Cancer is a terrible disease, and also one that we all know too well.
It is not a new problem, rather one that exists since thousands of years & is studied in unimaginable detail.
Then why do people still die of cancer?
Let's start understanding this by taking a step back.
It’s 1938, and Public Health Services are advising people that detecting and treating cancers early will save their lives.
Now fast-forward nowadays. We hear the exact same core message from the Public Health Services of our times, gradually and consistently backed up by more and more data.
How and why is public health advice from 1938 so relevant today, 85 years later? Does this mean we made no progress in curing cancer?
Certainly not.
Let me show you why👇
By zooming into cancer medical care in 1938, we quickly realize how rudimentary it actually was.
Think of radical mastectomy: a truly invasive procedure developed by William Stewart Halsted at the end of the 19th century, in which the whole breast, all lymph nodes under the arm, and the chest wall muscle were removed.
Radical mastectomies were still the norm following breast cancer diagnosis until 1970s.
Nowadays, such surgery is almost never done, and has been replaced by local removal of the tumor (lumpectomy), followed or preceded by multiple options of additional therapies.
Now, let’s better understand the real impressive transformations that cancer science & medical practice have undergone in the last decades. I’ve chosen 10 such milestones (1938-2023) to emphasize below.
This list is by no means exhaustive, rather simply a conceptual backbone.
1.
1941 - Hormonal Therapy for Prostate Cancer
Charles Huggins discovers that lowering testosterone production by removing the testicles or by giving estrogen leads to shrinkage of prostate tumors.
Hormonal therapy continues to be a main treatment for prostate cancer nowadays.
2.
1958 - Combination Chemotherapy
James F. Holland, Emil Freireich, and Emil Frei propose that using multiple chemotherapy agents simultaneously will make it more difficult for tumors to become resistant.
Their hypothesis builds upon generalizing the current state of art in tuberculosis treatment, in which the combination of antibiotics was more efficient than single agents.
Nowadays, combination chemotherapy is a widespread standard of care in cancer centers around the world.
3.
1978 - Tamoxifen
An anti-estrogen drug, originally developed as birth control treatment, is approved by the FDA for the treatment of estrogen receptor positive (ER+) advanced breast cancer.
In the following years, Tamoxifen was shown to also be effective for early disease.
Tamoxifen is a targeted treatment: it specifically targets only a particular type of cancerous cells (unlike chemotherapy).
It is delivered as a tablet, and is currently the gold standard treatment for ER+ breast cancers (80% of all newly-diagnosed breast cancers).
4.
1998 - Trastuzumab
FDA approves Herceptin (Trastuzumab), a monoclonal antibody that inhibits the tumor-stimulating effects of the over-expressed amplicon HER2, for the treatment of metastatic HER2+ breast cancers (and later on also for treating early-stage HER2+ disease).
Therapies involving Trastuzumab (usually in addition to chemotherapy) currently remain the gold standard in treating HER2+ breast cancers.
5.
2001 - Imatinib
FDA approves Imatinib (Gleevec) for the treatment of chronic myeloid leukemia (CML), transforming a cancer death sentence into a manageable condition.
Back in 1960s, Peter Nowell and David Hungerford (then a researcher at the University of Pennsylvania) found that CML patients had an abnormally short chromosome (later named the Philadelphia chromosome).
Later on, Nora Heisterkamp at NCI identifies the reason why the Philadelphia chromosome was shorter: when this chromosome forms, two genes get fused together, forming the BCR-ABL fusion protein.
Further, when this fusion happens in blood cells, it causes CML.
The drug Gleevec, first conceptualized by Brian Drucker at Oregon University, blocks this fusion, hence only targeting faulty cells that display it.
5 years after the first phase 1 clinical trial of Imatinib (1998), 98% of treated CML patients were disease-free.
Nowadays, Imatinib is a potential curative treatment: if a CML patient is in remission after 2 years of Imatinib treatment, their life expectancy is the same as a person who doesn’t have cancer.
In May 2001, this monumental discovery makes it on the cover of TIME magazine.
6.
2006 - Gardasil
On a completely different line of research, the first vaccine for the prevention of a human cancer is approved by the FDA in 2006.
Gardasil was originally developed by researchers at the University of Queensland in Australia.
It initially protected against infections from four Human Papillomavirus (HPV) strains: HPV16 and 18, causing 70% of cervical cancers, and HPV 6 and 11, causing 90% of genital warts.
The current form of this vaccine is Guardasil 9, which protects against 5 additional HRV types.
Harald zur Hansen, who contributed to proving that genital HPV infections can causally lead to cervical cancer, is awarded the Nobel Prize in 2008 for this discovery
The approval of Guardasil is an important step also as it is a prevention measure, rather than a cancer treatment
7.
2011 - Ipilimumab
In all fairness, the last decade belongs to immunotherapy, which aims to boost the natural body’s defense system to eliminate cancerous cells
The idea of unleashing the immune system against cancer goes many centuries back, but most progress is very recent
Ipilimumab is the first FDA-approved immune checkpoint inhibitor, which are monoclonal antibodies that release the breaks of the immune system to trigger immune-mediated anti-tumor responses.
Immune checkpoints themselves are molecules that work to maintain immune tolerance.
But these molecules are often used by tumor cells to their advantage, to evade immunosurveillance.
Ipilimumab activates the immune system by targeting CTLA-4, a co-inhibitory molecule expressed on T cells which negatively regulates T cell activation.
8.
2014 - Pembrolizumab (Keytruda)
The first PD-1 immune checkpoint inhibitor approved by the FDA.
PD-1 is expressed on the surface of several immune cell types (including T cells) and acts as a negative regulator of immune response.
Its ligand PDL-1 is expressed in normal tissues and regulates immune tolerance by suppressing T cell-mediated immune proliferation and cytokine secretion when binding to PD-1.
The interaction between PD-1 and PDL-1 diminishes immune activity & helps prevent autoimmune disease.
But, tumor cells hijack this mechanism and abnormally express PDL-1 to escape immune surveillance.
This is why antibodies targeting PD-1 or PDL-1 have been approved for the treatment of multiple cancer types.
Blockage of the PD-1 pathway has been very successful in the clinic.
In 2017, a conceptual shift in cancer immunotherapy takes place: Keytruda is approved for general use in any tumor with a certain genetic profile (based on tumor mutational burden), rather than specific sites.
9.
2017 - Kymirah (Tisagenlecleucel)
First chimeric antigen receptor (CAR) T cell therapy approved by FDA: T cells genetically modified & expanded ex vivo (outside the patient) to mount personalized tumor attacks, by targeting neoantigens (mutations displayed on cancer cells).
These engineered fighters are then infused back into the patient, with the idea of selectively attacking the cells they were designed to target.
A pioneering early-stage study coupled non-viral CAR-T therapy with CRISPR editing, showing promise for increased clinical efficacy.
twitter.com/simocristea/status/1594736869211869187?s=20
As of today, multiple cancer types show sustained clinical responses to immunotherapy.
But real drawbacks still exist
1) immunotherapy is expensive
2) response rates remain limited
3) there is no consistent satisfactory understanding of factors predicting these responses.
10.
2020 - AI in cancer
This decade belongs to artificial intelligence, which is quickly transforming the way we understand and interact with our own biology.
Large AI models can now efficiently learn the image features separating cancerous lesions from normal ones from large amounts of labeled data.
Such models are already deployed in medical centers across the world to assist with clinical cancer diagnosis.
The pace of change is extremely rapid, and powerful AI models will soon be able to
1) assist in efficient drug design
2) accurately predict patient-specific personalized responses to various therapies
3) flag high-risk conditions for clinical management, as a preventive measure
Ok, this all sounds truly impressive.
But how much does it matter in the end?
How do all these great therapeutic discoveries factor in for the one metric that we humans care about most: the time we have to live?
The harsh truth is: not great.
Despite impressive progress in cancer research, the drop in death rate from cancer is not as impressive.
This becomes even more apparent when compared with what used to be the main source of death in the developed world (cardiovascular disease), for which the drop has been twice as large.
Trend holds also for 🇨🇭, a best-case scenario for healthy lifestyle & optimal healthcare.
There are lots of complex reasons to explain these differences in magnitudes, some more intuitive than others.
Nevertheless, it does leave us thinking.
And it begs the question: why is progress against cancer so difficult?
The answer is that cancer is a relentless evolutionary process.
It evolves to escape most therapies we use against it, no matter how potent.
Every tumor is its own different word, and everything cancers want is to live.
Fighting an evolutionary desire to live is hard.
Cancer is a living process, but not a foreign one.
It is a living process living its own parallel life, as part of ours.
Gradually, it hijacks and overtakes our own inner working mechanisms.
This is why, conceptually, cancer is a very hard problem.
Because, in a sense, the enemy is ourselves.
It’s all different pieces of the same puzzle.
Now let’s get back to where we started.
1938: early cancers can be cured.
85 years later: can we now cure all early cancers?
Unfortunately not, and it’s also really, really complicated.
But, do we understand better today than in 1938 why this is?
Definitely.
And this takes us so much closer to where we want to be.
This was it for today's journey.
I will regularly post such essays on my newly-opened Substack, to make genomics knowledge more accessible.
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simocristea.substack.com/p/why-we-cant-yet-cure-cancer