The Search for Cancer Treatment Beyond Mutant-Hunting

Very informative except for one thing .Don't mean to be irreverent but what is the joke about the drunk looking for his wallet under the lamppost.

In fact, there is an experimental anticancer drug that modulates K-RAS, Tempol, currently under development at the NCI and the FDA. This is part of the emerging compelling evidence that essentially all cancers have abnormalities with respect to oxidative stress. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375391/

footnote and maybe it was not so much the plants the herbs or the new method but the take charge persona changing guinea pig size to a persona that even placebo would free them from the belly of the monster getting out of your world results in healing

“Herceptin” and “Gleevec”? You mean trastuzumab and imatinib, no? The trade names are made-up drug company nonsense words meant to subtly bias professional and patient alike. The companies are of course allowed to trademark names for their patented drugs. But I’m aware of no obligation by any provider to use them, in print or elsewhere. Unless your horizons are obscured.

In 2016, Dr. James Watson (of Watson-Crick DNA double helix fame) stated in this very newspaper: Locating the genes that cause cancer has been "remarkably unhelpful"... If he were going into cancer research today, he would study biochemistry rather than molecular biology. And according to biochemistry, - Whatever takes place in a biological cell is controlled by one or more enzymes. - For uncontrolled cell growth, the most critical enzyme is Ribonucleotide Reductase, RR, since it controls the rate-limiting step in DNA synthesis. This enzyme RR can be disabled by biophysical means leading to a highly effective and non-toxic treatment. Alas this GEIPE therapy is non-patentable and very low-cost and thus has been languishing for more than 20 yrs. despite being acknowledged by NCI and MD Anderson Cancer Center as a valid approach. See non-commercial site: cancer-free.net for more information, including articles published in journal Science and Cancer Research.

My son died of Leukemia at Kettering Memorial after germ cell transformed into blood cancer. There was a gene that caused both, according to the experts. As I understand it, most therapy remains the same. Chemotherapy and/or radiation. Everything else is a wild guess, and these fail most of the time. Nothing really has changed despite the claims of oh so much science success and comfort. What is taking so long? How many billions have been wasted on dubious or near-medieval research for the perpetual body machine? Life is about the cycles of eternal returns, and ecclesiastically, it is said: “The thing that hath been, it is that which shall be; and that which is done is that which shall be done: and there is no new thing under the sun.”

"By narrowing our definition of precision medicine too much, we almost narrowed our ambition to deliver precise, thoughtful therapy — or, at times, no therapy — to our patients. It would be a shame to view cancer through such narrow lenses again." Narrowing the lens seems part of human nature. The author mentions unsuccessful attempts using the K-ras mutation to develop cancer treatments. The eminent US Nobel laureate Harold Varmus, whose laboratory made substantial contributions to K-ras research, guided tens of millions of dollars in his role as NIH and NCI director to fund K-ras research on the premise "Guys, this is embarrassing. We don't have a drug." The quotation is taken from a broadcast aired on NPR's Morning edition March 9, this year with the title "The 30-Year Quest To Tame The 'Wily' Cancer Gene". Instead of the most innovative and original research regardless of topic, the research that directors feel most passionate about seems to get funded.

Insightful depiction of the factors that support cancer, which are missed by current therapies. One of those factors, as mentioned by the author, is the tumor microenvironment, which plays a key role in determining tumor progression and response to therapy. We know very well that tumor cells respond to environmental cues. The problem is that most studies examining tumor responses are conducted in artificial environments that fail to recapitulate the conditions found in the tumor neighborhood. Yet, we expect the tumors in patients to respond the same. Although we are completely aware of this, scientists seem to be ignoring this important factor when it comes to experimental design. The author, in spite of his awareness, commits the same fallacy and “proudly” states he will be using organoids, which also are minimally recapitulating the tumor microenvironment! Suddenly all his insightful views disappears in the blink of an eye! As long as we fail to recognize this fundamental contradictions, progress will be limited.

No one, including me, wants to hear the news, You have terminal cancer. However, A) death is inevitable. And B) "miraculous" cancer treatments will ALWAYS be so expensive that most people won't be able to afford them...except by bankrupting the health care industry to pay for them. Most people need to work harder how to live with the inevitability of death so that when they heard the bad news, they will be able to deal with it.

For the past few years I've been researching, to the extent I can, the available information on cancer, in medical and scientific publications, and also looking at the various concoctions and compositions made by numerous pharmaceutical companies. Looking at trials, real longer term trials, and being aware of safety limitations during use, and along with continued successful outcomes, especially in phase 2, and phase 3, trials, wherein overall response rate (ORR) is significantly higher than the FDA acceptable ORR, is a good indicator of the potential for a prospective therapy. Currently, in response to a new drug application, (NDA), the FDA has granted fast track, and accelerated approval, to new drugs in tje pipeline of an oncology company known as Verastem, Inc. Do the research, as it seems, given my limited knowledge, that this group may be onto a therapy with truly wonderful implications for several different cancers. Including the boogeyman of them all, pancreatic cancer. Incidentally, this therapy has an action FDA date of October 5, 2018, so one can hope.

I've read both the author's stellar books. I had not heard the terms basket or umbrella trials previously. I am particularly interested in umbrella trials, as 95% of pancreatic, 50% of lung and 50% colon cancer share KRAS mutation. But ... what if there are multiple ways in which KRAS can be mutant? Wouldn't some mutants be more or less amenable to treatment? This line of reasoning was inspired by Prof Pamela Kunz's work on neuroendocrine pancreatic cancer, in which she has found that different changes to the P53 gene (also implicated in pancreatic cancer) can have substantially different responses.

"By narrowing our definition of precision medicine too much, we almost narrowed our ambition to deliver precise, thoughtful therapy — or, at times, no therapy — to our patients. It would be a shame to view cancer through such narrow lenses again." Narrowing the lens seems part of human nature. The author mentions unsuccessful attempts using the K-ras mutation to develop cancer treatments. The eminent US Nobel laureate Harold Varmus, whose laboratory made substantial contributions to K-ras research, guided tens of millions of dollars in his role as NIH and NCI director to fund K-ras research on the premise "Guys, this is embarrassing. We don't have a drug." (source: https://www.npr.org/sections/health-shots/2018/03/09/589613244/the-30-ye... ). It seems NIH does not necessarily fund the most innovative and original research. Rather, the research that directors feel most passionate about gets funded.

You could have mentioned a perspective that links a focus on mutation acquisition with a its biological context: clonal evolution. Jamal-Hanjani et al. (NEJM 2017;376:2109-21) brought the language and concepts of evolutionary biology directly to bear on nsclc, That in turn can be used to identify the environmental factors that select for successful clones, and to look more closely at how they do so. And that could lay the groundwork for employing engineered clonal interference to contain genetically unstable clones.

My daughter did her graduate work in biogenetics at Arizona State University. The lab she worked in has millions of dollars of equipment. I have read that the industry is worth about $25 billion. Those who proclaim the success or failure of this industry seem to me to be making a premature judgment. I do not think genomics has run its course, though it may. Silicon Valley has had its share of bubbles and busts. The same can be said about genomics. At this point, I'd say, time will tell.

The pursuit of mutant cancer genes and drugs to target them has driven much of cancer research for decades. It became a frenzy after the enormous promises made about what would come from sequencing thousands of cancer genomes. Companies were founded and people - particularly those who over-sold the approach - undoubtedly got rich using government to subsidize their efforts. But it's been clear for some years that this approach was not working as promised. It's great that someone powerful has finally said so. Mukherjee could have called his article "The Emperor Has No Clothes" to follow up his magnificent book "The Emperor of All Maladies".

Understanding how malignant tumor growth occurs is one thing and developing anti-cancer drugs is another. Accumulating mutations is the a aspect of the first part, not the second part.

Dr. Mukerherjee is on target...again. I will be lecturing (tomorrow) on some of the limitations of personalized medicine in prostate cancer. We are making great progress in selected patients. As a long time researcher in targeted radiopharmaceuticals, I think the delivery of radiation in a precise manner is a terrific way to overcome some of the limitations of gene-directed precision therapies. I am grateful to Brian Druker and his ilk for all the many patients that "traditional" precision medicine has helped...and for the remarkable progress in immuno-oncology, but there is more to do... more avenues to explore, more patients in need.

1. Millions of people, world-wide, die or suffer terribly from diseases that are easily preventable or successfully treatable. Cancer is a terrible disease, but its impact upon potential years of otherwise health life is far less than that of maladies for which we have the keys of prevention and cure. 2. In medicine, most trials, seeking causation, prevention or cure, involve too few participants, too many variations in protocol, and too little information about the health and environmental histories of the participants. The first step in a radical improved change in the capabilities of healthcare will be the ongoing gathering of large amounts of data concerning many millions of people. Powerful computers would seek patterns that lead to illness and to healthy life. 3. The profit motive has probably been the greatest risk factor in the progress of medicine.

Phenotype is a gene by environment interaction. This part of basic biology that I teach to undergraduates in intro to biology applies to cancer. I am a beneficiary of targeted drug therapy for cancer. Because of genomic medicine I get to teach another generation of future scientists. Now we need to delve into the more complex interactions of cancer genetics. The easy work may be behind us and now the complex interactions need to be understood. Genomic data needs to be placed within the broader science of systems biology. We have known for a long time about things like epistasis, norms of reaction, pleiotropy etc. What these words mean is that knowing about the presence of a single gene mutation does not mean that you can predict the phenotype, cancer. You need to take into account the presence of other genes. A gene may give you cancer no matter what, or only if you have two or three other genes, that are not considered cancerous. We can do this, we need hard working smart people and the money to do the science.

Nice article, but is this about fashion in cancer research or in science reporting? All of the approaches mentioned are constantly under investigation, and the life's work of hundreds of researchers, so none of this is really new. And while it's true that cancer treatment has jumped on new opportunities, like targeted therapies and new immunotherapies, maybe that's entirely appropriate - when a new technology or approach comes along, it's worth trying all kinds of variants of it, knowing that many will fail but some will work. Ultimately, I don't know whether the apparent over-attention given to the new is a waste of resources, or an appropriate determination to fully exploit new discoveries. Quite likely, a bit of both, but that doesn't make for exciting science writing.

The author is neglecting the problem that cells within a tumor are far from identical. A healthy cell does a great deal of DNA proofreading and editing to increase the chances that a cell division leads to two identical cells. Our understanding of cancer is that the cells have lost this ability to proofread DNA, and therefore rapidly collect mutations. On one hand, these mutations make great therapeutic targets. However, it's almost impossible to find a tumor where *every* cell carries the mutation. The treatments may kill all of the cells with the target mutation, but some inevitably survive, multiply, and lead to a treatment resistant recurrence.

When will oncologists tear their eyes away from the glitter of genomic medicine and start studying, and using, existing, low-risk medicines for which there is already evidence of life prolongation in human cancer patients? For example, for many cancers, patients who have high-normal vitamin D levels at the time of diagnosis live longer than patients who are vitamin D deficient at that time. Yet there are no randomized trials that look at whether vitamin D replacement after diagnosis prolongs life. Several randomized trials show that cimetidine prolongs life in colorectal cancer patients, probably through a mechanism not related to histamine. But how many oncologists give cimetidine to their colorectal cancer patients? There are tantalizing hints that patients with uterine carcinosarcoma, my cancer, live longer if given metformin, but no proper studies on this cheap, low-risk, available drug have been done. When will oncologists develop more interest in using the tools they already have to prolong the lives of their patients?