External Speaker Series presentation featuring Professor Mustafa Djamgoz
Professor Mustafa Djamgoz (Imperial College London), the sixth presenter in Metrion Biosciences External Speaker Series, provides some insight into his research into the role of ion channels in cancer and metastasis.
You first an published observation regarding the upregulation of voltage-gated sodium channels (VGSCs) in cancer cell lines in 1995. What was your initial rationale for taking this approach?
The primary rationale was our conviction (from decades of research on ‘excitable’ cells) that electrical signalling plays a major role in cellular functioning in health and disease. Added to this, was our sense of curiosity whether (i) cancer cells generated electrical signals and (ii) electrical signalling differed between metastatic (i.e. aggressive) vs. non-metastatic or benign tumours.
In the 1995 paper, we adopted two such isogenic cell lines from rat prostate cancer as a model and their direct electrophysiological comparison led to the discovery of the VGSC and its role in promoting cellular invasiveness/metastasis in vitro and in vivo. Since then, such functional VGSC expression has also been discovered in cancers of breast, lung (several forms), colon, ovary, cervix and stomach by various international groups.
Where studied, the VGSC upregulation was found to occur concurrently with downregulation of voltage-gated outward / potassium currents, thereby making the membranes of these metastatic cells electrically excitable. We called this the “Celex Hypothesis” of metastasis, stating that it is the membrane excitability that makes these cancer cells hyperactive, disruptive, invasive and, ultimately, metastatic.
Following on your early research relating to sodium channels, we now have evidence for altered expression of potassium, calcium, TRP family, hERG and P2X channels in a range of tumour tissues. Which of these do you believe has the most promise to develop a new therapeutic?
Indeed, yes, there is such evidence, increasing almost daily! So, we are only scratching the tip of an iceberg! Our vision is exactly like that for the brain (a ‘biological universe’), all the ion channels are also in cancer (a ‘pathological universe’). The big question is which ion channel is the most important. Since metastasis is by far the most common cause of death from cancer, we have put the spotlight on VGSCs.
Nevertheless, we need to understand the pathophysiological role of all other ion channels, so we can exploit them most effectively, individually or, more likely, in combinations. So, it is like an orchestra, the VGSC could be the lead violinist but to be able to create the full symphony we must understand the other players as well.
Do you see ion channel modulator-based therapies for cancer solely as adjuncts to other chemotherapy and biologics approaches or is there potential for a stand-alone ion channel modulator therapeutic?
The problems associated with the current therapies for cancer are well known. I see both potentials for ion channel modulator-based therapies. Evidence is very strong that silencing Nav1.5 eliminates metastasis in breast cancer in vivo models. If this translates to the clinic, then VGSC blockers could serve as mono-therapeutic agents.
There is also evidence, for example, that the effect of epidermal growth factor (EGF) in promoting small-cell lung cancer (SCLC) invasiveness occurs substantially through VGSC activity. The EGF receptor is already a major target for SCLC but suffers from the fact that blocking one growth factor pathway often leads to another one taking over. So, a combination therapy may be more effective.
The identification of novel, highly selective ion channel modulators is challenging. The relative lack of novel external architecture means limited opportunities for antibodies and top ten pharma companies with large budgets have been frustrated by issues associated with small molecule selectivity. How would you solve this?
This is not easy to answer! All I can do is to offer our experience. The predominant VGSC (Nav1.5) expressed in breast and colon cancer is clearly a neonatal splice variant (nNav1.5). The spliced region has a unique amino acid sequence and this can be targeted using an antibody with a selectivity of at least two orders of magnitude compared with its ‘nearest neighbour (adult Nav1.5).
Furthermore, we have evidence that nNav1.5 and adult Nav1.5 are pharmacologically distinguishable, so a high throughput screen could reveal small molecules selective for nNav1.5. Finally, we have exploited the fact that growing tumours are hypoxic and hypoxia leads to the VGSCs to develop a persistent current (INaP) which, in turn, promotes invasiveness. The beauty of INaP is the fact that it could occur in any VGSC so its inhibitors may be applicable to several carcinomas irrespective of the subtype of VGSC(s) expressed!
What are the ultimate goals of your current research activities?
Ultimately, of course, to cure cancer! Now, I know, that’s a rather flippant remark. For a start, I would prefer not to use the word “cure” since once cancer touches someone, although it may somehow be put to bed (i.e. the patient is in remission), there will always be a danger that it will return, and it does at least in some cases.
So, we advocate ‘living with cancer’, rather like we can live chronically with diabetes and the AIDS virus. Living with cancer means suppressing metastasis since this is the main cause of death in cancer patients. In the foreseeable future, we plan to do this by exploiting the unique properties of the culprit VGSC as I discussed above.
Given access to suitable funding what would be your priority future research plans?
There is so much to do! Currently, we are focused on cancers of breast and colon due to the significant role played by nNav1.5 in metastasis. Whilst developing a monoclonal antibody to nNav1.5, we would like to take INaP blockers, such as ranolazine, into clinical trials within a few years. Then, we would like to look at other even harder-to-treat cancers like pancreas and glioblastoma. Finally, we would like to evaluate the prognostic potential of VGSC since all the signs are that this occurs very early in the acquisition of metastatic potential.
What made you choose to stay in academia rather than going into industry?
I was born an academic (!) and I was particularly lucky to train in the ‘old’ British system where curiosity and freedom ruled the research waves. I also enjoy teaching and always provoke my students to be better than me, so we can make real progress.
Having said that, I now wear two hats since our research has led to the founding of a small company (Celex Oncology Limited). I did struggle at the beginning to think and act like a man from industry, but I now feel that I can. The hardest thing still, at times, is not being able to freely and instantly discuss our experimental results.
Do you feel that pharmaceutical companies do enough to engage with academics and embrace their findings?
This is getting better since the needs of the two sides are mutually compatible, in fact potentially synergistic. Still, there is a long way to go and much more room for improvement. One important step would be for companies to share the long-term vision of academics and invest in what may seem like early-stage research. I have spoken to lots of organizations who claim to invest in early-stage research, but it was almost always not the case, at least from an academic’s point of view.
How do you feel that the landscape of academia has changed in recent years?
It’s changed a lot, and I cannot say that it has necessarily changed for the better. Much more now is money-driven and the ‘human element’ has been eroded, unfortunately! Still, as long as you manage within the four walls of the lab, it is ok!
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