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.
Parallel Worlds in Science 