The “War on Cancer”
Over 40 years ago, USA president Richard Nixon signed a document called “The National Cancer Act” which solidified the commitment of the government to fighting the raising rates of cancer. This later became know as the starting point for the very catchy-sounding “War on Cancer”.
A few decades after the big question is: are we winning the war? The short answer is unfortunately: no, we are not. The incidence and mortality of cancer worldwide is gradually increasing and showing no signs of slowing down – both of these are predicted to almost double by 2040!
This is despite our increasing knowledge of the causes of cancer and the new emerging treatment options. Indeed, this year’s Nobel Prize in Physiology or Medicine was awarded to James Allison and Tasuku Honjo for their amazing contributions to development of cancer immunotherapy. Importantly, important initiatives are being established for cancer prevention worldwide (this is an area I am truly passionate about as up to 50% of cancers are estimated to be preventable). Global tobacco control, introduction of the sugar tax and HPV vaccination are just few notable examples of such efforts.
There is a plethora of incredible breakthroughs and genius ideas in the field of cancer research. Below is what I consider to be the most elegant example of outside-the-box thinking about cancer therapy. But before we get into that, let’s remind ourselves how our cells protect the genetic code from damage (this will be very important for understanding the work covered in the later paragraphs).
DNA repair pathways
The DNA is the instruction manual of sorts for all the cells that make up our body. Within its code, there are over 20,000 genes which provide information about how to make the proteins that allow the cells to function, survive and form higher order structures such as tissues, organs and indeed the human body. As such, it is of upmost importance that the cells prevent any damage to this genetic code as that can lead to a multitude of diseases, most notably cancer.
The cells are hence equipped with a comprehensive DNA repair machinery that recognises and repairs any damage occurring to the genetic code. Such insults can either be of endogenous (i.e. from within the body; for example radical oxygen species produced as part of the cellular metabolism) or exogenous (i.e. environmental; for example UV light or chemicals found in cigarette smoke) nature.
Broadly speaking, there are four main DNA repair pathways: base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER) and double strand break repair. The later system actually consists of two separate mechanisms: the error-prone non-homologous end joining (NHEJ) and error-free homology-directed repair (HDR). In the next paragraph, we will focus specifically on BER and HDR, and how targeting one of these pathways in tumour cells deficient in the other pathway brought about one of the most promising cancer therapies of our time. If you are interested in learning more about the individual repair pathways and their link to cancer, click here for an in-depth review of these.
How to “over-mutate” the cancer cells
Some of us would have heard of the BRCA1 and BRCA2 mutations that increase the risk of both breast and ovarian cancer in women. Most notably, Angelina Jolie raised awareness of this when she underwent double mastectomy (removal of both breasts) surgery in 2013 after she was found to carry a mutation in the BRCA1 gene, which drastically increased the risk of her getting the two aforementioned cancers. Because that mutation was hereditary, this means that all of Angelina’s cells have one copy of that gene mutated and hence inactivated. This means that all it takes for her to develop cancer is to loose the other, “healthy” copy of the gene (either through mutation or other inactivating mechanisms)
The two genes mentioned above are a part of the HDR pathway alluded to earlier. This DNA repair mechanism relies on the presence of the other copy of the damaged DNA fragment in the cells. It uses said undamaged copy as a template to repair the DNA in an error-free manner. When the BRCA genes are mutated, the cell starts to accumulate mutations that can lead to cancer development. In these cancer cells, the HDR pathway is not functioning, so the cells rely on other pathways, most notably the BER pathway.
What a team of scientists from London and Cambridge have figured out back in 2005 (click here to access the original article), is that when you inhibit the BER pathway as well in these HDR-deficient cells, they will accumulate so many mutations they will die. They inhibited an enzyme called PARP, which lead to cells accumulating double-strand DNA breaks that are normally repaired by the HDR system. However, in the cancer cells carrying mutations in both copies of either BRCA1 or BRCA2 gene that pathway is of course not working, so these cells undergo a process called apoptosis (programmed cell death) and die. This concept has been termed “synthetic lethality” The beauty of this approach is that only the cells deficient in the HDR system (which will be the cancerous or pre-cancerous cells) will be killed by this approach and hence it will have very high specificity and low toxicity. Now, isn’t this just brilliant?
There are now multiple drugs targeting the PARP enzymes (reviewed briefly here). The first and most notable of those is Olaparib (manufactured by AstraZeneca). It first gained approval as a therapy for platinum-sensitive ovarian cancer positive for the BRCA mutations, but it is now investigated in clinical trials for treatment of breast and gastric cancers as well.
For me personally, the genius of this research lies in the amazing, outside-the-box thinking of the researchers. Indeed, during a conversation I had a pleasure to have with a senior scientist from AstraZeneca one of us might have even said that they were “thinking so far outside the box they couldn’t even see the box anymore” (please don’t judge us, we were both incredibly excited by this research and the promise it holds for cancer therapy!). Instead of the canonical and simple approach, which would be to try and restore the HDR pathway to prevent the accumulation of mutations, they did the unthinkable and inhibited an additional DNA pathway! I say unthinkable, because it went against the whole field of research at the time. It beautifully shows the importance of people who can think beyond the established dogma and the real difference they can make in the world…
I hope you enjoyed the article – as always let me know your thoughts in the comments.
- More information on the National Cancer Act of 1971: https://www.cancer.gov/about-nci/legislative/history/national-cancer-act-1971
- Global cancer incidence data for 2018 and 2040:
- Cancer statistics for the United Kingdom:
- An in-depth review of DNA pathways in the context of cancer:
- The original article about PARP inhibition:
or if you don’t have access to Nature articles, try:
- Short review about PARP-targeting agents: