Is there such a thing as a “cure for cancer”?

Well, “cure” is a strong word, and no one in oncology really likes it, whether medical doctors, pathologists, or scientists, because cancer has the bad habit of coming back, even years later, and so the word “cure” holds a promise that no professional feels comfortable in giving.

The closest thing to a “cure” for cancer that we have right now is surgery and certain prevention strategies, such as vaccines against particular viruses linked to certain cancers. The simple removal of the threat naturally neutralizes it. Of course, to take out the tumour in time, you need to know it’s there and this is where early detection saves lives and allows for curing certain cancers. However, detection of early-stage is easier in certain organs than others. Detection of tumours in internal organs or the vascular or lymphatic system is much harder than, for example, skin or breast tumours.

But are there any potential cures besides surgery? Or will there be?

Initially, cancer was so scary and so poorly understood that other than removing it, there didn’t seem to be any other option. Then, with the discovery of radiation and the usage of radiography towards tumours, radiotherapy started being implemented as a treatment.

Radiation induces DNA damage, which occurs mostly when cells are dividing and it triggers an induced-death mechanism by the DNA repair machinery and our immune system. Since malignant tumour cells are dividing faster (higher proliferation rate) than the surrounding healthy ones, it’s assumed that radiotherapy will affect mostly the tumour cells and not so much the healthy ones.

This theory has proven to be correct and it has evolved greatly, to become more localized to reduce any potential side effects in nearby cells and tissues. Radiation can be applied as an external beam, or internally (brachytherapy) through the usage of needles, spheres, catheters, etc. It’s a field on its own and has evolved greatly, due to the advancement of technology and 3D imaging, allowing for more localized administration of radiotherapy.

Chemotherapy is what most people think of when they think of cancer treatments. It started around 1940, and it refers to drugs that prevent cancer cells from dividing and proliferating or that kill them because they proliferate at higher rates than healthy cells, similar to the principle behind radiotherapy. However, this type of treatment can’t really be done locally and has serious side effects. Most of the side effects people associate with cancer are actually caused by the chemotherapy itself (loss of hair, extreme fatigue, susceptibility to infections, loss of appetite, feeling sick, nausea and vomiting, mouth sores, easy bruising and bleeding, etc). Not to say that certain cancers don’t cause these, but in general terms, these are side effects of chemotherapy.

Chemotherapeutic agents can be classified into different groups:

  • Alkylating agents – induce DNA damage (preventing proliferation)
  • Anti-metabolites – block enzymatic chains (preventing proliferation)
  • Antibiotics with anti-tumour function – interfere with DNA replication (preventing proliferation)
  • Plant alkaloids (topoisomerase inhibitors) – interfere with DNA replication or protein production (preventing proliferation)
  • Corticosteroids (hormones or hormone-like drugs) – fight directly against certain types of cancer (by increasing neutrophils and reducing other white blood cells), or indirectly (by alleviating certain side effects of other chemotherapeutic drugs)

This type of treatment has been considered successful as well and the improvements being done in this field are, similarly to radiotherapy, related to developing ways of local administration of these drugs, to minimize exposure and side effects.

Other types of treatments include targeted therapy, hormonal therapy, and immune therapy.

Targeted therapy is the development of antibodies or molecules that will disrupt a certain signaling pathway, interfering with specific cell functions. For example, there is a protein called epidermal growth factor (EGF), which is a powerful stimulator of cell proliferation, migration and invasion, among other functions. In breast cancer, there is a subtype of cancer that is characterized by a mutation in the EGF receptor 2 gene (HER2), which leads to a higher number of these receptors in those cells. Having more receptors means that these cells will have an overreaction (overstimulation) when EGF is present in comparison to normal cells. A similar mutation is present in certain lung cancers, in the EGF receptor 1 gene (EGFR). So targeted therapy can be an antibody or a molecule that binds to EGF itself or to one of the receptors and blocks them. By preventing EGF from binding to the receptor, we are reducing the stimulatory effect of cell proliferation, migration and invasion in those cancer cells. The theory of it is that cancer cells will be more vulnerable because it’s that mutation that is giving them an unnatural advantage over the normal cells. Therefore, blocking this pathway will prevent these cells from proliferating and allow for other treatments to be more effective.

The main difference from chemotherapy is that targeted therapy will target a specific part of a signaling pathway, instead of a wide approach. It’s like using bait on a hook instead of a wide net to catch a fish. However, because normal cells need and use these proteins, like EGF and its receptors, it still presents side effects as well, like high blood pressure, vomiting, skin problems, and problems with blood clotting and wound healing.

Hormonal therapy is mostly used for cancer types that are responding abnormally to certain hormones (hormone-responsive or hormone-dependent). For instance, certain types of breast cancer have mutations in estrogen and/or progesterone receptors. Using the same logic as described above with EGF, reducing the amount of circulating hormones, will reduce the stimulatory effect over the cancer cells. However, again, these hormones are essential to other body functions, and so the side effects are also very devastating for the patients.

Immunotherapy is the most exciting and successful field, especially considering side effects. Considering that cancer cells avoid immune destruction but also, as recently discovered, cancer cells manipulate certain immune cells nearby to protect them, it became very clear that optimizing our immune system against cancer cells is a great idea. The strategies are wide but can be summed up in two directions. On one hand, by using something similar to target therapy, as in using antibodies or molecules to inhibit certain pathways, to regulate the immune system. On the other, to stimulate the immune system to target the cancer cells. The combination of immunotherapy with any other treatment has proven quite useful and is now one of the main fields of interest and expansion moving forward.

Is it enough?

Ultimately, the scientific community has created many different treatment options that successfully destroy cancer cells… but at what cost? These treatments cause such loss to the patients, in terms of well-being, parenthood, comfort, immune protection, and even so, don’t offer any guarantees that cancer won’t relapse. With this in mind, we all agree, we need to do better.

 In the continuous effort to improve treatments efficacy and to improve patients’ comfort and overall quality of life, a new type of approach has started being developed – molecular medicine.

Molecular medicine consists of gathering molecular information from the patient such as biomarkers, epigenetic factors, gene profile, and previous treatment response, and combining it with previous records. This allows for patient stratification, in which each patient is grouped based on best registered treatment response and which “molecular indicator” best correlates with attribution of a given treatment. This approach recognizes that each type of cancer is divided into different subtypes, and within the different subtypes, each patient has a unique biological background and that within the patient’s tumour there are different types of cancer cells with different levels of sensitivity to drugs. It takes into consideration. This approach ultimately allows to avoid or postpone the development of resistant cancer cells while reducing the dosage of certain treatments and therefore, reducing side effects.

However, this field is still extremely limited to our understanding of how these different types of cancer work and which “molecular indicators” are most relevant.

So, what is in our future?

The future is personalized and Personalized Medicine is an approach of medicine that is patient-specific in every way. It’s about taking into consideration a person’s unique genome (all the genes in the body, expressed or not), proteome (all the proteins in the body), epigenome (all the epigenetic factors and how they interfere with genome expression), microbiome (genome of all the microorganism living within the body), lifestyle and other factors to diagnose and plan a specific treatment and determine a specific prognosis for that patient.

The three most promising tracks are the evolution of targeted therapy, the evolution of immunotherapy, and the evolution of metabolic therapy. All of which will be achieved not only through the development of better drugs but also by using gene editing and gene-edited cells.

Evolution of targeted therapy and immunotherapy:

The evolution of targeted therapy and immunotherapy consists on first, improving our understanding of these complex signaling pathways and mechanisms in each type of cancer; second, in developing better and more precise ways of local administration; third pairing or combining drugs to reduce dosage (therefore, side effects) and resistance; fourth to explore already existing drugs and repurpose them. These processes will be greatly improved by the evolution of disease models and usage of artificial intelligence, which I elaborate more on below.

Evolution of metabolic therapy:

The discovery that cancer cells adapt to their different metabolic rates (high consumption of glucose, poor energy production due to anaerobic environment, consequent production of lactic acid, etc) has led to an expansion in metabolomics in cancer (the study of all metabolic processes). In this field, there is strong evidence of how our microbiome determines how well our body may respond to certain treatments. This means that what we eat and our individual gut microbiome interferes with the effectiveness of treatments in the rest of our body, in direct and indirect ways.

Cancer can’t be cured by how you eat, but the treatment response can be improved by managing diet and supplementation carefully. The more we understand about this very complex field, the more potential new treatment approaches will develop.

Evolution of gene-editing and gene-edited cells:

Gene-editing consists in modifying certain genes to either silence them (prevent them from producing a malfunctioning protein or to express that protein in large amounts) or induce a certain gene expression and consequently the production of a specific protein that can help improve the disease. Another approach is to edit the cells in vitro and then administer them to the patients. One of these revolutionary approaches is the use of Chimeric Antigen receptor – T cells (CAR-T cell therapy), which requires collecting T cells from the patient or a healthy donor and then genetically modifying them to express a specific antigen receptor. This stimulates the T cells of the patient to target a specific protein.

Disease Models

Another parallel step in cutting-edge treatment is the improvement of disease models. Disease models are greatly used to help study how certain diseases develop and especially how they respond to certain drugs. The development of new treatments is inevitably dependant on the quality of our research and understanding of what each cancer in each patient represents.  If we can generate in vitro models that reproduce accurately how a specific patient will respond to treatment, we will not only provide with better dosage (reducing side effects) but also be able to mitigate possible resistance and re-emergence of cancer. We will be able to use these models to find new targets, predict what resistance mechanisms might develop, use them to discover new biomarkers that help with patient stratification or even with earlier diagnosis.

Until now, the disease models consist of 2 dimensional (2D) or spheroid (3D) models, using cell lines, and animals (in vivo), particularly the mouse, in which we use vast gene-editing tools to mimic human diseases or even inject the mouse with human cancer (xenograft model). While the first models are entirely human-based, they correlate poorly with the patient response because they are cultivated in vitro, isolated from other cell types, organs, and vascular, lymphatic, and nervous systems. The mouse models do provide a multiorgan system but naturally can’t recapitulate in its entirety a human response either.

Improving these models is crucial for the improvement of treatment and early diagnosis.

Currently, three main developing tools show great potential and are showing a better correlation with patient responses (although it’s still a very early technological development). These tools are organoids and induced pluripotent stem cells (iPSC) and artificial intelligence.

Organoids are very small functional representations of a certain organ, and with the development of bioengineering and nanomaterials, it’s an expanding field that is leading to the generation of multi-organoids that are interconnected in microfluidic chips, recreating a small version of a multi-organ body. This bridges the advantages of the current models explained above (cell lines and animal models). However, the main obstacles are the lack of consistency in organoid production, limits in how many organoids can be interconnected in a microfluidic chip, handling and usage for high-throughput techniques, among others.

The use of IPS cells allows for collecting a patient sample in a less invasive way and then reprogramming that cell to become a different one. An example would be that instead of collecting a lung biopsy, it is possible to collect a sample from the skin, reprogram the cells to a pluripotent state and then reprogram it again to a lung cell and then use this cell for further testing and analysis. This technique has great potential mainly because these cells manage to accurately reproduce epigenetic changes, and naturally to reduce risk from biopsy collection. This technique wouldn’t substitute entirely the direct organ biopsy, which is normally used for cancer pathology classification and analysis. Currently, these protocols are still being improved and the correlation with the patient response is also suboptimal. However, the potential use of this technology is very promising.

Finally, artificial intelligence is being developed with two main potential applications. The first is that by helping process information much faster, it can help us select the targets with the most probability of success instead of manually and individually testing out every possible target. It will speed up our understanding of diseases and also treatment development and response. Another main application is the creation of digital twins. This refers to generating multiple digital versions of the patient, allowing for theoretical testing of a multitude of treatments, helping select the best treatment options to be tested in other types of models. It will save significant resources, helping advance and personalize treatments.

Hope you enjoyed learning more about how cancer is treated and what current technologies are being developed to bring personalized medicine to reality.

The Tale of the Cancer Hydra

Most stories start with the adventures of a hero, who goes on an adventure to discover his/her powers and how he/she can use them to save others. However, it would be misleading to start this story with a hero – instead, it begins with a monster.

Around 1600 BC, in the sandy land of the thriving ancient civilization of Egypt, a high priest and physician collects horrible stories of a parasitic monster – an uncontrollable mass that grows in people’s bodies and kills them. The attempts to control it (or kill it) are described but ultimately the final description is that it’s a disease for which there is no cure. These records, in Edwin Papyrus1, are considered the first medical description of cancer. Others had witnessed the devastating effects of cancer, but as the knowledge was much smaller than the fear, most records report it in a more mystical and superstitious way.

So it begins the tale of what cancer, this parasitic monster, really is.

Once upon a time…

In the inspiring Greek civilization, Hippocrates took it upon himself to study this beast. In the new form of logical thinking, away from magic and superstition, he looked at it and described it as crab or karkinoma (a term still used today to classify different types of cancer, p.e. carcinoma, adenocarcinoma). This crab, with a body from which legs would emerge and claws that would hold tight to its surroundings, was believed to originate from a loss of balance between the “Four Humours”: black bile, yellow bile, phlegm, and blood.

Claudius Gallen, a Greek physician took these findings to Rome, where he described that the parasitic monster would develop if black or yellow bile accumulated in a certain part of the body, and if it were black bile, there would be no cure. Much later, Aulus Cornelius Celsus translated Hippocrates’ word into Latin and carried on with the great task of trying to defeat the monster newly named cancer (a term that refers to the disease caused by a malignant tumour).

Fast forward to the present…

We have found that it’s not the accumulation of humours but of DNA mutations that cause cancer. More crucially, we have found that cancer is actually a collection of diseases caused by different types of tumours. Defeating one monster is hard enough, but discovering that they are actually different from each other means that there is no single cure to defeat it. The key to understanding this is to first understand how tumours are really formed, and how they become cancer.

How do normal cells become tumour cells?

This process is called tumorigenesis and is not completely understood. One of the main reasons why not, is because the process itself is multifactorial and extremely complex, let me explain to you how:

As mentioned before, we do know that it’s the accumulation of DNA mutations that causes cancer, in the actual sense, that it’s DNA mutations that originate tumour cells.  Our DNA holds the information to generate all that we are by the expression of genes. As normal cells divide (process of proliferation), the DNA needs to be replicated each time, and every time there is a tight regulatory process that makes sure that the DNA doesn’t suffer changes. To help with this process there are genes and proteins that form the DNA damage repair machinery. These are specific genes and proteins that monitor if there are any errors during DNA replication and if so they trigger a repair or induced-death mechanism, to prevent that cell from “spreading the wrong DNA”.

The mutations in our DNA are naturally occurring and our machinery is highly efficient at detecting them and correcting them. However, some may slip through (for example, our skin moles), especially if cells are dividing too fast for the system to keep up with all the errors, and also, particularly damaging when the mutation occurs in a critical gene of the DNA repair machinery.

There is another team, our immune system, made of cells and protein complexes that’s responsible for constantly checking, detecting and eliminating threats (foreign – like viruses or bacteria – and domestic – like tumour cells- a little pun from the FBI).

When DNA replication is unchecked and originating mutations, it creates what we call DNA instability, the source of tumour cells. Tumour cells are abnormal cells, meaning, that their communication pathways (cell signaling pathways) and cell functions are altered. However, these cells are considered benign when whatever makes them abnormal is still relatively regulated. It takes different types of mutations, that impact certain cell functions in a particular “advantageous” way for these cells to become malignant (and therefore, causing cancer). Specifically, these cells need to acquire mutations that allow them:

  1. to proliferate constantly
  2. to avoid anti-proliferation control
  3. to become immortal
  4. to avoid death-inducing mechanisms
  5. to generate new blood vessels that support that continuous growth
  6. to migrate and invade other tissues
  7. to avoid immune system mediated destruction
  8. to adapt metabolically

To summarize the process, imagine a cell that suffers a mutation in a critical gene which allows this cell to survive with a DNA mutation. This cell proliferates, and the daughter cell will also have this advantage, to survive, but will also accumulate new DNA mutations, because the system isn’t working as it should. Then these two cells proliferate and pass on again this advantage and more mutations are accumulated. All these mutations are random, but when they affect genes linked to any of the cell functions mentioned above, it gives them a survival advantage over their environment. This accumulation of slightly different cells, with different levels of mutation and advantages, is what creates a tumour mass, and as it continues to grow and eventually spread, is what creates the disease (cancer).

It’s because it seems like these cells become competitive against their neighboring cells, that I chose to refer to them as a parasitic monster, because much like a parasite, a malignant tumour becomes different and toxic to the body, while it does its best to drain out any resources of energy, even if it kills the host.

So how do we kill it or how do we prevent it?

Prevention is key, just as avoiding eating parasite eggs, not having it to begin with is the main idea. The main causes of DNA instability, apart from inherited DNA mutations, are within our control to a point. They can be summarized as environment and inflammation. There are many environmental factors that cause higher rates of DNA mutation (carcinogens), which then makes it more likely that our machinery won’t detect them all. Exposure to UV light, tobacco, alcohol, and other chemicals in cosmetics, medications, food and air are considered carcinogens, and avoiding them or reducing exposure to them is a great way of preventing cancer. Inflammation is more complex than carcinogens. Inflammation is a natural, internal process that occurs when our immune system is repairing or fighting some threat. However, this process is only healthy when it’s short-lived. When we are exposed to long-term inflammation (chronic inflammation), there is a greater dysregulation of natural cell communication pathways. This is because inflammation is a coordinated event that needs to override certain communication channels, and when it does this for too long, it destabilizes the underlying ones, like an army overrunning your hometown. Certain foods, stress, poor sleep and diseases cause chronic states of inflammation, so reducing it would help preventing tumour formation. Also, many types of cancer are associated with infections by viruses or bacteria, this is why overall hygiene and access to vaccines is extremely helpful in preventing certain cancers. One of the biggest accomplishments of late was the success in developing a vaccine against different strains of the papillomavirus, which is the main cause of cervical cancer.

Finally, the big question: How to kill it? Well, since we’ve learned that this parasitic monster is actually different kinds of monsters, in which each cancer is constituted by a tumour mass, that is in turn constituted by different cells with slightly different types of mutations, it’s only understandable that to kill it we need different strategies. Find which they are in the next post.

  1. Edwin Papyrus, “The Art of Medicine in Ancient Egypt” by James P. Allen (2005).

From the Lab to the Patient

How does the work of a research scientist get to the patient in the clinic? It’s a great question!

It’s by a process called technology transfer, by in which, a lab result (“the technology”) needs to be transferred from hands (lab) to hands (company) in a protected format (IP: intellectual property protection). Maybe at this point, this process is obvious to you, or maybe you have several questions like: “Why does it need to be transferred? Why do you call it technology? Why does it need protection? Shouldn’t science be free?

If you have these questions in mind, I will gladly answer them, as I too had them and it’s very important to understand what comes next.

Technology refers to the “practical application of knowledge” (Merriam-Webster dictionary), but more specifically, in the context of this post, it refers to technology (compound, small molecule, process, protocol, model, etc.) that can significantly improve the diagnosis, treatment or prevention of a certain disease and is innovative enough, meaning that the inventive step (the part that is truly new and created by that lab/person in particular), is different and a significant improvement from what is already public knowledge or existing in the market. 

When a scientist achieves a lab result that can be considered an innovative technology, for it to be properly developed, tested for safety and effectiveness (clinical trials), approved by regulatory bodies (FDA, EMA) and reach market access (governments and insurance companies agree to cover it/ doctors agree to prescribe it), it needs to be transferred from the laboratory where it was developed to a company that has the resources and know-how to do it properly. This is why we call it, technology transfer, because the technology will be transferred from department to department, then to a different institute or company and then to the market.

If the technology is not innovative enough, scientists will publish the result and it will still contribute to overall knowledge and improvement, it just won’t need to go under this process because if it isn’t innovative enough, it means that it isn’t good enough to reach the patient. The process of technology transfer is extremely expensive, so much so, that it’s unthinkable for a non-profit or a government to cover all the expenses related to it. This is why for-profit companies take the responsibility and both the loss and profit that comes with technology transfer. This is also why, if the technology isn’t protected properly and/or a patent is not possible (p.e. because it isn’t innovative), companies aren’t able to profit from its development and therefore aren’t able to endure the costs of the tech transfer process. Behind the profit of one successful technology in the market, there are probably 10 others that failed and caused big losses.

Angry or frustrated that we are talking about profit?

Let’s see it from the opposite perspective: From the patient to the lab

For every patient that gets treated, part if not most of the costs are covered by either the government or insurance companies. At this level, there are a few key concerns: clinical outcome (effectiveness and safety), quality of life improvement (reduction in side effects, time of treatment or need for palliative treatments) and cost itself. These concerns are shared by the above stakeholders (patients/doctors/hospitals, governments and insurance companies).

Any new treatment, diagnostic tool, medical device and so on, needs to bring a considerable improvement in clinical outcome or quality of life that compensates the cost in comparison to what exists (standard care). This makes natural sense since no one would invest more time and money into a solution that only improves something by a very small margin that maybe it won’t even be used. How confident would the doctors be prescribing a new drug that only slightly improves in comparison to the standard? How confident would be the patients in taking it?

Based on this, is set that innovation is not only important for the companies bottom-line but mostly for the patients too.

The summary

Technology transfer is a vital part of improving people’s life with innovative scientific work and is sadly misunderstood by many. I hope this post has helped you understand the process of how our work in the lab gets to the patients.