Chemotherapy was born from the ashes of war. The first drug used as a chemotherapy agent came from an unexpected source: mustard gas, a highly toxic substance and one of the most effective weapons ever developed. The gas that was first used during World War I and has a long history as a chemical weapon also served as the molecular basis for the first chemotherapy agent, known as Mechlorethamine. A history that is a subtle invitation to understand the nature of cancer treatment from its burdens, very well represented by Mechlorethamine, to its success. From its beginnings to the present day, cancer treatment has been marked by numerous side effects, but that is a reality that is slowly changing. To raise awareness for Lung Cancer Awareness Month, let’s briefly tell the history of how lung cancer treatment is becoming a showcase of 21st-century discoveries.
Mechlorethamine and the nature of chemotherapy
Great things can arise from tragedy. In an effort to understand how mustard gas affected the human body, autopsies were performed on 75 soldiers exposed to it. These autopsies revealed a significant reduction in white blood cells in the soldiers. Apparently, when inhaled, the gas was especially toxic to white blood cells. This led to the hypothesis that a similar substance might be used to target cancerous white blood cells in lymphoma patients. Goodman and Gilman, two of the greatest pharmacists of all time, in their lab at Yale, designed a chemically altered version of mustard gas. When tested on a terminally ill lymphosarcoma patient, the drug yielded fantastic results, destroying cancer cells like never seen before. Mechlorethamine is still in use today under the interesting name "Mustargen".
Mechlorethamine became the first chemotherapy agent, marking the beginning of decades of investment and discovery in cancer treatment. However, like the many chemotherapy drugs that followed, it comes with significant side effects, and there is a reason for this. Pharmacology is about specificity, which means targeting specific disease mechanisms while minimizing effects on other systems in the body. This approach works well for bacteria, for example, as their cellular structures differ from ours, allowing for targeted drugs. But cancer presents a unique challenge, as cancer cells are, at their core, human cells. How, then, can we target cancer cells without harming healthy cells? Truthfully, throughout most of cancer treatment history, we couldn’t. Most chemotherapy drugs target molecules involved in cell reproduction, which, although also present in normal human cells, are more active in cancer cells. That is the reason why chemotherapy has so many adverse effects.
But there is a promising future ahead
This was the reality until things began to evolve near the 21st century. Cancer treatment has transformed in extraordinary ways. As we studied cancer in greater detail, we discovered genetic alterations, proteins, and receptors that are unique or more active in cancer cells. This understanding allowed us to develop drugs targeting these specific traits. We call this "targeted therapy," a broad and somewhat loosely defined category of drugs that aim for these unique cancer-specific characteristics. With targeted therapy, we can focus on attacking cancer cells directly, sparing more of the healthy cells.
One of the most exciting examples of targeted therapy’s impact is seen in treatments for Non-Small Cell Lung Cancer (NSCLC), which accounts for 85% of lung cancer cases. Several key mutations have been identified in NSCLC, and therapies designed to target these mutations have shown remarkable clinical success. Genes like EGFR, MET, ALK, RET, and HER2 frequently exhibit mutations in lung cancer, and specific drugs have been developed to target these abnormalities. For instance, a patient with an EGFR mutation (found in about 15% of cases in the U.S.) can receive a treatment designed to target that specific mutation. As cancer cells evolve to resist EGFR inhibitors, science has kept pace by developing second and third-generation drugs to outsmart this resistance.
Immunotherapy has also emerged as a first-line treatment for certain types of lung cancer. Immune checkpoint inhibitors are a novel category of Immunotherapy drugs that enable the body’s immune system to attack lung cancer. Normally, cancer cells evade immune response by sending "don’t attack" signals to immune cells. Immunotherapy drugs block these signals, allowing the immune system to recognize and target the cancer. It’s like lifting a disguise, enabling the body to fight back with its own defenses. For some lung cancer patients who have the specific receptor that these drugs aim for, this approach can lead to lasting remission. This highly specific treatment means that some patients may completely avoid common chemotherapy-related side effects, such as hair loss.
Since the prevalence of these mutations varies among patients, genetic testing has become essential in identifying them. This is why modern lung cancer treatment includes a comprehensive set of genetic tests, enabling doctors to tailor therapies to each cancer’s unique genetic profile. The vision of personalized therapy is no longer just a dream, it’s becoming a reality.
Over the past decades, these advancements have led to changes in what truly matters: significant improvements in overall survival and reductions in mortality. The two-year survival rate among men with NSCLC improved substantially, from 26% for those diagnosed in 2001 to 35% for those diagnosed in 2014. Mortality declined by 3.2% annually from 2006 through 2013, then decreased even more rapidly, by 6.3% annually, from 2013 through 2016.
Conclusion
These may not be the enormous gains some might expect, but given that lung cancer remains one of the most common cancers in the U.S. with nearly 250,000 cases per year, this progress represents thousands of lives each year. Though we've focused here on lung cancer, similar advancements are transforming treatment for other cancer types as well. As our understanding of cancer deepens, we’re developing drugs with greater precision to target cancer’s unique vulnerabilities, allowing us to combat the disease in ways we never thought possible. Lung cancer research, in particular, is a beautiful showcase of this new generation of therapies that improve survival rates and enhance quality of life. This progress not only saves lives but brings us closer to a future where cancer can be managed with minimal impact on patients’ daily lives.
Written by Luis Guilherme
