Looking at this through the lens of drug discovery is the wrong way to do this. The problem is with our drug discovery strategy, generally, not with the reproducibility of our research.
STK33, for example, is definitely implicated in cancer through a wide variety of mechanisms. It is often mutated in tumors, and multiple studies have picked it up as having a role in driving migration, metastasis, etc.
This doesn't mean we can make good drugs to it.
Making drugs is hard - they need to be available in the tissue in the right concentrations, often difficult to achieve with a weird-shaped, sticky molecule. They need to have specificity for the tumor, they need to have specificity for the gene target(s) of interest. They need to be effective at modulating the target.
More importantly, though, the drug is modulating a target (gene) that is involved in a biological system that involves complex systems of feedback control, produces adaptive responses, and otherwise behaves in unexpected ways in response to modulation.
In my experience this is usually underappreciated by most drug discovery strategies, which merely seek to "inhibit the target" as if its involvement in the tumor process means we can simply treat it as an "on-off" switch for cancer. This assumption is asinine, and of course will (and does) lead to frequent failure. STK33 is not an on-off switch, and attempting to treat it that way will likely result in a drug that does nothing.
This is absolutely correct. Pharma companies are running into a wall and are flailing to figure out what to do. It's quite clear that from first principles bathing the entire body in trillions of little molecules hoping that they only and completely shut down a single kind of protein, at the right time, in the right place, of the right cell, and do nothing more, is insane. There is some logic behind the ability for a small molecule to help against invading diseases (the antibiotics of the 20th century), but the same strategy will philosophically not work for entire classes of cancers or other innate biological problems. Though we all somehow just assumed that it would.
The pharmacy of the future will be entirely curative to non-invading diseases, will repair the DNA that's been mutated, will express or inhibit the proteins that need to be expressed or inhibited. And small molecules will be the payload of these fancy protein-based nano-machines. But this hunt to bring down the cost of those small-molecule targets at the cost of the reputation of the science itself might be foolhardy when the cost is near-infinite in the first place because they're looking from the wrong perspective.
tldr; Pharmaceutical companies' hammer that worked so well against the nails of bacterial infection is in no way suited to the plumbing of cancer. And now they're 'investigating the plumbers' to figure out why their fancy new 50-billion-dollar "water-hammers" don't work so well to unclog pipes.
I agree it's challenging to create small molecule treatments for oncology. That said, there have been some recent, massive successes recently. Look at Imbruvica which is a massive jump forward in treating MCL and CLL.
Even if you drop small molecules and focus on antibodies, it's not like it's all that easier.
Certainly there are success stories when so much effort is put forward. But look at all the things even Imbruvica does in addition to helping treat cancer [1].
If you want to fix MCL you figure out how to engineer a genetic payload that targets B-cells IFF they express particular genes, and reengineer those cells' genomes to either no longer reproduce abnormally, or shut them down. You do NOT covalently turn off an entire class of kinases in the ENTIRE body...
And that's the success story. Antibodies are just the tip of the protein-iceberg. They're the 'same things as a small molecule' but in protein form - baby steps into a whole new world. Sure, they can bind to stuff tightly, but if that (alone) is what you're aiming for, then they're not being used to try to fix the problem or engineer a way to the solution. There's lots more that we could do if we started actually engineering the proteins and their interactions, and delivering them in directed ways. We have access to those primitive engineering tools, but instead of focusing on those nascent tools, we're polishing up the old hammer.
Well, the wall they are running into is kind of self inflicted. The cure(s) have been present before them since 1920s yet we are in this state.
First off, the medical science is itself based on wrong theories, see what Pasteur himself had to say "Terrain is everything, the Germ is nothing", yet the medical industry is hell bent on developing cures based on germs.
As for cancer,HIV and other incurable diseases many researchers have come forward, some of them include Rife, Nessens, William Koch, Oxygen therapy, Lakhovsky MWO, Priore device etc.
Unless we revise the our theories and procedures and look into the works of above reseachers, we will never find the cure.
The reason they do this is easy to understand: in science you try the simplest processes first, before you do something really complicated. If the drug companies are using this process is because there are still having successes (low hanging fruits) that can be achieved right here, right now. I agree that the best way to create effective drugs will involve more complicated processes that will take a long time to develop, but above all, to approve through regulatory agencies.
STK33, for example, is definitely implicated in cancer through a wide variety of mechanisms. It is often mutated in tumors, and multiple studies have picked it up as having a role in driving migration, metastasis, etc.
This doesn't mean we can make good drugs to it.
Making drugs is hard - they need to be available in the tissue in the right concentrations, often difficult to achieve with a weird-shaped, sticky molecule. They need to have specificity for the tumor, they need to have specificity for the gene target(s) of interest. They need to be effective at modulating the target.
More importantly, though, the drug is modulating a target (gene) that is involved in a biological system that involves complex systems of feedback control, produces adaptive responses, and otherwise behaves in unexpected ways in response to modulation.
In my experience this is usually underappreciated by most drug discovery strategies, which merely seek to "inhibit the target" as if its involvement in the tumor process means we can simply treat it as an "on-off" switch for cancer. This assumption is asinine, and of course will (and does) lead to frequent failure. STK33 is not an on-off switch, and attempting to treat it that way will likely result in a drug that does nothing.