Kyrexa is advancing cancer treatment in companion animals through comparative oncology, and its lead drug rimcazole is ready for pivotal development following a successful pilot evaluation in dogs with advanced cancer.
Kyrexa’s vision to provide gentle and effective treatment for cancer in companion animals is explained in its introductory article. Kyrexa’s flagship drug was backed by decades of scientific research, which had been stalled by several key pieces of the jigsaw puzzle and distrust that a single common approach to cancer treatment was possible.
In this second article, Kyrexa describes how comparative oncology (the study of animal and human cancers) has shed light on what has been missing in previous research efforts: what was present in laboratory-based cancer models that do not adequately mimic real cancers that occur naturally in animals or humans.
Comparative oncology continues to uncover striking similarities between human and canine cancers, particularly driving synergies that will accelerate advances in tumor treatments for the mutual benefit of humans and our best friends. Thanks to comparative oncology, Kyrexa has gained important new insights into the mechanism of action of its tumor drug candidate rimcazole. Rimcazole is making good progress through pilot evaluation in dogs with a variety of advanced cancers. It is now entering a critical stage of development before accelerated release as an approved drug for dogs.
Cancer treatment in humans and dogs
Cancer – It’s a word that strikes fear into anyone’s heart, especially when it affects your dog. However, just like us humans, many dogs develop cancer, and many dogs die from the disease. Most people have experienced cancer and the impact that treatment, including chemotherapy, has had on friends and family. Traditional cancer treatments for dogs are primarily those used in humans and include surgery, radiation therapy, chemotherapy, targeted therapies, and vaccines. Most of the available medical options began as human treatments and were tested on healthy dogs as part of their development. These treatments were later transferred to the field of veterinary medicine. Because chemotherapy targets rapidly dividing cells, it affects various tissues in the body, including the bone marrow (which affects blood cell production) and the gastrointestinal tract (which causes intestinal side effects such as nausea, loss of appetite, vomiting, and diarrhea). The need to limit these unwanted side effects with lower doses means that for most dogs, medical treatment is only palliative. Many pet parents worry that their pet will suffer serious side effects and have to make regular, stressful visits to the veterinary clinic to extend its life with no hope of cure.
Rimcazole works in a fundamentally different way than traditional chemotherapy
Unlike traditional chemotherapy drugs that target rapidly dividing cells, rimcazole works in a fundamentally different way by selectively targeting tumor cells while sparing non-cancerous cells, including cells that are dividing, such as cells in the bone marrow, gastrointestinal tract, and hair follicles. Therefore, the unpleasant side effects associated with traditional chemotherapy are avoided.
A serendipitous combination of ideas and discoveries led Kailexa to wonder if the drug rimcazole was setting off an alarm that told cancer cells to die prematurely through cell suicide, or “apoptosis.” The novelty lay in the idea that the alarm sent by rimcazole triggered cell suicide as a general “failsafe” to prevent autonomous cells from attacking on their own. Cancer cells can and do go wild as individual cells by upregulating autonomous signaling that tricks them into believing they are with similar cells. Rimcazole turns off these signals, so cancer cells think they are autonomous, even if they are not. The result is a decisive self-destruction, thanks to the imperative to maintain the “social order” of evolution and biological development.
Many anticancer drugs are known to induce apoptosis to some degree in tumor cells, but cancer cells have ingenious ways to avoid this, leading to the development of resistance. Even treatments that precisely target genetically encoded tumor-specific changes are at risk of failure over time due to the tumor’s ability to find backup mechanisms to defeat the treatment.
Kailexa’s new technology is based on the hypothesis that the alarm sounded by rimcazole, which directs cell suicide, may be so fundamental that evolution has ensured that there is no way to silence it. This represents a fundamental difference from other treatment approaches.
The importance of social order
Kyrexa previously introduced the concept of the fundamental importance of endogenous cell death programs in response to external survival signals. This may generate a kind of “social order” in the body, ensuring that cells are in the right place at the right time during development. This original idea came from visionary scientist Professor Martin Ruff, who is credited with drawing widespread attention to the phenomenon of “altruistic cell suicide.” He proposed the idea that most, perhaps all, cells are always in a state of readiness for death, and that they only do so by continuously receiving recognizable signals from the environment. This helps ensure social order in the body. When this order breaks down and cells start to ignore their surroundings, cancer can develop. Dr. Ruff also showed that most non-cancerous cells cannot survive on similar cells alone, confirming that signals from different types of adjacent cells are required to suppress natural cell suicide. The exceptions are some cell types that exist in the body alone with similar cells and have no choice but to “stand on their own.” One such cell type is the epithelial cells that surround the lens of the eye.
Rimcazole inhibits autocrine, “autonomous” signaling
Coincidentally, an eye lens specialist worked at the same facility as one of Kairexa’s founders. Together they established that lens epithelial cells, along with cancer cells, were killed by rimcazole. On the other hand, other normal (non-tumor) cell types, which require signals from other cell types (paracrine signals), were not sensitive.
From this, it appeared that rimcazole, an antagonist of the prosurvival sigma-1 receptor, might signal to autonomous cells that they lacked “autocrine” signals from similar neighbors. This sets off an alarm that directs definitive cell suicide to avoid individual cells going rogue. Avoiding solitary cell survival at all costs may have been built into evolution to ensure that cells arrive at the right place at the right time during the development of complex organisms. Unlike many targeted therapies, which work for a period of time until cancer cells find a way out, rimcazole may provide insight into the broader potential of drugs that target autonomous signaling as a critical and durable Achilles heel for cancer.
Comparative oncology sheds light
Although early data looked promising, the program stalled for practical reasons. Data at the time indicated that the doses of rimcazole needed to be effective in treating cancer were not achievable with ongoing development.
Kyrexa’s founders questioned early assumptions about therapeutic doses. It is clear that rimcazole is very sensitive to the extracellular environment (the environment that surrounds cells in the body), and evidence of increased sensitivity makes this a further disadvantage. The problem was that all assumptions about therapeutic doses were based on highly artificial laboratory-based systems in which tumor cells were cultured in a favorable, survival factor-rich environment. Importantly, this risks losing the selective pressure on the tumor to maintain autonomy, upon which rimcazole sensitivity depends.
In reality, tumors that occur naturally in the body do not grow in favorable environments. Despite the fact that the tumor microenvironment is often unfavorable to growth, they proliferate and, in part, do so by gaining a degree of autonomy through autonomous signaling. This gave rise to the idea that naturally occurring tumors should be more susceptible to rimcazole than laboratory-based systems and that previous assumptions about therapeutic doses were incorrect.
Inspired by the emergence of comparative oncology and the evidence of strong similarities between human and canine cancers, the founders of Kyrexa believed there was a compelling rationale to conduct a pilot clinical trial of rimcazole in customer-owned dogs with spontaneous cancers, using doses of rimcazole previously thought to be ineffective but known to be safe. The study was conducted in dogs with advanced disease where other options had not worked or were refused by the dog’s owner, and was approved by an international ethics committee. The rationale underlying the pilot clinical evaluation was that naturally occurring cancers in real patients are more susceptible to rimcazole than previously suggested because of the selective pressure on the tumor to maintain growth in an unfavorable environment. Furthermore, it was reasoned that drugs targeting autonomous signaling may be effective in advanced cancers, including metastatic disease.
Pilot evaluations in dogs show clear promise of efficacy with consistently high quality of life and minimal side effects, including in advanced metastatic disease. For Kylexa co-founder Claire Nottenbelt, a veterinary oncologist known for her compassionate approach, high quality of life is a particularly important outcome. “Many owners want the best for their pets, but fear the effects of traditional cancer treatments. That’s why we were so happy to hear from pet parents whose dogs played like puppies during treatment.”
Comparative oncology further reveals the importance of immune responses to rimcazole’s antitumor effects
In its introductory article, Kyrexa explained how rimcazole, in addition to directly killing tumor cells, triggers a multipronged attack on tumors, including targeting the blood vessels that feed the tumor (anti-angiogenesis) and engaging the anti-tumor immune response. Importantly, pilot evaluations in dogs with cancer support the involvement of the immune response as a key feature and provide important insights to move the program forward. It also teaches us an important lesson. This means that translational medicine does not end just because a new drug is delivered to a clinical setting. This is an iterative process, where insights from the clinic inform the science and vice versa.
Although it may seem surprising that multiple mechanisms are involved, when one considers the dangers to biological development when allowing solitary cells their freedom, it becomes easy to see that multiple safeguards are needed to ensure that autonomous signaling is halted short of survival autonomy (solitary cell survival).
Because cancer selfishly ignores social order, it likely overlooks one important evolutionary constraint: the need to avoid solitary cell survival. That could be the ultimate Achilles heel.
We have comparative oncology and are grateful that dogs with cancer and their caregivers have brought us this important insight that could have far-reaching implications.
This article will be published in an upcoming Special Focus Publication on Animal Health.
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