Combination drug therapy for cancer has been thought to always involve the drugs working together in an additive or even synergistic fashion. However, one study shows that in some cases, the efficacy of drug combinations is solely due to patient-to-patient variability in response and the independent action of the drugs. So, assume you have two patients, Bill and Mary, both with the same type of cancer, and they are given combination therapy with drugs A and B. The traditional idea was that success would be due to A and B both working equally in both patients, or working synergistically; this new study suggests that in some cases, if you don’t know in advance which drug is best for what patient, you give both, and maybe Bill responds to A and Mary to B, and you see a success that you would not have seen if you had given both patients either A or B – so you get 100% success instead of 50%. Keep in mind that there are of course cases where combination therapy does wok additively or synergistically. Abstract:
Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.
“The Prince”, 1513:
"… men ought either to be well treated or crushed, because they can avenge themselves of lighter injuries, of more serious ones they cannot; therefore the injury that is to be done to a man ought to be of such a kind that one does not stand in fear of revenge."
Ch. 3; Variant translation:
"Never do any enemy a small injury for they are like a snake which is half beaten and it will strike back the first chance it gets".
And this is my paraphrase of Machiavelli's thought when applied to cancer treatment:
"Never
do a cancer a small injury for it is like a snake which is half
beaten and it will strike back the first chance it gets".
This means that we should carefully design the first strike against cancer.
The first strike should aim at multiple cancer targets, thus not leaving a chance for cancer to come back. Multiple targets require multiple drugs and multiple treatment conditions, all combined in one regimen that does not give the cancer cells time to evolve, adjust and thrive again. This approach is the approach of combination therapies.
The requirement for combination therapies is well explained in the documentary Surviving Terminal Cancer that I mentioned earlier this month.
Why can cancer strike back if we do not obliterate it with the first attempt? Why are monotherapies or even current combined therapies of 2-3 drugs unsuccessful? There are several considerations that address these questions:
1. Each cancer patient has a different mutation profile; therefore, the treatment regimen of each patient must be tailored according to the mutation profile.
2. All druggable targets (based upon the cancer mutation profiles) should be simultaneously "hit" from the very first round of treatment so that the cancer does not have time to evolve (i.e., to acquire additional mutations or favor smaller, already existent subsets of cells with differential mutation profile).
3. The mutation profile CANNOT be the only criterion for selection of the multi-drug regimens: it has been shown over and over again that when we target proven mutations, several survival pathways are activated. These survival pathways may not be even supported by mutations, and yet, they are activated and allow the cancer cells to survive the "assault" of the targeted drugs. Therefore, each anti-cancer regimen should include an anti-survival signaling cocktail of drugs.
4. Drug regimens need to be accompanied by additional treatment conditions. The majority of cancers are glycolitic, and ketogenic diet and intermittent fasting have been shown to counteract neoplastic development that relies on glycolysis. The two dietary patterns could be combined in 16/8 regimen, where ketogenic diet is consumed in a window of up to 8 hours a day, followed by a 16-hour fasting period. The application of 3-bromopyruvate, a hexokinase 2 inhibitor, might be synergistic with the ketogenic diet/intermittent fasting regimen.
5. One very strong differentiation factor between neoplastic and normal cells is the relatively higher sensitivity of the cancer cells to fever/higher body temperature. The first cells to die at high body temperatures corresponding to fever are the cancer cells. This differential sensitivity is the foundation of the anti-cancer effect of Coley's toxins as mentioned in my early post.
Can anyone imagine an anti-cancer treatment protocol that combines multiple drugs based upon cancer mutation profiles, an anti-survival signaling cocktail of inhibitors, hyperthermia (high body temperature) and a dietary regimen of ketogenic diet/intermittent fasting? Under current legislation rules this is an absurd idea. No oncologist will risk his/her license to oblige a cancer patient. We need legislation that supports these drastically new approaches to combination therapies. Such legislation will allow oncologists to follow on patients who select to administer novel combination approaches to treat their terminal cancer. The choice for cure should be given to these cancer patients. Today, we endlessly talk about the "empowered" patient, and yet, our legislation has taken this power away from the most vulnerable - the terminal cancer patients.
