Cancer doesn’t occur in a vacuum—a tumor grows from a person’s own cells, and it’s intimately entwined with nearby nerves, muscle, bone, and fat tissue. Blood and lymph carry nutrients and oxygen to the tumor, as well as immune cells that may attack the malignancy. The tumor, meanwhile, sends out nucleic acids, cytokines, metabolic byproducts, and packages of diverse cargo called exosomes. The tumor and the patient’s body thus engage in an ongoing biological dialogue that ultimately determines the course of the disease.
However, cancer research often adopts a reductionist approach that focuses only on the biology of the tumor itself. As The Mark Foundation’s CEO, Michele Cleary, PhD, has noted, this approach has laid the foundation of our understanding of cancer, but it doesn’t fully account for the complex interactions between the disease and every system of the human body, no matter how distant from the tumor site.
Decoding the complicated whole-body response to cancer is the focus of the recipients of one of the first awards from The Mark Foundation’s new Endeavor program. A team led by Tobias Janowitz, MD, PhD, and Semir Beyaz, PhD, of Cold Spring Harbor Laboratory seeks to better understand the interactions between cancer cells and other tissues and to connect the behavioral, neuroendocrine, metabolic, microbial, and immune responses that occur during cancer progression. A major goal of this research is to find ways to improve the functioning of cancer patients’ body systems, thereby making the disease less disabling.
“What’s unique about our research program is that we try to connect different aspects of how the body responds to cancer and to look at causality,” Dr. Janowitz says. “Few researchers look at how the body responds to the cancer, and in particular how that response is connected between different organ systems. This will help us understand how the disease process of cancer can have such a comprehensive effect on the whole body.”
Consistent with the vision of the Endeavor program, the project is “extremely collaborative,” Dr. Beyaz notes. “We bring together scientists from various backgrounds, and we’ve formed this synergistic team with the common goal of understanding how cancer reprograms organismal biology. This is important not just for gaining more information about how cancer makes us sick, but also for developing novel treatment approaches.”
Identifying novel approaches to cancer therapy that take into account the patient’s complex physiology is one of the objectives of the Science of the Patient partnership between The Mark Foundation and the American Association for Cancer Research. Among the five projects funded in February 2021 is an investigation by Marcus Goncalves, MD, PhD, of a treatment strategy for endometrial cancer that combines cutting-edge targeted therapies with a dietary intervention, in recognition of obesity’s systemic effects on this type of cancer.
Endometrial cancer is the most common gynecologic malignancy in the developed world, and obesity dramatically increases the risk of death, in part by stimulating production of insulin and, in turn, a family of enzymes (PI3K) that can drive the proliferation of cancer cells. Dr. Goncalves, of Weill Cornell Medicine, is investigating whether a diet low in carbohydrates (often referred to as a “ketogenic” diet) can reduce insulin levels in overweight or obese patients with endometrial cancer and improve response to PI3K inhibitors, a promising class of anti-cancer drugs. His laboratory will assess the efficacy of this combination of drug and diet through animal studies and analysis of patient samples from an ongoing clinical trial.
The strong effects of obesity on certain cancer types highlight the important role of communication between the tumor and distant tissues throughout the body. New York University’s Amanda Lund, PhD, a 2020 recipient of a Mark Foundation Emerging Leader Award, studies the role of the lymphatic system, a network of organs and vessels that transport fluid and immune cells, in anti-tumor immunity.
Dr. Lund has demonstrated that the lymphatic system is not simply a passive transportation network, but instead actively and selectively controls the cells and signaling molecules that pass through it. This suggests that lymphatic vessels may play a critical role in the immune system’s control of tumors—and thus the body’s ability to curb tumor progression. Her sophisticated analyses of lymph fluid using advanced “omics” techniques could lead to a better understanding of how melanoma, the most lethal skin cancer, metastasizes to the lymph nodes and progresses to advanced disease.
By taking into account the intricate connections of the patient’s various physiological systems, the work of these Mark Foundation researchers promises to enrich our understanding of cancer in a truly personal context, and provides hope that new, more effective therapies can be developed that will not only extend lifespan, but ensure a higher quality of life for cancer patients.