An explanation for what’s driving drug development
In one of the most highly cited cancer papers, The Hallmarks of Cancer1, researchers Doug Hanahan and Bob Weinberg described six common traits of cancer. Their 2011 update, Hallmarks of Cancer: The Next Generation2, added two more traits for a total of eight “hallmarks” of cancer. They also describe an additional two “enabling characteristics” that are not necessary, but if present, hasten the cancer process.
The hallmarks listed in these papers are understood by every cancer researcher and referenced by thousands of research papers. This is what researchers know and you don’t – yet.
What Does This Mean For Patients?
- The time needed to accumulate all these impairments explains why cancers are more likely as we age.
- The requirement to have all these impairments together explains why cancers develop so rarely.
- Inheriting a mutation of an enabling characteristic explains why hereditary cancers develop in younger people. In essence the deck is stacked against them.
- A treatment targeting any one of these hallmarks would prevent a tumor from developing.
Implications for Cancer Treatment
The last item above explains a lot about the current direction of cancer drug development. If you were to repair any of these functions, you could potentially stop cancer. Targeted treatments being developed today attempt to repair one or more of these traits in an effort to halt cancer growth.
For example, one hallmark is that cancer cells evade detection by the immune system. This means that cancer cells have developed some way to keep the immune system from recognizing the cancer cells as undesirable. Current immunotherapy drugs are trying to “fix” the immune response to recognize the cancer cells. In pancreatic cancer, treatments currently in later-stage clinical trials that target this hallmark include GVAX vaccine (Johns Hopkins & Aduro BioTech), Algenpantucel-L (NewLink Genetics), CAR T-cell therapy (U of Penn)4.
Patients should note that when cancer cells are targeted in a specific hallmark, they will often develop an alternate method of re-impairing the hallmark function and continue growing as a tumor. For example, there are many ways of deactivating the immune system. Fixing one part of the immune response usually leads to the cancer cells developing an alternate method to halt the immune response. Cancer cells’ ability to continue mutating as they divide means they can eventually stumble on an alternate mechanism. I imagine the tumor as a massively parallel computer that can try thousands of mutation experiments simultaneously where only needs one to succeed at foiling the treatment. Researchers can only target a specific one of these mechanisms at a time.
In the future, perhaps we will combine these therapies in a multi-pronged attack on cancer cells such as is proposed for NSCLC5? Or alternating between two effective treatments to keep cancer from developing resistances? I suspect that this process is at the beginning of a long road.
Hallmarks of Cancer
Here are the hallmarks of cancer in plainer English. The explanation in FutureLearn‘s MOOC Cancer and the Genomic Revolution6 was well presented.
| Hallmark1, 2 | Example Therapeutic Targets2 |
|---|---|
| Growth signals stuck ON | EGFR Inhibitors |
| Ignore anti-growth signals | Cyclin-dependent Kinase Inhibitors |
| No "kill" switch | Proapoptotic BH3 Mimetics |
| Unlimited replication | Telomerase Inhibitors |
| Compels new blood supplies | VEGF signaling Inhibitors |
| Migrate to other organs | HGF/c-Met Inhibitors |
| Energy production using little O2 | Aerobic Glycolysis Inhibitors |
| Deactivate immune system | Immune Activating anti-CTLA4 mAb |
| Enabling Characteristic2 | |
| Easier Mutation | PARP Inhibitors |
| Favorable inflammation environment | Anti-inflammatory drugs |
I’ll try describing the hallmarks of cancer with an automobile factory analogy. In this analogy, cancer cells are automobiles and uncontrolled growth is accomplished by means of the factory building these autos. These automobiles are often defective, unsafe, but they’re practically free and plentiful. But because of the random defects in these autos, many of them don’t even work at all. But some do and they can have scary defects.
In a more correct analogy, each tumor cell is its own factory producing more defective cars, but we’ll stick with the one factory for now.
The heading for each Hallmark is followed by the name from the original paper in italics and in parentheses. I think you’ll understand why I’ve interpreted them.
Always ON Growth Signals (Sustaining Proliferative Signaling)
One attribute of cancer cells is that they are always replicating, growing the tumor larger and larger.
In our automobile factory, the assembly line never stops. It is working three shifts every day of the year, putting our defective cars out on the road.
Ignore Anti-Growth Signals (Evading Growth Suppressors)
Cancer cells ignore signals that neighboring cells send saying that there’s enough of them and they should stop dividing.
Our dealerships can’t even store all the cars we’re making. They are saying, “Stop! We don’t want any more of your cars!” But their pleas fall on deaf ears. This factory keeps producing cars.
No Kill Switch (Resisting Cell Death)
Cancer cells are made with lots of mistakes in their DNA. Normally, if those defects cannot be fixed, the cell is instructed to kill itself.
Our workers are pretty sloppy and we’re always producing cars with random mistakes. But in our factory, we have no quality control so that all cars are shipped. A lot of them don’t work at all. But some of them do and have some pretty scary attributes. In some, the brakes don’t work. In others, the accelerators are stuck on. In still others, airbags won’t deploy. All defects that should be caught and cause these autos to never see the light of day. But we’ve got no quality control so every car ships.
Unlimited Replication (Enabling Replicative Immortality)
Cancer cells can replicate themselves almost without limit. Normal cells can only replicate up to about 20 times. Their telomeres are shortened by every replication, but cancer cells have found a way to replicate without shortening their telomeres.
In our factory, the robots, machines and tools never wear out or break down. We can produce cars almost without limit.
Compel New Blood Supplies (Inducing Angiogenesis)
Cancer tumors grow very rapidly but still need to be supplied with blood and nutrients. These cells send out signals tricking arteries into branching into the growing tumor.
Our factory managers have bribed their suppliers to provide all the raw materials we need to continue making our cars. They’re not paying them properly and we’ve resorted to trickery to obtain our supplies.
Migrate to Other Organs (Activating Invasion & Metastasis)
Eventually cancer cells develop a way to metastasize. As an example, a cluster of perhaps 100 cells detaches from the tumor, entering the blood stream and gets caught by the liver as it tries to filter out impurities. There it lodges and starts to grow inside the new organ.
This automobile factory becomes so successful at producing cars that the managers decide to open a new factory in another state or country.
Energy Production Using Little O2 (Deregulating Cellular Energetics)
Cancer cells use sugar in a different way than normal cells. For not well-understood reasons, cancer cells have developed a less efficient process to make energy that also uses less oxygen.
Our factory needs lots and lots of energy to make these cars, 24×7. We have access to the same power source that any factory would have, but we also have solar and wind power to supply our energy demands. We’ve developed alternate sources of energy.
Deactivate the Immune System (Avoiding Immune Destruction)
Cancer cells are really normal cells that have mutated to have all the above attributes. The immune system does not recognize them as foreign invaders because they really aren’t – they came from inside our own bodies. Even if the immune system did start to attack, cancer cells have figured out how to distract the immune cells.
Our factory has figured out how to avoid government regulations. We keep producing defective cars, cheating our suppliers, have unapproved power sources, and clearly run afoul of labor laws, but no one comes in to shut us down. Perhaps the factor owners have paid “protection money” to keep regulators looking the other way?
Summary
Articles like The Hallmarks of Cancer provide an insight into the thinking of researchers. Understanding the Hallmarks can help direct you to promising treatments and understand why we’re not at a curative treatment stage yet. Highly mutative tumor cells can bypass any single drug we develop. Eventually we may develop enough targeted treatments that used together will halt cancer growth.
To me, it reinforces the idea that surgical removal is still the best and only pancreatic curative option. Working towards that option will be my primary goal.
References
[1] Hanahan D, Weinberg RA (January 2000). “The Hallmarks of Cancer”. Cell 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9. PMID 10647931
[2] Hanahan, D.; Weinberg, R. A. (2011). “Hallmarks of Cancer: The Next Generation”. Cell 144 (5): 646–674. doi:10.1016/j.cell.2011.02.013. PMID 21376230
[3] Scowcroft, Henry (2010). Science blog: http://scienceblog.cancerresearchuk.org/2010/11/10/ncri-conference-the-hallmarks-of-cancer/
[4] Cancer Research Institute’s Pancreatic Cancer web page (accessed 7 Aug 2015) http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/pancreatic-cancer
[5] Turke, Alexa B, et al. (January 2010). “Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC”. Cancer Cell 17 (1): 77-88. doi:10.1016/j.ccr.2009.11.022. PMID 20129249
[6] FutureLearn MOOC, Cancer and the Genomic Revolution, University of Glasgow. https://www.futurelearn.com/courses/cancer-and-the-genomic-revolution/
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