The current research focus continues to be androgen receptor [AR]-centric.
What if we accept that PCa is always going to find an escape path, & AR will continue to be involved in most cases?
"Given the difficulties in stopping all AR reactivation mechanisms, we propose that the identification of the driver signaling events downstream of the receptor offer viable, alternative therapeutic targets"
We are never going to see the end of this battle with the AR that Charles Huggins [2] started before I was even born.
It sounds like a good idea to me, but multiple pathways will have to be inhibited IMO.
Curr Opin Pharmacol. 2018 Mar 30;41:1-11. doi: 10.1016/j.coph.2018.03.002. [Epub ahead of print]
Delineation of the androgen-regulated signaling pathways in prostate cancer facilitates the development of novel therapeutic approaches.
Awad D1, Pulliam TL2, Lin C1, Wilkenfeld SR1, Frigo DE3.
Author information
1
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
2
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA; Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
3
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA; Department of Biology and Biochemistry, University of Houston, Houston, TX, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Molecular Medicine Program, The Houston Methodist Research Institute, Houston, TX, USA. Electronic address: frigo@mdanderson.org.
Abstract
Although androgen deprivation therapy (ADT) is initially effective for the treatment of progressive prostate cancer, it inevitably fails due to the onset of diverse resistance mechanisms that restore androgen receptor (AR) signaling. Thus, AR remains a desired therapeutic target even in the relapsed stages of the disease. Given the difficulties in stopping all AR reactivation mechanisms, we propose that the identification of the driver signaling events downstream of the receptor offer viable, alternative therapeutic targets. Here, we summarize recently described, AR-regulated processes that have been demonstrated to promote prostate cancer. By highlighting these signaling events and describing some of the ongoing efforts to pharmacologically modulate these pathways, our goal is to advocate potential new therapeutic targets that would represent an alternative approach for blocking AR actions.
Published online 2013 Dec 16. doi: 10.1093/carcin/bgt480
PMCID: PMC3941741
PMID: 24343361
Cancer as a metabolic disease: implications for novel therapeutics
Thomas N. Seyfried,* Roberto E. Flores, Angela M. Poff, 1 and Dominic P. D’Agostino 1
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This article has been cited by other articles in PMC.
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Abstract
Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual’s unique physiology.
Patrick,
I came across this paper in my searching on the internet. This is all way beyond my education and work experience but I was wondering what you thought of this. What would be the practical therapeutic approach if this is true?
"What would be the practical therapeutic approach if this is true? "
IF true, it certainly is a practical approach. The ketogenic diet is quite demanding, but with a bit of willpower, practice, and measuring blood glucose and ketone serum levels one can shift metabolism from primary carb-based to primary fat based.
There's no "proof" but Seyfried's work has attracted attention, and critics. There are a lot more people making a living from cancer than dying from it, and Seyfried threatens a lot of rice bowls.
If you want to try this, I strongly recommend discussing with an open-minded doctor, and finding a nutritionist to help. It's easy to overeat protein on a ketogenic diet, which stresses your kidneys and other bad things.
The goal is 90% of calories from healthy fats, 7% from proteins, and 3% from carbs. You'll be eating a lot of avocados!
When there is mention of Otto Warburg, I start to feel uneasy. The full text of the paper has 66 references to dear old Otto. [1]
"Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies."
The paper dismisses glutamine as a therapeutic target, which leaves glucose. While some PCa cells may come to favor glucose, prostate cells prefer fatty acids & this persists for most PCa cells. The radio-labeled glucose PET scan cannot generally be used in PCa.
There is a theory that cancer that is dependent on glucolysis will die in the absence of glucose. If we severely restrict carbohydrate intake (very high fat diet), the body will function quite well on ketone bodies. Such diets are used on small children subject to seizures. It is a difficult diet for adults, but can be done.
But would it work for PCa, which does not rely on glucose? Some research from Freedland suggests that a low-carb diet might be beneficial. 10%? !5%?
A possible diet:
- small portion of fish
- no starchy carb at all
- plenty of nutrient rich low calorie vegetables cooked with olive oil
- nuts to drive up the fat % of the meal.
It would certainly control triglycerides, which I suppose is my bugbear.
Thank you for your analysis. I seriously doubt I have the discipline to follow such a strict diet but I found the paper interesting. I will try and incorporate as much of it into my normal diet as I can.
Why does Warburg make you uneasy? He won a Nobel prize in medicine, back in the days (1931) when it was not the political trophy it has become today. He was nominated for the Nobel 47 times.
That doesn't make him perfect by a long shot, but citing Nobel winners doesn't automatically trigger my BS alert.
So many internet sites cite Warburg in support of "cancer hates oxygen" & "sugar is the cause of cancer". While the more serious sites include PCa as a cancer that is dependent on glucose.
That sounds like guilt by association. Some flaky sites do cite Warburg, but just becomes some folks misuse his research doesn't impugn the quality of his work.
I've read both Tripping Over the Truth and Seyfried's full book, Cancer as a Metabolic Disease. Seyfried's book is quite technical and has plentiful references, not just to Warburg. It will be easier to disagree with him than to refute him.
The genetic theory of cancer origin has been a massive failure, a dead end. Seyfried may or may not be correct, but at least he is taking a fresh look at the problem. I've often wondered by Warburg's work has been ignored for so long.
Mostly, I have no problem with Warburg. I do have a problem with:
"Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation." (1966)
If anyone is interested in reading up on the keto diet, there is a professor at University of South Florida, his name is Dominic D'Agostino. He does research on ketosis applications. Some of it is for cancer. Hunt around on the website, link below.Yeah, he has a ton of critics and nay-sayers. I don't know that he could be continuing the research and teaching at a university if it was all false. That said, I am not sure that D'Agostino's work mentions prostate cancer. I think that it talks about other types. Sorry, it's been a while (years) since I read all the articles.
I tried it for a while. My PSA dropped slightly. And I did lose a lot of needed weight and I've kept it off. It is a fair amount of work. As far as protein, if you get too much protein (more than a moderate amount) it will knock you out of ketosis. I believe the reason is the liver converts the protein into glycogen. So if you are monitoring your ketosis state, in theory, you should not be consuming an amount that would stress the kidneys. People picture the keto diet as steak and eggs covered with butter for every meal, in reality protein is something like 10 to 15% of your calories. When I was dieting, a lot of my calories came from Medium Chain Triglyceride oil. There are even websites with a keto vegan diet.
I did read an article long ago (sorry, no link) that ketones in your blood stream will kill cancer cells. An interesting concept if true, as I believe that external ketone supplements exist.
The US Navy supports D'Agostino (or did at one time, I haven't checked recently) because he does research on the divers getting the bends and treating it with hyperbaric oxygen therapy.
He found a strong synergy with ketosis and hyperbaric oxygen in treating cancer. IIRC Seyfried and D'Agostino have been focusing on brain cancer, a really nasty one. Fairly fast, no effective treatments, invariably fatal. They had some promising initial results, with patients living much longer than expected.
Their has never been a war on cancer. Going to the moon was an employment program for STEM graduates. What did we get from going to the moon, Tang! Now, they want to waste money going to Mars. If we put that effort and additional monies, and work on Saturdays we could have a real war on cancer. Seems to me in WW II certain industries had 3 shifts on Sunday too.
The all out effort to find a cure is not there. When Nixon said in 1971 we are going to have a war on cancer, my question is when is it going to start. I don't think we can wait another 47 years for it to start.
Back in 2004, it was no big deal to catch up on PCa research (on PubMed). But the rate of new studies has increased tremendously since then. I think it's because the baby boomers have made the market much larger, and attractive to researchers.
Coupled with that, is the fact that the boomers have greater life expectancy than earlier generations. The low smoking rate alone means that we are living longer & increasing our risk of a PCa diagnosis.
The third factor is the PSA era. While the PCa death rate is decreasing, we have more cases than in the DRE era.
For years, the PCa treatment landscape hardly changed. But in recent years there have been all sorts of new products. Market forces in action.
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