{What's this doing on the Cruzbike forum? Well, some of the smartest people I know are on this forum, so why not? - Jim Parker, MD}
The title of a 2010 documentary movie about cancer treatment, Cut Poison Burn, refers to three types of conventional treatments aimed at fighting cancer. Many cancers tend to form a mass, and surgery (cut) takes advantage of the mass-forming quality of cancers. Cancer cells also divide rapidly. Thus, chemotherapy (poison) is used to target rapidly dividing cells. Radiation (burn) also targets the mass-forming quality of cancers.
My proposal is based on targeting the unique metabolic qualities of cancer cells, thus adding “starve” to “cut, poison, and burn”. This is not a new idea, but the method we propose may be. It holds the potential to slow or cure cancer without the use of any expensive/proprietary drugs, radiation equipment, or long-term side effects. The drugs needed are inexpensive and of little or no toxicity. We present this proposal in the hope of stimulating discussion, research, and clinical trials.
-----------------------------------------------------
The Warburg effect was first described 80 years ago, when Dr. Otto H. Warburg discovered that many cancer cells get all their energy from glycolysis--the splitting of a 6-carbon glucose molecule into two 3-carbon molecules. Healthy non-cancerous cells have other pathways to extract energy from sources other than glucose, but cancer cells are less flexible. Some research suggests that they may be able to use lactate as fuel in addition to glucose, but this remains unclear (1).
The normal range of glucose in the blood is approximately 80 to 110 mg/dl. Our bodies maintain a
constant minimum level of glucose, thus cancer cells are never without an abundant supply of glucose. Contrary to popular belief, our brains do not completely depend on glucose to stay alive and active. The brain can burn ketones. Ketones are 2-carbon molecules formed when we burn fatty acids (fats) for energy. Fatty acids cannot cross the blood-brain barrier, but ketones can. Most people are not efficient at burning fat because they don’t need to be. Most people eat a steady supply of carbohydrates which are easily converted to glucose. If people drastically cut down on their carbohydrate intake, the body will ramp up enzymes and pathways to improve fat-burning capacity. This process has been termed keto-adaptation, because the body increases its capacity to produce and burn ketones.
Here is the proposal: Selected cancer patients will be put on a very low carbohydrate diet for at least two weeks to allow for keto-adaptation. Next, in a monitored health care facility, they will undergo an infusion of insulin (and other agents to be discussed later) which will drop the blood glucose to a level that, hopefully, is deadly to cancer cells but not to healthy cells.
Supplementary methods to increase the kill rate for cancers will need to be explored. But based on existing studies (3,4), the administration of 2-DOG (2-deoxyglucose) may be useful. The analogy I like to use is the Trojan War, where the Greeks used both a siege and the Trojan Horse to bring about the fall of Troy. Cancer cells treat 2-DOG like glucose and transport it into the cell, but it cannot be metabolized by cancer cells. In the Trojan War metaphor, the 2-DOG is the Trojan Horse. The siege is the ketogenic diet and the infusion of insulin or other hypoglycemic agents (e.g. metformin) in the ketone-protected patient. We do not know what period of starvation will kill cancer cells. It could be 2 hours or 24 hours, or it might not work at all. Some cancer cells may just go dormant until the glucose returns. We have reason to believe, however, that depriving cancer cells of glucose will stimulate cell death.
Oxygen plays a central role in human metabolism. Thus, the addition of either hypoxia (low oxygen levels) via use of an altitude tent, or hyperoxia (high oxygen levels) via hyperbaric oxygen therapy (HBOT) may improve the effectiveness of my proposed treatment. Indeed, the latter therapy in combination with a ketogenic diet proved significantly beneficial in a 2013 study of metastatic cancer in mice (5).
It must be emphasized that insulin infusion into “normal” (non-keto-adapted) patients results in coma and death due to severe hypoglycemia. However, research done decades ago (2) showed that insulin infused into starving keto-adapted patients--at doses that would have killed normal people--left the patients unfazed. They remained alert and functioned normally despite blood glucose levels below 30 mg/dl.
Here’s a sample of a protocol for this technique, for discussion only (do not try this at home). Patient A has metastatic carcinoma with less than 2-years average life-expectancy. A PET scan is obtained prior to the procedure. This test involves injecting patients with fluoro-deoxy-glucose (FDG). FDG is another glucose analog. The body treats it like glucose, but we can image it clearly with a PET scan, and see where and how large a cancer is inside the body. Only patients with FDG-avid cancers would be eligible for this treatment.
After informed consent, the patient is brought into ketosis at a blood ketone level of approximately 5 mmol/L. This may be done with dietary restriction of carbohydrate, or infusion of ketones, or both. The patient has a PICC or other central venous access device for simple blood sampling and infusion. Next, the patient, in a fasting state, is placed comfortably in an altitude room/tent simulating 14,000 feet elevation (or alternately, in a HBOT chamber). ACLS-trained personnel and appropriate resuscitation equipment are standing by, including IV glucose solution and an oxygen supply. EKG leads monitor cardiac activity. The heart works well running on ketones, so the hypoglycemia should not cause any cardiac events, but better safe than sorry. Baseline glucose and ketone levels are monitored and sampled every 5 minutes. Pulse oximetry is used to chart the oxygen saturation of the blood. Insulin is infused intravenously at a slow rate, monitoring the patient’s response. The goal is a maximum reduction of blood glucose concentration with few or no symptoms in the patient. The patient should be alert and oriented throughout the procedure. Ketone levels are also maintained at appropriate levels throughout the procedure.
Once maximum asymptomatic hypoglycemia is achieved, the level of hypoglycemia is maintained for X hours (X may vary widely). Finally the insulin infusion is stopped, glucose returns to normal levels, and the patient can leave the high (or low) oxygen room. The patient has a follow-up PET scan within a week to determine the response. If the response is only partial, the treatment is repeated with longer hypoglycemia, and/or with a change of other factors, such as oxygen level, 2-DOG dosing, or metformin supplementation.
The technique will need testing and refining. It’s quite feasible that the period of treatment may need to be repeated over several weeks, or cycled over 24-hours. It may also turn out that the hypoxia is less important than the hypoglycemia, or that alternating high and low blood oxygen levels may enhance cancer apoptosis (cell death). The addition of 2-DOG and/or metformin may or may not improve the effectiveness of the treatment.
This idea first occurred to me while sitting in a Panera Bread restaurant in Charlotte, NC on 12/5/15, after reading an excellent book by Jeff Volek and Stephen Phinney called The Art and Science of Low Carbohydrate Living. My passion for cycling and the need to lose weight prompted a desire for a deeper understanding of human metabolism, which led to reading this fine book. My wife, Maria Parker, and her passion for finding a cure for brain cancer, which deprived her of her sister in 2014, also motivated me to think about how cancer’s unique metabolism could be used against it. My son, William Parker, also contributed significantly to the refinement of this proposal and uncovering similar proposals including a 2009 hypothesis by MW Nijsten and GM van Dam (6) and a 2014 one by Adam Kapelner and Matthew Vorsanger (7).
Jim Parker, MD
1) Goodwin ML, Gladden LB, Nijsten MWN, Jones KB. Lactate and Cancer: Revisiting the Warburg Effect in an Era of Lactate Shuttling. Frontiers in Nutrition. 2014;1:27. doi:10.3389/fnut.2014.00027.
2) Cahill GF, Jr., Aoki TT: Alternate fuel utilization by brain. In: Cerebral Metabolism and Neural Function. Passonneau, JV et al, Eds. Williams & Wilkins, Baltimore, 1980. Pp 234-42.
3) Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, Wa Cheng K, Hall H, Zhang D, Lu Y, Ravoori M, Kundra V, Ajani J, Lee JS, Ki Hong W, Mills GB: Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Molecular Cancer Therapeutics. 2011 Dec;10(12):2350-62. doi: 10.1158/1535-7163.MCT-11-0497. Epub 2011 Oct 12.
4) Sahra IB, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Marchand-Brustel YL, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F: Therapeutics, Targets, and Chemical Biology:Targeting Cancer Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis in Prostate Cancer Cells.
Cancer Research. March 15, 2010 70:2465-2475; Published OnlineFirst March 9, 2010;doi:10.1158/0008-5472.CAN-09-2782
5) Poff AM, Ari C, Seyfried TN, D’Agostino DP: The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer. PLoS ONE 8(6): e65522. doi: 10.1371/journal.pone.0065522
6) Nijstem MW, van Dam GM: Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate. Med Hypotheses. 2009 Jul;73(1):48-51. doi: 10.1016/j.mehy.2009.01.041. Epub 2009 Mar 4.
7) Kapelner A, Vorsanger M: Starvation of Cancer via Induced Ketogenesis and Severe Hypoglycemia. arXiv:1407.7622v2 [q-bi
T] 8 Dec 2014.
The title of a 2010 documentary movie about cancer treatment, Cut Poison Burn, refers to three types of conventional treatments aimed at fighting cancer. Many cancers tend to form a mass, and surgery (cut) takes advantage of the mass-forming quality of cancers. Cancer cells also divide rapidly. Thus, chemotherapy (poison) is used to target rapidly dividing cells. Radiation (burn) also targets the mass-forming quality of cancers.
My proposal is based on targeting the unique metabolic qualities of cancer cells, thus adding “starve” to “cut, poison, and burn”. This is not a new idea, but the method we propose may be. It holds the potential to slow or cure cancer without the use of any expensive/proprietary drugs, radiation equipment, or long-term side effects. The drugs needed are inexpensive and of little or no toxicity. We present this proposal in the hope of stimulating discussion, research, and clinical trials.
-----------------------------------------------------
The Warburg effect was first described 80 years ago, when Dr. Otto H. Warburg discovered that many cancer cells get all their energy from glycolysis--the splitting of a 6-carbon glucose molecule into two 3-carbon molecules. Healthy non-cancerous cells have other pathways to extract energy from sources other than glucose, but cancer cells are less flexible. Some research suggests that they may be able to use lactate as fuel in addition to glucose, but this remains unclear (1).
The normal range of glucose in the blood is approximately 80 to 110 mg/dl. Our bodies maintain a
constant minimum level of glucose, thus cancer cells are never without an abundant supply of glucose. Contrary to popular belief, our brains do not completely depend on glucose to stay alive and active. The brain can burn ketones. Ketones are 2-carbon molecules formed when we burn fatty acids (fats) for energy. Fatty acids cannot cross the blood-brain barrier, but ketones can. Most people are not efficient at burning fat because they don’t need to be. Most people eat a steady supply of carbohydrates which are easily converted to glucose. If people drastically cut down on their carbohydrate intake, the body will ramp up enzymes and pathways to improve fat-burning capacity. This process has been termed keto-adaptation, because the body increases its capacity to produce and burn ketones.
Here is the proposal: Selected cancer patients will be put on a very low carbohydrate diet for at least two weeks to allow for keto-adaptation. Next, in a monitored health care facility, they will undergo an infusion of insulin (and other agents to be discussed later) which will drop the blood glucose to a level that, hopefully, is deadly to cancer cells but not to healthy cells.
Supplementary methods to increase the kill rate for cancers will need to be explored. But based on existing studies (3,4), the administration of 2-DOG (2-deoxyglucose) may be useful. The analogy I like to use is the Trojan War, where the Greeks used both a siege and the Trojan Horse to bring about the fall of Troy. Cancer cells treat 2-DOG like glucose and transport it into the cell, but it cannot be metabolized by cancer cells. In the Trojan War metaphor, the 2-DOG is the Trojan Horse. The siege is the ketogenic diet and the infusion of insulin or other hypoglycemic agents (e.g. metformin) in the ketone-protected patient. We do not know what period of starvation will kill cancer cells. It could be 2 hours or 24 hours, or it might not work at all. Some cancer cells may just go dormant until the glucose returns. We have reason to believe, however, that depriving cancer cells of glucose will stimulate cell death.
Oxygen plays a central role in human metabolism. Thus, the addition of either hypoxia (low oxygen levels) via use of an altitude tent, or hyperoxia (high oxygen levels) via hyperbaric oxygen therapy (HBOT) may improve the effectiveness of my proposed treatment. Indeed, the latter therapy in combination with a ketogenic diet proved significantly beneficial in a 2013 study of metastatic cancer in mice (5).
It must be emphasized that insulin infusion into “normal” (non-keto-adapted) patients results in coma and death due to severe hypoglycemia. However, research done decades ago (2) showed that insulin infused into starving keto-adapted patients--at doses that would have killed normal people--left the patients unfazed. They remained alert and functioned normally despite blood glucose levels below 30 mg/dl.
Here’s a sample of a protocol for this technique, for discussion only (do not try this at home). Patient A has metastatic carcinoma with less than 2-years average life-expectancy. A PET scan is obtained prior to the procedure. This test involves injecting patients with fluoro-deoxy-glucose (FDG). FDG is another glucose analog. The body treats it like glucose, but we can image it clearly with a PET scan, and see where and how large a cancer is inside the body. Only patients with FDG-avid cancers would be eligible for this treatment.
After informed consent, the patient is brought into ketosis at a blood ketone level of approximately 5 mmol/L. This may be done with dietary restriction of carbohydrate, or infusion of ketones, or both. The patient has a PICC or other central venous access device for simple blood sampling and infusion. Next, the patient, in a fasting state, is placed comfortably in an altitude room/tent simulating 14,000 feet elevation (or alternately, in a HBOT chamber). ACLS-trained personnel and appropriate resuscitation equipment are standing by, including IV glucose solution and an oxygen supply. EKG leads monitor cardiac activity. The heart works well running on ketones, so the hypoglycemia should not cause any cardiac events, but better safe than sorry. Baseline glucose and ketone levels are monitored and sampled every 5 minutes. Pulse oximetry is used to chart the oxygen saturation of the blood. Insulin is infused intravenously at a slow rate, monitoring the patient’s response. The goal is a maximum reduction of blood glucose concentration with few or no symptoms in the patient. The patient should be alert and oriented throughout the procedure. Ketone levels are also maintained at appropriate levels throughout the procedure.
Once maximum asymptomatic hypoglycemia is achieved, the level of hypoglycemia is maintained for X hours (X may vary widely). Finally the insulin infusion is stopped, glucose returns to normal levels, and the patient can leave the high (or low) oxygen room. The patient has a follow-up PET scan within a week to determine the response. If the response is only partial, the treatment is repeated with longer hypoglycemia, and/or with a change of other factors, such as oxygen level, 2-DOG dosing, or metformin supplementation.
The technique will need testing and refining. It’s quite feasible that the period of treatment may need to be repeated over several weeks, or cycled over 24-hours. It may also turn out that the hypoxia is less important than the hypoglycemia, or that alternating high and low blood oxygen levels may enhance cancer apoptosis (cell death). The addition of 2-DOG and/or metformin may or may not improve the effectiveness of the treatment.
This idea first occurred to me while sitting in a Panera Bread restaurant in Charlotte, NC on 12/5/15, after reading an excellent book by Jeff Volek and Stephen Phinney called The Art and Science of Low Carbohydrate Living. My passion for cycling and the need to lose weight prompted a desire for a deeper understanding of human metabolism, which led to reading this fine book. My wife, Maria Parker, and her passion for finding a cure for brain cancer, which deprived her of her sister in 2014, also motivated me to think about how cancer’s unique metabolism could be used against it. My son, William Parker, also contributed significantly to the refinement of this proposal and uncovering similar proposals including a 2009 hypothesis by MW Nijsten and GM van Dam (6) and a 2014 one by Adam Kapelner and Matthew Vorsanger (7).
Jim Parker, MD
1) Goodwin ML, Gladden LB, Nijsten MWN, Jones KB. Lactate and Cancer: Revisiting the Warburg Effect in an Era of Lactate Shuttling. Frontiers in Nutrition. 2014;1:27. doi:10.3389/fnut.2014.00027.
2) Cahill GF, Jr., Aoki TT: Alternate fuel utilization by brain. In: Cerebral Metabolism and Neural Function. Passonneau, JV et al, Eds. Williams & Wilkins, Baltimore, 1980. Pp 234-42.
3) Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, Wa Cheng K, Hall H, Zhang D, Lu Y, Ravoori M, Kundra V, Ajani J, Lee JS, Ki Hong W, Mills GB: Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Molecular Cancer Therapeutics. 2011 Dec;10(12):2350-62. doi: 10.1158/1535-7163.MCT-11-0497. Epub 2011 Oct 12.
4) Sahra IB, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Marchand-Brustel YL, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F: Therapeutics, Targets, and Chemical Biology:Targeting Cancer Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis in Prostate Cancer Cells.
Cancer Research. March 15, 2010 70:2465-2475; Published OnlineFirst March 9, 2010;doi:10.1158/0008-5472.CAN-09-2782
5) Poff AM, Ari C, Seyfried TN, D’Agostino DP: The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer. PLoS ONE 8(6): e65522. doi: 10.1371/journal.pone.0065522
6) Nijstem MW, van Dam GM: Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate. Med Hypotheses. 2009 Jul;73(1):48-51. doi: 10.1016/j.mehy.2009.01.041. Epub 2009 Mar 4.
7) Kapelner A, Vorsanger M: Starvation of Cancer via Induced Ketogenesis and Severe Hypoglycemia. arXiv:1407.7622v2 [q-bi
T] 8 Dec 2014.
