CANCER

Cancers are notoriously difficult to treat, let alone cure. In many ways, physicians and patients play a chess game against the disease. Patients receive a new therapy; tumors counter with new ways to resist it.

Traditional cancer therapies, such as chemotherapy and radiation, work by blasting many cells and hoping cancer cells are affected more than healthy cells. The problem with this approach is twofold: the side effects can be devastating, and cancer cells are incentivized to adapt and resist the treatment. It’s a one-size-fits-all approach that doesn’t typically take into account the patient’s own unique genetic, cellular and environmental factors. All too often, the cancer wins.

Cancer is a maddeningly complex disease that must be attacked from many angles to contain and ultimately cure it. At the Salk Institute, we recognize the challenge, and though we are sometimes humbled by it, we will not be deterred. The Salk Institute was founded to take on the most difficult biological problems. As we like to say, this is where cures begin.

Salk scientists look at cancer holistically—focusing not only on the tumor cells themselves but also on their surrounding tissues, the immune system, the microbes that live within us, and how each individual’s environment and habits influence their risk and therapeutic responses. These are the elements that, together, allow tumors to form, grow, spread and resist standard therapies.

By uncovering new information about how these elements influence all types of tumors, we are revealing new universal vulnerabilities—vulnerabilities in cancer’s armor—for which we can customize new therapeutic weapons that may apply to many cancers, including pancreatic, brain, lung and breast.

If you squeeze an inflated balloon, no matter how hard you try to contain it, parts will poke through your fingers. Cancer also foils containment, developing genetic mutations that help it survive, grow and escape the immune system and many treatments.

However, this genomic flexibility can also make tumors less resilient. Every time a cancer cell mutates away from its normal cousins, it adopts a less efficient, and often irreversible, mechanism to gain a temporary survival advantage. As tumors go to plans B, C and D, these adjustments inform Salk’s overall strategy: We are finding multiple ways to pop those balloons. And a deep knowledge of the fundamentals of cell biology and genomics, coupled with computational expertise, is how we do it.

Already, Salk scientists have identified several genomic weak spots that make cancer cells easier to kill. We also recently used a computational approach to discover that a current cancer therapy, which works by targeting specific molecules encoded by cancer genes, may work for thousands more patients than originally thought.

Tumors grow fast and eat like a pack of wolves, constantly scouring their environments for new food sources. They often rewire their metabolism, such as switching their fuel source from glucose to the amino acid glutamine. This remodeling is an irreversible necessity for cancer cell survival, making metabolism a potentially powerful target for stopping cancer. What’s more, tumors with different genetic mutations rewire their metabolism in unique ways, providing another opportunity to target different subsets of cancer.

Salk scientists have been exploring this metabolic connection for more than a decade, providing critical insights. We are learning to hit cancers through their food supplies. These metabolic strategies could have a profound impact on tumors: depriving them of nutrients, altering their protective microenvironments and potentially empowering the body’s immune system to destroy them.

Immunotherapy—boosting a patient’s own immune system, allowing it to better detect and destroy cancer cells—has emerged as a powerful alternative (or addition) to chemotherapy. For some, these treatments are very nearly cures. But many patients receive no benefit from immunotherapy, a gap that must be filled.

Salk scientists are investigating how the immune system responds (or fails to respond) to cancer. They want to understand why T cells infiltrate some tumors and not others; whether macrophages and other immune components can be optimized to attack tumors; and how nutrient-starved tumor microenvironments affect glucose-hungry T cells. Here, we circle back to metabolism, and this is no coincidence. Many cancer-related mechanisms interact with each other, making collaborative, interdisciplinary research essential.

Our microbiomes—the unique communities of microbes that live in and on our bodies—constantly interact with healthy and cancerous cells. These millions of bacteria, viruses and other microorganisms may influence how our immune systems react and how tumors survive. Scientists are discovering that the makeup of a person’s microbiome, the specific species of microbes and their relative quantities, may in part determine cancer risk and response to therapy.

Diet, exercise and body mass adjustments can put tumors at a disadvantage. However, there may be another even more profound weapon against cancer—sleep. It’s long been known that people who work the night shift are at greater risk of developing cancer. Salk research indicates that this night work may interfere with their circadian rhythms—our bodies’ 24-hour clock. By detaching their bodies from the normal day-night cycle, shift workers may be experiencing an overall decline in cellular health, increasing the risk that tumors can grow and thrive.

The research team realized this lack of circadian regulation in cancer cells might actually be a vulnerability. What happens if we reimpose day-night discipline? When the researchers chemically reimposed circadian discipline on cancer cells, the cells simply couldn’t survive under the increased regulation. This was true in several types of cancer cells. By contrast, normal cells thrived.