Kyrexa is advancing cancer treatment for companion animals through comparative oncology, with their lead drug rimcazole, now ready for pivotal development following successful pilot evaluations in dogs with advanced cancers.
Kyrexa’s vision to deliver kind, but effective, treatment for cancer in companion animals was discussed in its introductory article. Kyrexa’s lead drug was underpinned by many decades of scientific endeavour, which had stalled due to some missing key pieces of the jigsaw and a disbelief that a single common approach to the treatment of cancer could ever be envisaged.
In this second article, Kyrexa explains how comparative oncology – the study of cancer in animals and humans – shone a light on what had been missing from the research efforts to date, all of which had been in laboratory-based models of cancer that did not adequately mimic authentic cancer that arises spontaneously in an animal or human.
Comparative oncology is continuing to reveal remarkable similarities between human and canine cancer, in particular, driving synergies that are accelerating progress in oncology therapeutics to the mutual benefit of man and his best friend. It is thanks to comparative oncology that Kyrexa obtained critical new insight into the mechanism of action of a candidate oncology therapeutic, rimcazole. Rimcazole has been successfully progressed through pilot stage evaluation in dogs with a range of advanced cancers. It is now poised to enter a pivotal stage of development prior to an accelerated drug launch as a licensed medicine for canines.
Treating cancer in humans and dogs
Cancer – it’s a word that strikes fear into the heart of everyone, especially when it affects your family dog. And yet, just like us humans, many dogs will develop cancer, and many will die as a result of their disease. Most people have some experience of cancer and the impact that treatments, including chemotherapy, can have on friends and family members. Traditional cancer treatments in dogs are largely those used in humans and include surgery, radiation therapy, chemotherapy, targeted therapies and vaccines. Most of the medical options available have started as human treatments and were tested in healthy dogs as part of their development. These treatments were then transitioned across to the veterinary field. Chemotherapy targets any rapidly dividing cells and therefore has impacts on a variety of tissues within the body, including the bone marrow (affecting blood cell production) and gastrointestinal tract (causing intestinal side effects including nausea, inappetence, vomiting and diarrhoea). The need to limit these unwanted side effects by lower dosages means that, for most dogs, medical treatments are only palliative. Many pet parents fear that their pet will have to suffer significant side effects and have regular stressful visits to a veterinary hospital in order for their lives to be prolonged without hope of a cure.
Rimcazole works in a fundamentally different way from conventional chemotherapy
Unlike traditional chemotherapy drugs that target rapidly dividing cells, rimcazole works in a fundamentally different way by selectively targeting tumour cells while sparing non-cancerous cells, including those undergoing cell division – such as the cells of the bone marrow, gastrointestinal tract and hair follicles. The unpleasant side effects that come with traditional chemotherapy are therefore avoided.
A serendipitous coalescence of ideas and discoveries led Kyrexa to question whether the drug rimcazole was sounding an alarm, causing cancer cells to instruct their own untimely demise through cell suicide – ‘apoptosis’. The novelty lay in the idea that the alarm sent by rimcazole was triggering cell suicide as a general ‘failsafe’ intended to prevent self-reliant cells from striking out alone. Cancer cells can and do go rogue as individual cells by an upregulation of self-reliant signalling that tricks them into believing they are in the company of like cells. Rimcazole switches off those signals so the cancer cell now thinks it is on its own – even if it isn’t. The consequence is decisive self-destruction – thanks to evolution and the imperative to maintain ‘social order’ during the development of organisms.
Whereas many cancer drugs are recognised to induce apoptosis within tumour cells, to greater or lesser degrees, cancer cells have devious ways of circumventing this, leading to the development of resistance. Even therapies that are precisely targeted to genetically encoded, tumour-specific alteration(s) risk failure over time due to the tumour’s ability to find back-up mechanisms to override the treatment.
Kyrexa’s novel technology is based on the thesis that the alarm sounded by rimcazole instructing cell suicide may be so fundamental that evolution has ensured there is no way of silencing it. This marks it out as radically different from other approaches to treatment.
The importance of social order
Kyrexa previously introduced the concept of the fundamental importance of an intrinsic cell death programme that is responsive to external survival signals. This may generate a type of ‘social order’ within the body, ensuring that cells end up in the right place at the right time during development. This original idea came from a visionary scientist, Professor Martin Raff, who can be credited for bringing the phenomenon of ‘altruistic cell suicide’ to widespread attention. He posited the idea that most, possibly all, cells are in a constant state of readiness to die and are only prevented from doing so by the continuous receipt of recognisable signals from their environment. This helps to ensure social orderliness within the body. Cancer is a potential consequence when this order breaks down and cells acquire a cavalier disregard for their surroundings. Raff went on to show that most non-cancerous cells cannot survive in the company of like cells alone, supporting the need for signals from neighbouring cells of a different type to suppress innate cell suicide. The exceptions are a few cell types that exist within the body in the company of like cells alone and have no alternative other than to be ‘self-reliant’. One such cell type is the epithelial cell that surrounds the lens of the eye.
Rimcazole inhibits autocrine, ‘self-reliant’, signalling
Serendipitously, an expert in the lens of the eye worked in the same institution as one of Kyrexa’s founders. Together, they established that lens epithelial cells, along with cancer cells, were killed by rimcazole. Whereas other normal (non-tumour) cell types that require signals from cells of other types (paracrine signals) were not susceptible.
From this, it looked as though rimcazole – an antagonist of the pro-survival sigma-1 receptor – may be sending a signal to self-reliant cells that they are running low on the ‘autocrine’ signals from like neighbours. This sounds an alarm that instructs decisive cell suicide to avoid individual cells going rogue. The avoidance of lone cell survival at all costs may have been hardwired during evolution to help ensure that cells find their way to the right place at the right time during the development of complex organisms. Unlike many targeted therapies that work for a period until the cancer cell finds a means of escape, rimcazole may offer insight into the wider potential for drugs that target self-reliant signalling as a decisive, enduring Achilles heel for cancer.
Comparative oncology shines a light
As promising as the early data looked, the programme stalled for pragmatic reasons. The data appeared at the time to point to a need for doses of rimcazole that, in order to be effective for the treatment of cancer, were not feasible for ongoing development.
Kyrexa’s founders questioned the earlier assumptions around the therapeutic dose. It is clear that rimcazole is acutely sensitive to the extracellular milieu (the environment surrounding cells in the body), with evidence of enhanced susceptibility, the more unfavourable this becomes. The problem was that all the assumptions regarding therapeutic dose had been based on highly artificial laboratory-based systems in which tumour cells had been cultured in a favourable, survival factor-rich environment. Critically, this risks loss of the selective pressure on the tumour to maintain self-reliance – on which rimcazole susceptibility in turn depends.
In reality, naturally occurring tumours within the body do not grow in favourable environments. They grow despite the tumour microenvironment frequently being unfavourable to growth, and they do so in part by acquiring a degree of autonomy through self-reliant signalling. This led to the idea that naturally occurring tumours should be more susceptible to rimcazole than the laboratory-based systems and that the prior assumptions around therapeutic dose had been misplaced.
Inspired by the emergence of comparative oncology and the evidence of strong similarity between human and canine cancer, Kyrexa’s founders considered that there was a compelling rationale to conduct a pilot clinical trial of rimcazole in client-owned dogs with spontaneous cancer, using doses of rimcazole that were hitherto considered likely to be ineffective but were known to be safe. The trial was conducted in dogs with advanced disease, where other options had been ineffective or were declined by the dogs’ owners, and received international ethics board approval. The rationale underpinning the pilot clinical evaluation was that cancer arising spontaneously in an authentic patient, with the attendant selective pressure on the tumour to sustain growth in unfavourable surroundings, would be more susceptible to rimcazole than had previously been suggested. It was further reasoned that a drug targeting self-reliant signalling may be effective in advanced cancer, including metastatic disease.
The pilot evaluation in dogs has demonstrated clear promise of efficacy, with consistently high quality of life and minimal side effects, including in advanced metastatic disease. For Kyrexa’s veterinary co-founder, Clare Knottenbelt – a veterinary oncologist renowned for her compassionate approach – the high quality of life is a particularly important outcome. “Many owners want to be able to do the best for their pet but fear the consequences of traditional cancer treatments, so hearing from pet parents that their dogs played like puppies during treatment was hugely gratifying.”
Comparative oncology has shed further light on the importance of an immune response to rimcazole’s anti-tumour action
In its introductory article, Kyrexa explained how rimcazole triggers a multi-pronged attack on the tumour involving direct killing of the tumour cells as well as targeting of the blood vessels that feed the tumour (anti-angiogenesis) and engagement of an anti-tumour immune response. Crucially, the pilot evaluation in dogs with cancer supports engagement of an immune response as a dominant feature, providing vital insight for the programme as it moves forward. It also teaches us an important lesson: translational medicine doesn’t stop when a new drug reaches the clinic. It is an iterative process, with insight from the clinic enlightening the science and vice versa.
Although it may seem surprising that multiple mechanisms are involved, when one considers the jeopardy to the development of an organism if lone cells are given free rein, the need for multiple safeguards so that self-reliant signalling stops short of survival autonomy (lone cell survival) becomes easier to understand.
In its selfish disregard of social order, cancer may perhaps have overlooked one key evolutionary constraint – the need to avoid lone cell survival. That may potentially turn out to be the ultimate Achilles heel.
We have comparative oncology, and dogs with cancer and their carers, to thank for bringing us this key insight that could have far-reaching implications.
