Kyrexa’s research has transformed the use of the drug rimcazole from a potential failure into a promising cancer treatment for both dogs and humans
Kyrexa described in the preceding articles how dogs with cancer shone a light on a longstanding programme of work – deep-rooted in sound science, which had stalled due to a technical hurdle.
The series of articles tells the story of how Kyrexa’s new line of thinking revived the prospect of rimcazole as a safe and effective drug for patients with cancer – be they animal or human patients – contrary to what the laboratory studies had taught to that point. Preliminary clinical studies in dogs with advanced cancer have demonstrated that rimcazole is indeed safe and has promising anti-tumour efficacy. It is now on a regulator-endorsed pathway to approval as a licensed medicine for dogs with cancer.
This final article explains how the action of rimcazole on a molecule called the dopamine transporter – previously considered to be an unwanted side-activity of rimcazole – has turned out to be key to rimcazole’s safe and effective use to treat cancer. Rimcazole switches off the dopamine transporter – increasing levels of the feel-good chemical dopamine. That isn’t all it does, however: inhibition of the dopamine transporter provides a critical boost to the effectiveness of rimcazole in a way unforeseen previously.
Kyrexa has patented an invention that centres on the molecular association of the sigma-1 receptor with the dopamine transporter. This association is reasoned to drive enhanced ‘self-reliance’ in authentic cancer in patients – compared to cancer studied in the laboratory; this, in turn, confers greater susceptibility to rimcazole in patients with cancer, enabling it to be given at doses that are both effective and safe. The dopamine transporter was hitherto thought to be a molecular enemy precluding the safe and effective action of rimcazole, but it has turned out to be the opposite: the key that unlocks safe and effective use.
A carer’s vivid description of their dog with terminal cancer – one of the first patients to receive rimcazole treatment – that the “light had come back” in their pet’s eyes was another ground-breaking moment. The Kyrexa team realised the value of dopamine transporter inhibition to quality of life for a cancer patient during rimcazole treatment, as well as the potential for changing survival outcomes. This has been borne out by consistent reports of excellent quality of life during treatment.
Kyrexa’s mission is to deliver kinder cancer care. Nowhere is this more important than in veterinary oncology, given a pet has no understanding of the treatment choices made on their behalf. Make no mistake, however – that does not mean going easy on the cancer. In this case, it is achieved by outwitting the cancer and turning it against itself in a way that avoids harm to normal tissues.
The journey of discovery
The journey began with the discovery by a team led by one of Kyrexa’s co-founders that a molecule called the sigma-1 receptor suppresses the cell’s natural suicide programme. This process of natural cell death – apoptosis – acts as a crucial safeguard to prevent rogue or damaged cells from going awry. Genetic engineering techniques that introduced extra copies of the sigma-1 receptor into cells resulted in the cells becoming highly resistant to apoptosis.
The team also discovered that, conversely, switching off the sigma-1 receptor by chemical compounds and one in particular called rimcazole, caused cancer cells to die by apoptosis. Remarkably, normal cells remained alive when exposed to the drug. These findings were published in 2004 in Cancer Research, a prestigious journal of the American Association of Cancer Research.
How does rimcazole distinguish between cancerous and non-cancerous cells?
Cancer cells, in their selfish will to survive, have cast aside the usual social controls that require cells to listen to their neighbours to prevent cell suicide. Self-reliant cancer cells disregard the normal rules of cell behaviour – migrating where they shouldn’t and surviving at the expense of their healthy neighbours. Self-reliance has been selected against during evolution to ensure that cells find their way to the right place at the right time during the development of an organism. Evolution has forced cells to communicate in an orderly way with their environment and their neighbours. If a cell goes rogue during development, it should self-destruct by apoptosis to retain the social order.
Rimcazole kills cancer cells without harming normal tissues because cancer cells have acquired self-reliance – allowing cancer cells to selfishly disregard the usual social controls that keep cells in order and in tune with each other. Rimcazole switches off self-reliant signalling – leaving the cancer cell suddenly exposed and unable to rely on its neighbours to suppress cell suicide. Non-cancerous cells, in contrast, have the back-up of signals from friendly neighbours to keep them alive, despite rimcazole.
However, along the journey, a technical hurdle emerged: the laboratory models of cancer were pointing to a requirement for doses of rimcazole that would be too high to be safe. This caused the programme to stall.
A molecular association between the dopamine transporter and sigma-1 receptor overcomes the technical hurdle in patients and turns Foe to Friend
Rimcazole, in addition to sigma-1 receptor inhibition, turns off the dopamine transporter (DAT), which was widely considered to be an undesirable side-activity – ‘the foe’. However, the dopamine transporter undergoes a molecular association with the sigma-1 receptor that enhances its receptiveness to signals, leading Kyrexa to re-examine the assumption that rimcazole’s inhibitory action on DAT is detrimental.
Kyrexa reasoned that the molecular interaction between DAT and the sigma-1 receptor could provide a selective advantage to cancer cells in an authentic patient, through enhanced self-reliant signalling. This would favour the sigma-1-DAT molecular interaction in tumours within unfavourable environments (such as those occurring in real-life patients). However, when tumour cells are grown in the laboratory, they are provided with more favourable conditions and the same need for the molecular association supporting a high degree of self-reliance would not exist.
Rimcazole is known to bind avidly to the dopamine transporter. Kyrexa reasoned that this would enhance rimcazole’s binding to the sigma-1-DAT molecular complex – leading to increased susceptibility to rimcazole in tumour cells in real-life patients, compared to laboratory models of cancer. The key difference is that tumours in an authentic patient, such as a dog or human with cancer, are driven to survive in harsh, unfavourable conditions which are not present in laboratory models of cancer.
This also sits well with the model put forward by Hayashi and Su – published in the prestigious journal Cell in 2007, whereby the sigma-1 receptor operates as a molecular chaperone to support the cell’s ability to withstand stressful stimuli and noxious environments.
A DAT-sigma-1 receptor complex could improve stress adaptation of the tumour – preferentially supporting tumour growth in harsh microenvironments. Kyrexa predicted that the molecular complex would confer enhanced susceptibility to rimcazole, meaning that in authentic cancer patients rimcazole would be effective at lower doses than those predicted from laboratory models. Pilot studies in dogs with cancer support this mechanism.
Cancer stem cells must be eradicated to ensure long-term cure
Cancer stem cells are a small subset of cancer cells that can lurk within tumours and hide from conventional treatments by becoming ‘dormant’, meaning they can resist those treatments and then re-awaken sometime later to cause recurrence. Cancer stem cells are highly adapted to withstand a stressful environment (one that is nutrient- and oxygen-deprived) and, as a result, have a greater ability to survive against the odds. These cells are the hardest to treat with conventional treatments. Killing tumour cells without eliminating cancer stem cells allows the tumour to regrow and leads to disease recurrence. Cancer stem cells are therefore thought to be key drivers of cancer persistence. Treatments that can successfully eradicate cancer stem cells offer the best hope of long-term cure.
Through their adaptation to stress, cancer stem cells display the highest degree of self-reliance within a population of tumour cells. Paradoxically, cancer stem cells are therefore likely to be more susceptible to rimcazole than other cancer cells through a cooperative inhibitory action on the DAT and sigma-1 receptor. This contrasts with conventional treatments that are less effective on cancer stem cells.
It was recently reported that colorectal cancer stem cells are killed when exposed to an inhibitor of the dopamine transporter, supporting the theory that cancer stem cells may be particularly reliant on a DAT-sigma-1 receptor molecular axis to enable adaptation to stressors that non-stem cancer cells may be unable to withstand. Susceptibility of cancer stem cells to inhibition of a DAT/sigma-1 receptor stress adaptation axis raises a real possibility of long-term disease control or cure.
A molecular friend to dogs with cancer
In a pilot study of dogs with advanced cancer, the harnessing of this molecular association has demonstrated tumour stabilisation and tumour shrinkage in some patients alongside evidence of engagement of an anti-tumour immune response – demonstrating a decisive, multimodal action. The dogs also experienced excellent quality of life, with some owners reporting that their dogs “played like puppies” despite advanced disease. The critical involvement of the dopamine transporter not only explains the mood-lifting qualities of the drug in canine patients treated with rimcazole but could be key to long-term cure through targeting of a cooperative interaction between the dopamine transporter and the sigma-1 receptor that drives stress adaptation and self-reliance in cancer stem cells. The effect on the dopamine transporter – hitherto widely considered to be an undesirable side-activity of rimcazole (‘the foe’) – may be the key to long-term cancer control with benefits to quality of life in cancer patients (‘the friend’).
Kyrexa: The company
Kyrexa was formed in 2023 as a small start-up in Scotland – by a team of two founders and investor directors who share the vision to deliver kinder cancer care that works. Scotland has a proud track record of ground-breaking inventions and discoveries that have made a difference – in medicine and other areas. Apoptosis (natural cell suicide) was one such ground-breaking discovery by a team of Scottish scientists. It is fitting that Kyrexa’s lead drug acts through this mechanism.
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Please note, this article will also appear in the 28th edition of our quarterly publication.
