Metastatic Cancer: A Paradigm Shift in Understanding and Treatment

Metastatic cancer is cancer that has spread from its original location (primary tumor) to other parts of the body. Unlike the localized stage, where cancer remains confined to its starting point, metastatic (or stage IV) cancer forms new tumors in distant organs or tissues. This spread can occur through the bloodstream or lymphatic system, making the cancer much more difficult to treat as it can impact multiple areas at once. Common sites for metastases include the lungs, liver, bones, and brain, depending on the type of cancer. Once cancer becomes metastatic, it is often seen as more aggressive, and the treatment focus shifts from cure to management and control of the disease.

For decades, metastatic cancer—the leading cause of cancer-related deaths—has been treated as a formidable opponent, a rogue system with nearly unstoppable momentum once it escapes its primary site. Traditional approaches have often viewed metastasis as a random, genetically driven event. However, groundbreaking research is now challenging this view, offering a more nuanced understanding: metastatic cancer is fundamentally a metabolic disease.

This shift in understanding is nothing short of revolutionary. By uncovering the metabolic dependencies of cancer cells and the tumor microenvironment, researchers are rethinking how metastases form, thrive, and resist treatment. The implications are vast, offering new hope and tangible strategies for combating some of the deadliest cancers, including colorectal, breast, and lung cancers.

Metabolism and Metastasis: A New Frontier

The metabolic theory of cancer posits that metastasis is driven not just by genetic mutations but also by profound alterations in cellular energy pathways. Unlike healthy cells, which rely on mitochondrial oxidative phosphorylation for energy, cancer cells often switch to glycolysis—even in the presence of oxygen—a phenomenon known as the Warburg effect (https://pubmed.ncbi.nlm.nih.gov/18820763/). This metabolic reprogramming enables them to thrive in nutrient-scarce and hypoxic environments, a hallmark of metastasis.

Recent studies further reveal that metastatic cancer cells display heightened metabolic plasticity. They can adapt their energy production methods, tapping into lipids, amino acids, or even scavenging from their surroundings to fuel their growth (https://www.nature.com/articles/s41568-021-00364-5).

Moreover, tumor-associated macrophages (TAMs), key players in the immune system, are often hijacked by metastatic tumors. TAMs undergo metabolic reprogramming themselves, shifting to glycolysis or glutamine metabolism to support cancer growth (https://www.sciencedirect.com/science/article/abs/pii/S0092867420307624). This symbiotic relationship between cancer cells and TAMs underscores the metabolic basis of metastasis.

Impact on Colorectal, Breast, and Lung Cancers

1. Colorectal Cancer (CRC):

• Metabolic rewiring plays a pivotal role in tumor progression and metastasis to the liver and lungs. Studies indicate that CRC cells exploit glutamine metabolism and lipid oxidation to adapt to these new environments (https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30221-5). Clinical trials are now investigating inhibitors of glutaminase and agents targeting fatty acid oxidation.

• Immunometabolic Therapies: Combining glutaminase inhibitors with checkpoint inhibitors is being explored to enhance immune attack on tumors (https://clinicaltrials.gov/ct2/show/NCT03894540).

2. Breast Cancer:

• Particularly the triple-negative subtype, is notorious for its metabolic flexibility. Metastatic breast cancer cells often rely on fatty acid metabolism to colonize distant organs like the bones and lungs (https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00252-8). Therapies targeting this pathway, such as CPT1A inhibitors, are being tested.

• Immunometabolic Therapies: Trials are investigating the use of CSF1R inhibitors to alter TAM behavior, potentially enhancing immunotherapy's efficacy (https://jitc.bmj.com/content/7/1/169).

3. Lung Cancer:

• Frequently exploits metabolic pathways to fuel metastasis, especially in non-small cell lung cancer (NSCLC). Research shows that NSCLC metastases rely on fatty acid metabolism and oxidative phosphorylation (https://cancerres.aacrjournals.org/content/81/5/1111).

• Immunometabolic Therapies: There's interest in how metabolic changes in TAMs can be leveraged to improve responses to immune checkpoint inhibitors (https://jitc.bmj.com/content/7/1/169).

Clinical Trials on the Horizon

• Metastatic Colorectal Cancer: A Phase II trial (NCT03894540) is examining the combination of CB-839, a glutaminase inhibitor, with immunotherapy, aiming to see if this duo can extend survival or reduce tumor size more effectively than current treatments. Patients interested in this trial should discuss with their oncologist about eligibility and potential benefits.

• Metastatic Breast Cancer: The Phase I trial (NCT03138003) for Etomoxir, a CPT1A inhibitor, seeks to understand its safety and effectiveness in altering cancer cell metabolism. This could be a breakthrough for those with aggressive forms of breast cancer, offering another tool in the treatment arsenal.

• Multiple Metastatic Cancers: Trials incorporating ketogenic diets with standard treatments (NCT04116541) are exploring whether this dietary change can enhance the impact of conventional therapies for cancers like colorectal and glioblastoma. Participants might find these trials accessible if they're open to dietary adjustments under medical guidance.

• General Advice: For those intrigued by these trials, speaking to your healthcare provider is crucial to explore if you're a candidate. You can also visit ClinicalTrials.gov to search for other trials or learn how to join one.

If you're interested in these trials, you can visit ClinicalTrials.gov to find more detailed information, discover other trials, or learn how to participate in one.

This evolving understanding of metastatic cancer as a metabolic disease represents a monumental shift in oncology. It reframes metastasis not as an inevitable outcome but as a process with vulnerabilities—vulnerabilities we are now beginning to exploit.

For patients, this means renewed hope. It means that even in the face of metastatic disease, there are reasons to believe in progress, innovation, and a better tomorrow. And for researchers and clinicians, it is a call to action—to embrace this paradigm shift and harness it for the benefit of all.

Metastatic cancer remains a formidable challenge, but we are no longer fighting blind. Armed with this new metabolic lens, we are not just imagining a world where cancer is beaten—we are building it, one discovery at a time.