Kang Y, Sanchez-Molano J, Furones C, Atkins CM. STAT3 signaling after traumatic brain injury.J Neurochem 2012;120:710-20.
  4. Fujio Y, Maeda M, Mohri T, Obana M, Iwakura T, Hayama A, et al. Glycoprotein 130 cytokine signal as a therapeutic target against cardiovascular diseases. J Pharmacol Sci 2011;117:213-22.

John A Loudon

Dental practitioner, Baulkham Hills, NSW

Paul Kubler

Clinical pharmacologist

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