Skopje, 16 July 2025

There are different approaches to cancer therapy, depending on the tumor’s nature. When we talk about carcinomas, we exclude tumors of non-epithelial origin, such as sarcomas, leukemias, and lymphomas. Of all carcinomas, only around 15 percent are naturally immunogenic and can be treated accordingly, while the other 85 percent cannot. The main challenge is how to convert those into immunogenic ones, Dr. Milan Risteski from the Zan Mitrev Clinic said in an interview with MIA.

He points out that the concept of targeted therapy is based on the understanding of a specific proliferative molecule or receptor on the tumor cell membrane, and that thanks to these altered genetic properties, the tumor progresses. This forms the basis of targeted therapy. However, unlike immunotherapy, targeted therapy unfortunately always leads to resistance. In immunotherapy, fortunately, as Dr. Risteski notes, there are patients who can be cured even in metastatic settings, which is not the case with targeted therapy.

In response to a question about whether the drug ivermectin blocks the production of new cancer cells, which the tumor uses to grow, he said that in studies, the drug has shown an ability to reduce the expression of a certain type of receptor on cancer cells, essentially bringing it down to the same level as in normal cells.

“The remarkable mechanism of action that ivermectin possesses, aside from accelerating pyroptosis, lies in its ability to enhance the function of caspase system responsible for programmed cell death. It can be very powerful ally. However, few are willing to fund studies that do not yield direct profit. The drug no longer has patent protection, it is now a generic medicine. It is very difficult to reintroduce an old drug for use in modern medicine,” Dr. Risteski said.

Speaking about the causes of cancer, Dr. Risteski notes that cancer metabolism has been a topic of discussion since the time of Dr. Warburg, who proposed that cancer cells depend exclusively on sugar. While this idea was widely accepted for years, he stresses that it's not entirely accurate.

“In studies where tumor cells were placed in a physiological solution without glucose but with glutamine, they still managed to survive, even without oxygen. This shows that cancer cells don’t rely only on sugar. They need to ferment glutamine into glutamate and also obtain nitrogen. Cancer cells have one set of requirements to survive, and another to survive and multiply. To stay alive, they need nutrients, not necessarily oxygen. Their main nutrient is glutamate, followed by glucose,” Dr. Risteski said.

In cases of extreme starvation, the oncologist notes, tumors will even use fatty acids to survive.

“Food alone isn’t enough for them to survive, there must also be growth factors, which the tumor cells themselves secrete. Tumor biology is extremely complex; it’s not driven by a single mechanism. When we deal with tumors driven by crucial gene mutations present even before birth, the predisposition to various types of cancer is significantly higher, almost certain. All these factors build on top of one another. There is no tumor that advances and defeats the body due to a single mutation alone. I believe that in about a decade we will learn how to convert non-immunogenic tumors into immunogenic ones, and that will become the foundation for treating advanced stages of cancer,” Dr. Risteski said.

Treating oncology patients is a long-term process. To what extent are the latest protocols applied in our country, and what is your vies on these protocols and their implementation?

When we say "protocol," we primarily refer to a whole sequence of actions that are specifically designed to ensure the best method of treatment. Protocols are not only oncological or radiotherapeutic, they also include surgical protocols. Regarding oncological and radiotherapy protocols, these guidelines are mostly followed, except in situations where we reach a point for which no existing protocol applies. Protocols have been developed for the most common types of cancer and the most typical clinical situations. However, in any condition outside of those typical situations, there are no protocols, and only some logical approaches based on existing knowledge remain, which can guide treatment for those patients.

Following the COVID pandemic, the drug ivermectin has once again come into focus, this time in the context of cancer treatment. Should ivermectin be included alongside other medications in treating oncology patients?

Ivermectin is an old drug, patented in the 1970s, with a long-standing use in treating parasitic diseases. However, even before COVID, the entire group of antiparasitic drugs began to attract interest thanks to researchers working in the field of basic oncology studies. The whole public discussion about ivermectin and cancer treatment emerged after the case of a marathon runner from Missouri, Paul Mann, who had metastatic castration-resistant prostate cancer. At that point, everything had already been tried, the disease had progressed into a resistant, untreatable form. All options had been exhausted: endocrine therapy, radiation therapy, chemotherapy. The chemotherapy options had been reduced to just two drugs, with no others having any effect.

This was the first case in which a person, with nothing left to lose, reached out to researchers involved in basic experimental studies, who suggested he try ivermectin. This is the first isolated case in which ivermectin has shown an effect. Based on individual cases, we cannot generate significant interest for large-scale studies. Currently, there is an ongoing study in Los Angeles on ivermectin in triple-negative breast cancer. What do the findings say? Mice are not randomly chosen, they are ideal for research because their basal metabolic rate, the speed at which a cell functions, is four times faster than in humans. If a model is chosen where the metabolic rate is similar to that of humans, the studies would take much longer. We have many evidence that ivermectin possesses multiple distinct antitumor mechanisms. What we observe in animal models is encouraging, with a certain success rate, but not in all patients. All tumors are different. In mice, a single cell clone is introduced that develops into cancer, and their immune system is chemically suppressed so that the tumor can grow, allowing researchers to study the drug’s effect on the tumor. This is not a perfect model, because in reality the immune system plays a role in humans. Transplanted tumors are not the ideal method, and even under such controlled and ideal testing conditions, ivermectin is not 100 percent effective. 

What needs to be done is to identify which tumor cells or host (patient) characteristics are suitable for treatment. From that point, we are at least 10 years away. The issue here is philosophical and ethical because patients do not have those 10 years and want to try the drug. So, you can neither encourage nor forbid them, it is their life, not yours. The matter is very complex since we do not have an established protocol for a single dose, daily dose, or dose density... We know nothing. We do know that up to 12 milligrams per day is safe, but how many days in a row, this is unknown. I am speaking about ivermectin. For fenbendazole, we know that a dose of 800 to 900 milligrams per day over several days is safe. But, at the end of the day, when you know a patient has a short survival time, it is neither ethical nor professional to shorten that time further with the average effects of another drug. That is the current situation. If you ask me whether there is a future for this, yes, theoretically, especially for people who understand tumor cell biology well, there is a future. But all those phases of testing have to be completed. Is everything smart in those phases? In this case, everything I have read from hundreds of studies is mostly done very intelligently and rationally, unlike cannabis research. With cannabis, there are many pointless studies where even the conclusions are difficult to interpret. However, with ivermectin and fenbendazole, it is much easier, they are chemical substances, unlike cannabis, which has active ingredients in unknown concentrations, making it very difficult to measure and follow the pharmacokinetics of any active ingredient through the body.

Are there any negative effects for people who take ivermectin on their own?

The side effects of the drug are listed on several medical websites, with drugs.com being the most informative. So far, I haven't received any reports from patients I know are taking it on their own. I have a close relationship with my patients, so they would tell me, but I haven’t been informed of any negative effects. However, they don’t take it in extremely high doses where toxicity would be more likely. Everything is done with great caution.

Does ivermectin block the production of new cancer cells, which the tumor uses to grow?

Yes, it has a cytostatic effect, but it’s not just about inhibiting cell proliferation. It also supports processes like programmed cell death, and something called autophagy, where already formed cells are marked for breakdown by the immune system. It may even help trigger what's known as pyroptosis, a third type of cell death in which immune cells, typically activated by inflammation (though not necessarily in this case), kill cancer cells.

All of this is described in the mechanisms of action, and it doesn’t stop there, ivermectin also appears to play a role in the tumor tissue’s metabolism, meaning it affects more than just the tumor’s proliferative behavior. The key question is whether it can achieve this on its own or only in combination with other drugs. The answer leans more toward the latter, combining it with other therapies. In animal models, this has been demonstrated in studies on pancreatic ductal adenocarcinoma, where adding ivermectin to gemcitabine enhanced the chemotherapy’s effectiveness.

There’s a very clear reason for this. Every cell in our body, and especially cancer cells, has receptors on its surface called "multi-drug resistance" receptors. They’re important because they help cells get rid of anything harmful. Cancer cells take this to the extreme—during their development, they can multiply the gene for a receptor called NBR1 thousands of times. That’s why the surface of kidney cancer cells is packed with these receptors, making them resistant to nearly all chemotherapy drugs. Standard cancer drugs simply don’t work on kidney cancer—it has to be treated in a different way. Ivermectin has shown in studies that it can reduce the expression of this type of receptor on cancer cells, essentially normalizing it to the levels found in healthy cells. 

Another, in my view, remarkable mechanism of action, aside from accelerating pyroptosis, is that ivermectin enhances the function of the caspase system responsible for programmed cell death. This makes it potentially a very powerful ally. However, there is little interest in funding studies where there’s no direct profit involved. The patent has expired; it's a generic drug. Reintroducing an old drug into medical practice is extremely difficult. There have been similar cases in the past, for instance, thalidomide, a drug from the 1960s, was reintroduced in hematology, but it took 30 years. Funding models and patent protection are always crucial factors in research. I would welcome funding for such studies, but a positive result in animal studies doesn’t guarantee the same for humans. Even successful Phase 1 and 2 trials in humans don’t necessarily lead to a successful Phase 3 trial.

What are your insights regarding the effects of modern therapies in treating oncology patients?

We are not talking about a single concept here; these are multiple therapeutic approaches, depending on the tumor’s nature. When we speak of carcinomas, we exclude tumors that aren’t of epithelial origin, such as sarcomas, leukemias, and lymphomas. Out of 100% of carcinomas, only about 15% are inherently immunogenic, meaning they can be treated using this approach. The remaining 85% are not suitable for such treatment. The challenge is how to make them immunogenic. The concept of targeted therapy, based on identifying a specific proliferative molecule or receptor on the tumor cell membrane, relies on the fact that due to altered genetic traits, the tumor progresses. This is what drives targeted therapies. However, unlike immunotherapy, targeted therapy unfortunately always leads to resistance over time. The advantage of immunotherapy is that we do have patients, even in metastatic stages, who can be cured, something we don’t yet see with targeted therapies. When it comes to local treatment approaches, there have been many advancements. In Macedonia, radiofrequency ablations have been performed for quite some time, and now microwave ablations are also being introduced. These are local, not systemic, treatments and are applied when the disease is in a localized stage. Radiotherapy surgery (radiosurgery) was developed globally over 20 years ago for specific types of tumors with small volume and is being performed very successfully. On the other hand, the combination of monoclonal antibodies and cytostatics, known as antibody-drug conjugates, has already reached the third generation. Similarly, T-cell therapy with chimeric antigen receptors (CAR-T) is now in its third generation. There are many new approaches, and this kind of progress is to be expected.

Are these approaches being applied in our country?

Some are being used, but most are not.

One theory suggests that cancer is caused by parasites; another sees it as a metabolic disease, proposing that improving diet or inducing starvation may cure several types of cancer. The third, and perhaps most widely accepted theory attributes it primarily to genetic predispositions or mutations that develop in cells .So, what is cancer?

When we mention parasites, I’ll say right away - no. But certain viruses can, by binding to parts of the genome, especially in critical regions, contribute to cancer development, though not with absolute certainty. HPV is the oldest known example - yes. Epstein-Barr virus - also yes. We won’t list them all here. In short, a virus alone, without chronic inflammation and immune system suppression, cannot cause cancer. Cancer metabolism has been a topic of discussion since the time of Dr. Warburg, who proposed that cancer cells depend exclusively on sugar. While this idea was widely accepted for years, he stresses that it's not entirely accurate. In studies where tumor cells were placed in a physiological solution without glucose but with glutamine, they still managed to survive, even without oxygen. This shows that cancer cells don’t rely only on sugar. They need to ferment glutamine into glutamate and also obtain nitrogen. Cancer cells have one set of requirements to survive, and another to survive and multiply. To stay alive, they need nutrients, not necessarily oxygen. Their main nutrient is glutamate, followed by glucose.

How do we get glutamine into our body?

It is introduced through food, but our cells also produce it. We nourish ourselves with three main types of food: carbohydrates, which can be simple or complex, fats, and proteins. Simple carbohydrates, especially glucose and fructose, are the primary fuels from which we produce what can be considered our gasoline, adenosine triphosphate (ATP), the molecule that provides energy for all our processes... Complex carbohydrates are much larger molecules; we cannot directly use them as fuel for our cells. However, they serve as an excellent fuel source for something we often forget: our microbiome, the beneficial bacteria living inside us. What does this mean? My body is made up of ten trillion cells. Out of 107 kilograms, seven kilograms are bacteria. The number of these bacterial cells is 100 trillion, which is ten times greater than the number of my own cells. Without those complex carbohydrates, these gut bacteria would not be able to survive in my intestines. Many of the substrates for their enzymes are required not only by my body but by every body. Without them, our lifespan would be significantly shorter.

They are an indispensable part of us. When it comes to energy storage, the body manages all of this. In reality, the best source of energy for our body is fats, and the only large reservoir of food in our body is fat. Not only subcutaneous fat tissue but also deep visceral fat tissue. In cases of extreme starvation, the oncologist notes, tumors will even use fatty acids to survive. Food alone isn’t enough for them to survive, there must also be growth factors, which the tumor cells themselves secrete. Tumor biology is extremely complex; it’s not driven by a single mechanism. When we deal with tumors driven by crucial gene mutations present even before birth, the predisposition to various types of cancer is significantly higher, almost certain. All these factors build on top of one another. There is no tumor that advances and defeats the body due to a single mutation alone. 

Do you think there will be a cancer cure soon?

Not just one cure. There are many combinations of methods and concepts, depending on the tumor’s growth phase. The more genetically complex the tumor, the more complex the treatment. Unfortunately, one single drug or approach won’t work. I believe that in about ten years, we will learn how to convert non-immunogenic tumors into immunogenic ones, which will then become the basis for treating more advanced stages of cancer.

Journalist: Renata Pepeljugoska

Photo: Frosina Naskovikj

Video: Vladimir Rabasovikj

Source: MIA