We hear "cancer breakthrough" every year. But people keep dying.
We hear "this time's different". But it never is.
Why then am I excited about a new cancer drug the FDA just approved in August? [1]
Why do I think that this time, we are actually witnessing cancer's downfall?
Table of Contents
- The shaky foundation
- The undruggable wall
- Then came the trial
- Thirty-five days
- The fourth piece: a cancer vaccine
- Was Coley wrong, or just early?
- A vaccine built for one person
- Why I think we are witnessing cancer's downfall
- References
The shaky foundation
Well, in 2012, something alarming happened in the world of cancer research.
Two researchers called Glenn Begley and Lee Ellis noted that while our understanding of genetic mutations and how they drive cancer had expanded, our ability to translate cancer research to clinical success had been remarkably low. Clinical trials in oncology have the highest failure rate compared with other therapeutic areas. They went on to say: "this low success rate is not sustainable or acceptable" [2].
They suspected that the foundation that a lot of cancer research was built upon was shaky at best. The scientific community assumes that the claims in a preclinical study can be taken at face value. Unfortunately, this is not always the case.
So they went back and tested 53 landmark cancer papers, whose results laid the foundation for cancer drugs and targets.
They could only confirm the findings in six [2].
A later, independent project repeated experiments from twenty-three cancer biology papers. For the originally positive findings, the median effect in the repeat experiments was eighty-five percent smaller [3].
So I understand the skepticism. A cancer cell dying in a dish is a long way from a person living longer.
But recognizing this reproducibility crisis was the first step in correcting these errors, and allowing scientists to make actual progress.
That's not the reason why I think that this time, we are actually witnessing cancer's downfall.
Back to the cancer drug that the FDA approved in August.
The undruggable wall
In 1982, scientists studying a human bladder tumor found something that rewrote cancer biology. A single typo in the DNA, one wrong letter, was enough to turn a normal gene into one that drives cancer [4].
That gene belonged to a small family called RAS. RAS proteins are switches that tell cells to grow and divide. When the typo jams the switch "on," the cell never stops. The RAS family drives about nine in ten pancreatic cancers, and nearly one in five cancers of any kind [5].
You can see why drug companies wanted to block it.
But knowing which protein causes trouble doesn't tell you how to stop it.
The RAS protein is almost perfectly smooth. No pocket, no keyhole for a drug to fit into. Four decades of attempts failed, until the field gave it a nickname: undruggable [6].
In 2013 came the first crack. Jonathan Ostrem and colleagues at the University of California, San Francisco, found a way in: a hidden pocket. Their compounds could attach to a particular mutant form of the protein, called G12C, using a pocket that earlier structures hadn't revealed [7].
There was a catch. The attachment depended on the specific mutation. Change that mutation, and you lose the feature the drug needs.
The new drug, daraxonrasib, gave up on picking each version's lock. It uses another protein to help it bind. It first joins with a protein already inside the cell, called cyclophilin A. Together, they attach to active RAS and interfere with its growth signal [8].
This lets the drug block several common versions of RAS, including versions that matter in pancreatic cancer.
Then came the trial
Five hundred patients, across six countries. All with pancreatic cancer that had spread and had already come back after chemotherapy, about as grim a setting as oncology has. Half got the new drug, and the other half got standard chemotherapy.
Across all the patients, median survival was 6.7 months with chemotherapy. With daraxonrasib, it was 13.2 months [8].
At twelve months, 53.3 percent of the daraxonrasib group were alive, against 18.7 percent of the chemotherapy group [8].
About six and a half months difference between the medians, and it earned a standing ovation from cancer researchers and doctors when the results were announced [9].
Six and a half months is clearly not the reason why I think we are witnessing cancer's downfall. What I'm doing is building you a picture and putting pieces on the table. And once you see the pieces on the table, it fits together and explains why I'm so optimistic.
So far, we have recognition and correction of the reproducibility crisis, and a previously "undruggable" target that in August received FDA approval in record time.
Thirty-five days
Which is the third piece. The FDA accepted the application on July 22. It approved the drug on August 26. Thirty-five days. There's an effort right now to speed up the regulatory process [1].
While the application was still sitting at the FDA, the agency had already cleared an expanded-access program, a legal route for dying patients to get an unapproved drug. Since May, that program has sent daraxonrasib out to doctors on behalf of more than 2,000 patients, across nearly all fifty states [10].
This is critical, because mutated RAS proteins aren't only related to pancreatic cancer. The same gene drives about half of colorectal cancers and roughly a third of lung cancers [11]. And the RAS gene family stands behind nearly 20 percent of all cancers [5].
It's already being tested in lung cancer [12]. And it's being combined with other therapies.
Which brings me onto the fourth piece. Something that's only possible now because of the advances in AI.
A cancer vaccine.
The fourth piece: a cancer vaccine
In the summer of 1890, a seventeen-year-old named Bessie Dashiell caught her hand between two train-car seats. The pain wouldn't go away.
A biopsy found an aggressive bone cancer, a sarcoma. Surgeons amputated her arm below the elbow. It wasn't enough. The cancer had already spread, and in January 1891, Bessie died [13].
Her surgeon was a young New Yorker named William Coley, and her death broke something in him. He spent weeks combing the hospital's old records for anything that might have saved her.
What he discovered would pave the way, 135 years later, for the first Phase 3 win for a cancer vaccine that was personalized to each individual patient.
And it caused the stock price of Moderna, who built it, to soar by 177 percent in a single day. The largest single-day percentage gain in the S&P 500 this century.
Deep in those files, Coley found a case from seven years before. Fred Stein, a German immigrant, had a sarcoma on his neck that kept growing back after every operation. His doctors called him hopeless. Then Stein caught a severe strep skin infection that tore through hospital wards before antibiotics existed.
And as the infection raged, his tumor melted away.
Coley had to know how that story ended. He spent weeks knocking on doors through the tenements of the Lower East Side, and found Stein. Alive, seven years on. No sign of cancer [14].
Was it the immune system activation to fight off the infection that also caused the cancer to go away?
So in 1891, Coley did something that would end a career today. He took a patient named Zola, an Italian immigrant with a tumor in his tonsil that was too advanced to cut out, and deliberately infected him.
Zola's tumor regressed completely. He stayed cancer-free for years, before, eventually, the tumor returned [15] [13].
Coley turned that observation into a treatment: killed bacteria, injected as "Coley's Toxins," given to roughly a thousand patients. Some tumours regressed, but the results were unpredictable and the treatment faced substantial criticism [16].
Which left a question hanging for eighty years: was Coley wrong, or just early?
Was Coley wrong, or just early?
For most of the twentieth century, the answer looked like "wrong."
But in 1976, a urologist injected the tuberculosis vaccine directly into the bladders of nine bladder-cancer patients. It worked. Fifty years later, it is still standard care for high-risk early bladder cancer [17].
In the years that followed, the idea of using the immune system to target cancer grew.
Yet making vaccines against cancer remained difficult.
Across 1,306 vaccine treatments, the objective response rate, tumors actually, measurably shrinking, was only 3.3 percent [18].
What was going wrong?
If immune cells can kill cancer, why can't a vaccine reliably tell them which cells to attack?
One problem is that a cancer cell is still, in many ways, one of your own cells.
Now look at the failed cancer vaccines. Most pointed the immune system at proteins that cancer shares with the body. That's the explanation for the failures.
But a mutation can produce a protein fragment that healthy cells don't have. Scientists call these new targets neoantigens [19].
Now the immune system has something more specific to recognize.
Which leaves one problem. Your tumor's mutations are not my tumor's mutations. Every patient's target list is different. A shelf vaccine can't work. You'd need a personalized vaccine per patient.
A vaccine built for one person
Here's what's required.
First: sequence the patient's tumor and their healthy blood, and subtract. Whatever is mutated in the tumor but not the blood goes on the candidate list.
Second: predict which of those mutant fragments the patient's immune system can actually display on the cell surface. A target the immune system can't see is useless.
Neural AI networks do that prediction, trained on hundreds of thousands, and later more than thirteen million, measured examples of which fragments bind [20] [21].
And in August, the breakthrough came.
1,137 patients were enrolled in a phase 3 study. These patients had their melanoma surgically removed, the melanoma cells were analyzed by the AI platform Moderna created, and a personalized vaccine was produced.
The group who received their personalized cancer vaccine improved the time they lived without their cancer returning or dying.
The trial's principal investigator is Georgina Long of Melanoma Institute Australia, joint 2024 Australian of the Year. Her words: the first Phase 3 study to show that a therapy designed on "the unique mutational 'fingerprint' of a patient's own tumor" can reduce the risk of recurrence or death [22].
Melanoma is one of the most heavily mutated cancers there is, the most raw material for neoantigens; so in theory, one of the easier cancers to build these personalized treatments for.
Merck and Moderna alone are running nine trials of this therapy: two in melanoma, four in lung cancer (three already at Phase 3), one in kidney, two in bladder [23].
And buried in that list is one of my favorite details in this entire story: in high-risk early bladder cancer, it's being trialled alongside BCG, the same tuberculosis vaccine instilled in 1976 [23].
This in my view is the main reason why Moderna's stock price jumped so much. The hope is that this personalized treatment can be translated onto other types of cancer.
And it's bigger than one partnership. In May, Nature Reviews Drug Discovery mapped the whole clinical pipeline of therapeutic cancer vaccines [24].
Why I think we are witnessing cancer's downfall
Here's why I think we are witnessing cancer's downfall. Not witnessed. Witnessing.
We have recognition and correction of the shaky foundation of cancer research.
We can now successfully target previously "undruggable" proteins, and these drugs are now FDA approved. This isn't some hope for the future. The drug is here now.
We have a regulatory framework that is fast-tracking these drugs, and allowing people to try them while the FDA process is ongoing.
We can combine these breakthroughs with existing treatments, and with new personalized treatments such as the cancer vaccines.
And we have AlphaFold, which predicts the 3D structure of proteins from their amino acid sequences, and how proteins and drug molecules fit together.
The pace of genuine breakthroughs and innovation that reaches real patients, rather than failing in the lab, is speeding up.
Better treatments also leave another problem to understand: why some cancers are becoming more common in younger adults.
References
2. https://www.nature.com/articles/483531a
3. https://elifesciences.org/articles/71601
4. https://www.nature.com/articles/300149a0
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC7367715/
6. https://www.nature.com/articles/s41392-021-00780-4
7. https://www.nature.com/articles/nature12796
8. https://www.nejm.org/doi/full/10.1056/NEJMoa2605555
9. https://x.com/DrSamuelBHume/status/2061225858384248845
11. https://www.cancerbiomed.org/content/22/7/762
13. https://www.cancerresearch.org/blog/the-legacy-of-bessie-dashiell
14. https://pmc.ncbi.nlm.nih.gov/articles/PMC1888599/
15. https://www.thepharmacologist.org/william-coley
16. https://pmc.ncbi.nlm.nih.gov/articles/PMC7232517/
17. https://journals.asm.org/doi/10.1128/cmr.00194-23
18. https://pmc.ncbi.nlm.nih.gov/articles/PMC1435696/
19. https://www.science.org/doi/10.1126/science.aaa4971
20. https://academic.oup.com/jimmunol/article/199/9/3360/7977122
