Why Aren’t Cancer Drugs Better? The Targets Might Be Wrong

It feels like this article was cut short. My take-away wasn't that these mistakes were a complete failure but instead were clues as to where to look next. Many medical breakthroughs are discovered by mistake. What does this mean for improved survival? Could an additional step eradicate the cancer cells altogether? Why not keep going and find out what that next step is? I am a breast cancer survivor. In my early 40's, I had an extremely aggressive tumor with a high oncotype score, meaning it's likely I will experience a recurrence. When I first met my oncologist in 2017, I brought my research from medical journals/clinical trials to her office and asked about each new treatment. She just smiled and listened patiently. Then she said the best course of action was "slash and burn" (major surgery and chemo) – exactly the same treatment and the same chemo drugs that would have been recommended if it had been 1973. The only reason cancer has not been eradicated is because curing cancer has not been prioritized. R&D takes money and long term commitment, not just by Big Pharma but by the NIH and public institutions. When Big Pharma can make a mint off of a drug that might prolong life a few months or years, they have no incentive to find a cure.

It feels like this article was cut short. My take-away wasn't that these mistakes were a complete failure but instead were clues as to where to look next. Many medical breakthroughs are discovered by mistake. What does this mean for improved survival? Could an additional step eradicate the cancer cells altogether? Why not keep going and find out what that next step is? I am a breast cancer survivor. In my early 40's, I had an extremely aggressive tumor with a high oncotype score, meaning it's likely I will experience a recurrence. When I first met my oncologist in 2017, I brought my research from medical journals/clinical trials to her office and asked about each new treatment. She just smiled and listened patiently. Then she said the best course of action was "slash and burn" (major surgery and chemo) – exactly the same treatment and the same chemo drugs that would have been recommended if it had been 1973. The only reason cancer has not been eradicated is because curing cancer has not been prioritized. R&D takes money and long term commitment, not just by Big Pharma but by the NIH and public institutions. When Big Pharma can make a mint off of a drug that might prolong life a few months or years, they have no incentive to find a cure.

Decades, billions of dollars, millions of lives lost. What's taking so long? Big Pharma profits from sick people. Fact.

The central problem with cancer treatment is that cancer cells rapidly divide and have lost the ability to "proofread" DNA with each division. The result is that a tumor isn't a group of identical cells, but rather a collection of similar cells with a gargantuan number of mutations. It's almost statistically impossible for a particular target to be present in every cancer cell within a tumor. While it's certainly possible to create a drug that is highly effective against a particular target, there will almost never be a situation where that drug can eradicate ever last cancer cell. If even a single cancer cell survives, the cancer will likely recur, and the bulk of the cells will now be resistant to the previous treatment.

Cancer Is a complex disease with multiple characteristic features and behaviors known as the “Hallmarks of cancer”. [ Please read slowly because the next sentences are too long, with too many commas, dashes and phrases... it’s worth it to illustrate the overview of cancer molecular network activity - and to emphasize how multi-targeted anti-cancer molecular intervention is the way forward ] Each characteristic Hallmark of cancer is produced by multiple ongoing pro-cancer molecular activities - in multiple molecular pathways - concurrently. Molecular pathway activities are propagated through cascades of ongoing, concurrent, pro-cancer molecular SIGNALS - relayed along these overlapping molecular pathways - simultaneously. Molecular signaling is relayed in molecular ‘patterns of signaling traffic’ between and among multiple molecular sites in multiple pathways - concurrently and simultaneously. These multiple, concurrent, pro-cancer, molecular pathways ... exist in overlapping molecular NETWORKS of ongoing pro-cancer molecular signaling traffic ... producing the multiple overlapping Hallmarks of cancer. Each pro-cancer molecular signaling pathway consists of multiple molecular sites which are targets for anti-cancer molecular intervention (drug treatments). Targeting one molecular site on one pathway in one network is not enough. Ever. Precision medicine compels inevitable usage of multiple concurrent (well-tolerated) MULTI-TARGETED therapeutics - simultaneously

Its odd that the article reports on the failures between 2000-2015 but the last few years have seen many successes with immunotherapy/checkpoint inhibitors. I agree that there is much work to be done but why not take statistics that are up to date rather then picking dates for dramatic effect....its 2019.

As a molecular geneticist working with one of the canonical model organisms, I find this report of pharmaceutical company naivete _appalling._ RNAi is _notorious_ for the potential of misleading "off-target" effects. These "off-target" effects are often due to the fact that organisms have multiple copies of genes (and protein products) that are similar in structure & function. Such "functional redundancy" complicates even fundamental research in model organisms; humans with their more complex genomes offer more opportunities for functionally redundant related genes & proteins to muddy the water. I applaud the fact that two undergraduates had the perspicacity to see through the muddle and conduct the critical experiment. The shame of it is that highly paid professionals in a biotech/pharma company _ought_ to have done it a long time ago as part of routine validation of an RNAi-derived target. Precision gene-editing with CRISPR has been around for _years_ already.

Cancer cells have been found to rapidly and substantially mutate (Greenman et al, Nature 446, 153–158, 2007), and to change their phenotype, leading to, for example, drug resistance (Maguire et al, Expert Opin Drug Discov. 2006 Sep;1(4):351-9). Reductionist drug development strategies that target one or a few pathways therefore have been the bane of successful oncology therapeutics. Newer strategies that enable the immune system through "physiological renormalization" (Maguire et al, Physiol Rep. 2019 May;7(9):e14072) to better attack the cancer (https://news.berkeley.edu/2018/10/01/uc-berkeley-research-led-to-nobel-prize-winning-immunotherapy/ may provide a more efficacious and safer strategy.

Cancer is a billion-dollar industry...no one wants a cure...but the people who die from it.

this is a confusing article: it is reported that drugs targeting (ie inhibiting) a specific protein can cause cancer cells to die in a dish but when the gene encoding that protein is knocked-out (at the DNA level), the cells live. This isn't all that surprising in light of many reports that cells and, indeed, animals can often efficiently compensate for genetic loss of a gene but do (or cannot) compensate for acute disruption of protein function (by RNAi or a small molecule inhibitor). What is reported here could be yet another example? The million dollar question is: how does this 'genetic compensation' occur, by what mechanism?

I'm a little confused as to the conclusion that drugs currently in development should be scrapped because they targeted the "wrong" protein, even if most of the cancer cells subjected to them died anyway. By all means, refine the drugs further to target additional proteins. But if they work on 80%, say, of tumors that don't have another specific mutation, that's still a lot of patients that aren't left waiting another 10 years. But maybe I misunderstood something.

The author of the article seems to mix two concepts (target identification and drug development), incorrectly suggests that RNAi has no role in drug development and therapeutic use. Target selection for drug development is difficult, but that is that case no matter what technology the researchers are using for the target selection (e.g. RNAi, antibodies, CRISPR, etc.) because biology is complicated. Once a target has been validated, if used in the right way, the same technology (RNAi, antibodies, CRISPR, etc) can be turned into highly precise drugs. The first RNAi drug was approved by the FDA in 2018, and many more are being successfully developed, i.e. it looks like it will become a promising drug development platform technology.

Target selection is an issue for all types of medical research. Relationships between biomolecules and disease are not as clear-cut as is often assumed or taught. This is true in cancer - but is also true in cardiac disease and Alzheimer's disease.

With the work of many doctors including microbiologist Cristina Sánche, the study of cannabis and ErbB2-driven breast cancers has shown great promise. She has been vocal about popularizing the healing apoptotic effect of cannabinoids on cannabinoid receptor containing cancer cells while leaving the healthy cannabinoid receptor containing cells be. The sooner we deregulate this plant, the sooner we can start to study it seriously in America.

Why? Jobs! Jobs! Jobs!

The 1960s were a more productive decade for the development of cancer drugs than today. In the 1960s, if a drug killed cancer cells in culture or animals, it went to the clinic pretty quickly. Today, there is less concern on whether a drug works, compared to the so called mechanism through which the drug works. NIH, venture capital, and pharma are more interested in whether a drug is specific for a particular target rather than whether it works. Most successful drugs are somewhat "dirty" in that they affect several different mechanisms and thus are more likely to be effective than a compound that only affects one mechanism. In our quixotic quest for specificity, we have forgotten efficacy. What is most frustrating is that there are many compounds that are on the shelf that could treat cancer effectively, but will never be developed because they are not specific for a target. To paraphrase William Jennings Bryan "Mankind should not be crucified on the cross of specificity"

Why would they sell me a pill curing my cancer when they’re getting $1,500 a day for the ones I’m taking now?