BREAKING DOWN LUNG CANCER
The hit TV series Breaking Bad features anti-hero Walter White, who starts out as a sympathetic character: a mild-mannered high school chemistry teacher with a nagging cough that turns out to be lung cancer. Money problems precipitated by costly treatments, poor insurance, and a modest salary push him to start cooking up meth to ensure his family’s financial security. Spoiler alert: The treatments succeed beyond his expectations, restoring his health long enough for him to become an unexpected meth kingpin.
Breaking Bad is a fictionally extreme example of the chaos that can arise from a lung cancer diagnosis. In fact, lung cancer is the leading cause of cancer-related deaths in the United States. Let’s take a closer look at the molecular causes, the different types, and some treatments in the clinic and on the market.
While Walter White did not smoke cigarettes, 90% of those affected by lung cancer are smokers. Other causes of lung cancer include environmental or workplace exposure to carcinogens (known cancer-causing agents) such as radon, asbestos, or air pollution.
Smoking causes cancer because inhaled smoke contains a range of chemicals, and many known carcinogens, including benzene, formaldehyde, methanol, and acetylene. Some carcinogens are genotoxic, meaning they cause cancer by directly interacting with and damaging DNA. If that DNA damage occurs in a gene that regulates cell division, cancer may result. Non-genotoxic carcinogens have no direct interaction with DNA; they disrupt cellular structures and change the rate of cell division or processes that increase the rate of genetic error.
Radon gas exposure can result in cancer because it is radioactive, and the high-energy radioactive particles given off as the gas decays can cause direct damage to cellular DNA. Radon gas is released from the normal decay of radioactive elements occurring naturally in soil and rocks. Radon is not considered dangerous because it usually occurs at very low levels. However, it can sometimes reach hazardous levels in well-insulated, tightly-sealed homes built on soil rich in uranium, thorium, or radium.
Asbestos used to be a common insulating material used in buildings and ships. The microscopic fibers in asbestos can be inhaled and become lodged in lung cells, triggering the activation of inflammatory pathways that result in the release of mutagens and factors that promote tumor growth. Since its hazards became well-documented in the mid-1970s, it is no longer used as insulation.
In addition to carcinogen exposure, there are likely genetic elements that make certain individuals more or less susceptible to lung cancer. Even though 90% of lung cancer cases are caused by smoking, only about 10% of smokers get lung cancer. In African-American populations, even when differences in smoking rates and access to healthcare are controlled, lung cancer rates are higher. Both of these scenarios suggest that genetic factors may make certain people more (or less) susceptible.
SMALL CELL LUNG CANCER
About 10% of lung cancer is a small cell, meaning it occurs in the microscopic cells found in the bronchi—the tubes that branch off of the trachea, enter the lungs and divide into even smaller branches within the air sac.
Currently, targeted therapies are available for small cell lung cancer (SCLC). These include the following:
Immune checkpoint inhibitor therapies include Opdivo (Bristol Myers Squibb; New York City, NY) and Keytruda (Merck; Kenilworth, NJ). Checkpoint proteins are proteins on the surface of white blood cells, such as T-cells, that send a “stop attacking” signal when activated by proteins on the surface of healthy cells in the body. Many types of cancer cells take advantage of this system by activating the immune checkpoint proteins and minimizing the immune response against a tumor. Checkpoint inhibitor therapies prevent cancer from activating checkpoint proteins, enabling the immune system to go after the tumor more fully. Both drugs are being tested as monotherapies and in combination with other drugs. Opdivo (nivolumab) was granted FDA approval for the treatment of SCLC in March 2022. FDA also approved Keytruda for the treatment of SCLC in June 2019.
In 2020, the FDA approved Durvalumab (IMFINZI) developed by Astrazeneca as a groundbreaking treatment for SCLC. The drug functions as an immunotherapy agent, targeting the PD-L1 pathway to enhance the immune system’s ability to combat cancer cells. It is often used in combination with chemotherapy as a first-line treatment to improve survival rates. This approval has been a significant advancement in SCLC treatment, offering new hope for both patients and healthcare providers.
Therapies in development for SCLC include:
- Rova-T (Abbvie; North Chicago, IL), now in Phase III clinical testing, is an antibody-drug conjugate that delivers a toxic chemotherapeutic agent directly to SCLC cells. Rova-T is being studied as both a monotherapy and in combination with Opdivo.
- Aeglea Biotherapeutics (Austin, TX) is developing Pegzilarginase, a therapeutic enzyme meant to starve small cell lung cancer cells by breaking down the amino acid asparagine. Healthy cells can synthesize this amino acid, whereas SCLC cells can’t. Pegzilarginase is now in Phase III clinical studies and is being tested as both a monotherapy and in combination with Keytruda.
NON-SMALL CELL LUNG CANCER
Cancer that occurs within any cell outside of small cells is referred to as non-small cell lung cancer (NSCLC), making up the majority (~90%) of lung cancer cases.
Several drugs targeting new blood vessel growth— angiogenesis inhibitors—have been approved to treat NSCLC. These include Avastin (Genentech; South San Francisco, CA) and Cyramza (Eli Lilly; Indianapolis, Indiana). These drugs cut off the supply of new blood vessels to the tumor, essentially starving them.
In a significant development for the treatment of NSCLC, the FDA approved Tecentriq (atezolizumab) developed by Genentech for adjuvant treatment in October 2021. This approval marks a crucial step in expanding the therapeutic options for NSCLC patients, particularly those with PD-L1 expression. The adjuvant treatment aims to reduce the risk of cancer recurrence after initial treatment, such as surgery, has been completed. This FDA approval is based on clinical trials that demonstrated the efficacy of Tecentriq in this setting, offering a new avenue of hope for patients and healthcare providers alike.
Some drugs target specific NSCLC– associated mutations. For example, between 10% and 35% of NSCLC cases are caused by the over-expression of the growth factor receptor EGFR. These types of NSCLC—more common in non-smokers—can be treated by drugs that target and inhibit this receptor. These include Iressa (Astra Zeneca; London, UK), vectibix (Amgen; Thousand Oaks, CA), Tarceva (Roche; Basel, Switzerland), and Afatinib (Boehringer Ingelheim; Ingelheim, Germany). In the ever-evolving landscape of NSCLC treatments, Dacomitinib (Vizimpro) developed by Pfizer (New York, NY) remains a key player in 2023, despite its FDA approval back in 2018. Not just a one-trick pony, this drug serves as both a first-line treatment and a retreatment option for advanced cases. Its versatility extends even further, as it’s being explored in multi-drug therapies beyond just lung cancer. With well-documented side effects, Dacomitinib continues to be a reliable choice for clinicians and patients alike. Rain Therapeutics (Fremont, CA) has just completed Phase II trials of Tarlox, an EGFR inhibitor for patients who do not respond to those already on the market.
In the cellular world, anaplastic lymphoma kinase (ALK) acts like a rogue traffic light, causing 5% of NSCLC cases by allowing cells to divide uncontrollably. Drugs like Xalkori (Pfizer; New York City, NY) and Zykadia (Novartis; Basel, Switzerland) step in to halt this, but resistance can occur, leading to Pfizer’s development of lorlatinib. Sometimes ALK even fuses with EML4, creating a super-villain that researchers are studying closely. New drugs Ensartinib and Alecensa are also entering the scene, each with unique approaches to tackling ALK. On another front, immune-boosters Opdivo and Keytruda are enhancing our body’s own defenses. The battle against ALK-positive NSCLC is multi-faceted and ever-evolving.
In the complex world of cellular biology, think of anaplastic lymphoma kinase (ALK) as a malfunctioning traffic light that green-lights non-stop cell division, contributing to 5% of NSCLC cases. Our first-line heroes, Xalkori (Pfizer; New York City, NY) and Zykadia (Novartis; Basel, Switzerland), intervene but sometimes meet resistance, cueing Pfizer’s new drug, lorlatinib. Adding complexity, ALK can fuse with another protein, EML4, creating a tougher villain that researchers are keen to dismantle. Newer drugs like Ensartinib and Alecensa are broadening our attack strategies. Meanwhile, immune-boosting agents like Opdivo and Keytruda serve as cellular neighborhood watch, empowering our natural defenses. The fight against ALK-positive NSCLC is a dynamic, multi-front battle, far more than just a list of drugs.
Diagnosed with NSCLC, Walter White specifically had an inoperable stage 3A adenocarcinoma. This means the cancer was initiated in the mucus-producing cells of the lungs and had spread to the lymph nodes (or other sites near the lungs) but had not spread to distant sites within the body. ALK mutations cause some types of adenocarcinomas, so it is possible that Walter’s miraculous recovery was caused by one of the ALK inhibitors discussed above.
The landscape of lung cancer treatment is undergoing significant transformation, offering renewed hope for patients and healthcare providers. With the FDA’s approval of groundbreaking treatments like Durvalumab (IMFINZI) for Small Cell Lung Cancer (SCLC) in 2020 and Tecentriq (atezolizumab) for Non-Small Cell Lung Cancer (NSCLC) in 2021, we’re seeing promising advancements in both targeted therapies and immunotherapies. These developments are not just about new drugs; they also involve a deeper understanding of the molecular and genetic factors contributing to lung cancer. Even in popular culture, characters like Walter White from “Breaking Bad” serve as a lens to view the complexities of this devastating disease. As research continues, the hope is that these therapies will become even more effective, offering a brighter future for those battling lung cancer.
FREQUENTLY ASKED QUESTIONS
1. What is the difference between Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC)?
SCLC is a fast-growing type of lung cancer that makes up about 10% of lung cancer cases. NSCLC is slower-growing and accounts for about 90% of cases. The treatments for these two types are often different, with SCLC usually requiring more aggressive therapy.
2. How do immunotherapies like Durvalumab (IMFINZI) and Tecentriq (atezolizumab) work?
These immunotherapies target specific pathways, like the PD-L1 pathway, to help the immune system recognize and attack cancer cells. They are often used in combination with chemotherapy.
3. Are these new treatments available for all stages of lung cancer?
No, many of these treatments are approved for specific stages or types of lung cancer. For example, Durvalumab is approved for extensive-stage SCLC, while Tecentriq is approved for adjuvant treatment of NSCLC.
4. What are the side effects of these new lung cancer treatments?
Side effects can vary but may include fatigue, nausea, and immune-related reactions. Always consult your healthcare provider for a complete list of side effects and how to manage them.
5. How do these new treatments interact with traditional chemotherapy?
Many of these new treatments are designed to be used in combination with traditional chemotherapy to improve efficacy. However, the specific interaction can vary, so it’s crucial to consult your healthcare provider.
6. What are the genetic factors that may influence lung cancer susceptibility?
While smoking is a significant risk factor, genetic elements may make certain individuals more or less susceptible to lung cancer. Research is ongoing to identify these genetic factors.
7. Could Walter White from Breaking Bad have benefited from any of these new treatments?
It’s hard to say without knowing the specific molecular characteristics of his cancer. However, given that he had NSCLC, some of the newer treatments like Tecentriq might have been options for him, depending on the stage and other factors.