Although in use for over 50 years now, chemotherapy is a blunt instrument in the battle against cancer and one that’s based on an outdated understanding of tumour biology. Personalised treatment has been the Holy Grail of cancer researchers and we seem to be edging closer to it.
The US Food and Drug Administration recently approved the drugGilotrif (generic name afatinib) for the treatment of a specific type of lung cancer. The medicine can only be used in combination with genetic screening to determine effectiveness for each individual patient.
This drug, and a few others that have come before it, herald the start of a new era in cancer therapy. Rather than treating people based on last century’s classification of cancers, they allow doctors to tailor unique treatment plans for each person based on their genetic make-up.
But to understand how and why these drugs work, we need to look at the first chemotherapy drugs and what we know about cancer molecular biology.
Cancer classification
One of the most common ways of classifying cancers is based on the area of the body where the cancer originated: a woman who has ovarian cancer for instance, or someone has pancreatic cancer.
Even when the cancer has spread to other parts of the body, it’s still classified this way. The problem with this classification method is that just because cancers emerge from the same area doesn’t mean they are treatable with the same drugs.
When someone has a bacterial infection, for instance, we know broadly that if the patient has disease x then treatment with drug y will most likely cure it.
But in cancer, two men of the same ethnic background, of the same age, and health status, who present with the same stage cancer could have completely different outcomes from the same treatment.
The hammer and the egg
Most of the drugs developed last century are based broadly on a family of compounds called cytotoxics.
These act by interfering with the inner workings of cancer cells, causing enough damage so the cell itself recognises something is wrong and initiates a process called apoptosis, which is a kind of cell suicide.
These drugs work, not because they are able to recognise and attack cancer cells, but because cancers are fast growing.
In the same way that a sports car burns through fuel faster than an ordinary car, because cancer cells grow so rapidly they take up all nutrients faster (including drugs) than normal cells. And because they take up the drugs faster, they’re more likely to get a lethal dose.
Unfortunately, cancer cells are not the only fast-growing cells in the body and other rapidly-growing cells are also affected by these drugs. It’s the killing of normal cells that gives rise to the notorious side effects of chemotherapy.
Photo – Chemotherapy attacks all kinds of fast-growing cells alongside cancer tumours. Mark Seton
Fast-growing cells include the lining of the stomach and intestines, so patients get nausea, and can experience vomiting and diarrhoea. Blood cells and bone marrow are fast growing, so the body produces fewer red cells (leading to anaemia) and white cells (leaving people susceptible to infections).
Hair follicles are fast growing so some people lose their hair during chemotherapy. A fetus is also a collection of rapidly growing cells.
Thankfully, our growing understanding of cancer molecular biology means we’re starting to find ways to differentiate normal cells from cancerous ones, and target these specific differences to make drugs that are more effective and have fewer, as well as less severe, side effects.
Smart-bomb treatment
It’s now becoming more common to select treatment regimens and drugs based on genetic screening, rather than classification.
The best example of this is breast cancer treatment. We can test for three specific markers – estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) to indicate appropriate treatment.
Almost two-thirds of breast cancers are ER- or PR-positive and the women who have them respond to endocrine therapy. These women are treated with a drug called tamoxifen, but the drug wouldn’t be expected to be effective for a patient with ER negative cancer.
A patient found to be HER2-positive would be treated with a monoclonal antibody-based drug called trastuzumab, which is ineffective in HER2-negative patients.
An antibody is a large molecule made by the body to recognise specific bacteria, viruses and foreign material. Monoclonal antibodies are made by identical immune cells that are all cloned from one parent cell.
The newly-approved cancer drug, Gilotrif, is approved for the treatment of late-stage metastatic non-small cell lung cancers. Treatment with the drug is only provided after patients have undergone screening for two specific genetic mutations, which it targets, using a diagnostic kit approved by regulators.
Traditional cytotoxic drugs are currently used alongside these more targeted treatments. But as we learn more about the biology of different cancers, we can develop smarter and more selective drugs. Hopefully, cytotoxics will one day be phased out of cancer treatment altogether.
Author: Nial Wheate - PhD FRACI CChem FHEA - University of Sydney
Associate Professor Wheate completed a Bachelor of Science degree with 1st class honours from the University of New South Wales whilst at the Australian Defence Force Academy. He then completed a PhD in medicinal chemistry under Professor J. Grant Collins. Since then he has worked in the School of Biomedical and Health Sciences at the University of Western Sydney (Australia) and the Strathclyde Institute of Pharmacy and Biomedical Science (Scotland) before taking up a position in the Faculty of Pharmacy at the University of Sydney (Australia) in 2012. Associate Professor Wheate is currently the Program Director of the pharmacy undergraduate degrees at The University of Sydney and was previously the Head of Cancer Research in the Faculty of Pharmacy. He holds the positions: Member, Academic Board of The University of Sydney Member, University Executive - Student Life Committee Member, Undergraduate Studies Committee (As nominee of the Academic Board) Associate Professor Wheate's research interests lie in drug delivery and pharmaceutical formulation. He has a particular research interest in the drug delivery application of macrocycles (including cyclodextrins, cucurbiturils, calixarenes, and pillararenes) and their host-guest complexes.
