Investigating the Importance of the Gut Microbial Endocrine Organ in Kidney Cancer Development and Therapeutic Response
Abstract
Significance: Kidney cancer is among the most common forms of cancer in humans and is estimated to lead to ~14,000 deaths this year. Although this cancer affects the general public, military personnel and their families are at particularly high risk given their higher rates of exposure to cancer toxins. Early-stage kidney cancer can be treated using surgery. However, late-stage cancer (that has spread outside of the kidney, i.e., metastatic) is treated with drugs that starve the cancer by choking its blood vessels and/or enhance the ability of the patient’s own immune system to kill these tumor cells (immune therapies). Although these therapies can slow the growth of cancer for a short period of time, in most cases they eventually stop working. It is therefore important to understand why some kidney cancers do not respond to specific therapies and also to understand why some therapies develop resistance over time and stop working. Most importantly, developing new drugs that are more effective in treating this devastating disease is of paramount clinical relevance. Recently, scientists have discovered that bacteria living in our intestines (called the gut microbiome) can impact various aspects of human health. This idea, in fact, is behind the increasing use of probiotics (e.g., your favorite nutrient- and microbe-balanced yoghurt), which presumably promote better health by altering the type and the number of microorganisms living in our gut. Amazingly, the gut microbiome may also affect kidney cancer growth, and how well immunotherapy works. Moreover, chemicals made by these gut microorganisms are not only excreted in urine, but can also find their way into human blood, and thus reach distant organs. The foundation of this project is to understand how the gut microbiome in patients with kidney cancer, via secreted chemicals, influences the growth and the response of kidney cancers to therapy. We hope that in the future, this knowledge will enable development of new therapies (imagine a kidney cancer-curing yoghurt?), which will improve the clinical outcomes for patients afflicted by this devastating disease. Hypothesis and Objective: Our kidneys act as a barrier that prevents the entry of unwanted chemicals into circulation. We hypothesize that abnormal kidney function in patients with kidney cancer affects the amount and type of gut microbiome-derived chemicals in our bloodstream, and, in turn, impacts the growth of tumors and their response to current therapies. Specific Aims: Our project has two main aims. First, we will identify the chemicals from gut microorganisms that are elevated in kidney cancer patients (versus healthy human beings). We will also simultaneously interrogate changes in these chemicals in patients receiving immune therapies. Finally, it is now possible to house laboratory mice under germ-free conditions, where their gut is almost devoid of any microorganisms. Comparing kidney cancer in these germ-free mice will allow us to directly associate the importance of gut microorganisms in disease progression and response to therapy. Second, we will ask if gut microbial chemicals could directly affect the growth of kidney cancer cells (even without the influence of the immune system). We will study how bacterial chemicals identified in the first aim impact the growth properties of kidney cancer cell lines and kidney cancer organoids, which are three-dimensional cellular structures derived from human tumors that allow us to mirror the behavior of human kidney cancer. In summary, our project will understand how gut bacterial chemicals can impact kidney cancer via indirect effects due to immune function (Aim 1) or direct effects on cancer cells (Aim 2). Innovation and Impact: This proposal is innovative because, instead of simply listing the names of thousands of bacteria/bacterial products (as has happened in earlier studies), we address why these bacteria and their c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210430
Entities
People
- Jonathan Brown
Organizations
- Cleveland Clinic
- United States Army