New Team Science Award Aims to Unlock Mysteries of Kidney Cancer Metabolism
Summary
- A new two-year, team science award at Sylvester is exploring how metabolism, body composition and circadian rhythms intersect in renal cell carcinoma, the most common form of kidney cancer.
- The program is led by Sylvester’s Tracy Crane, Ph.D., R.D.N., David Lombard, M.D., Ph.D., Scott Welford, Ph.D., and Jaime Merchan, M.D.
- The award will include a first-of-its-kind pilot study of intermittent fasting in newly diagnosed renal cell carcinoma patients.
Renal cell carcinoma, the most common form of kidney cancer, has some particular metabolic quirks. The cancer accumulates large amounts of lipids inside its cells, giving it a characteristic “clear cell” appearance, almost like little bubbles of water under the microscope.
The unusual behavior of renal cancer may take a creative approach to combat. A multidisciplinary team of scientists at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, is gearing up to do just that. With a two-year, $400,000 Sylvester Team Science Award, this group of researchers will work to gain a deeper understanding of renal cell carcinoma’s metabolism through detailed laboratory and clinical studies and will implement a cutting-edge dietary intervention in patients.
“We have complimentary disciplines coming together to answer hard questions that will change outcomes for patients,” said Tracy Crane, Ph.D., R.D.N., co-lead of Sylvester’s Cancer Control Program and director of lifestyle medicine, prevention and digital health.
Dr. Crane is leading the new program, which is called Metabolism And renal Cancer (MAC 3), along with Sylvester’s David Lombard, M.D., Ph.D., co-leader of Sylvester’s Cancer Epigenetics Program and clinical professor of pathology and laboratory medicine at the Miller School, and Scott Welford, Ph.D., co-leader of the Tumor Biology Program and professor of radiation oncology at the Miller School.
Through their collaborative project, the Sylvester researchers will:
• Study the details of renal cell carcinoma lipids
• Uncover how circadian clock genes may contribute to the disease
• Analyze how body composition impacts response to treatment
• Test intermittent fasting in a group of newly diagnosed patients.
“This is the first time at Sylvester that a team of basic scientists and translational and clinical researchers have joined forces to conduct high-quality research in kidney cancer tumor metabolism,” said Jaime Merchan, M.D., co-leader of Sylvester’s Translational and Clinical Oncology Research program, professor of medical oncology at the Miller School and a co-investigator on the new project. “It is a very impactful project because it is really going to connect the laboratory with the clinic.”
A Mysterious Connection to Lipids and Metabolism
Although renal cell carcinoma is not a common cancer, with around 80,000 cases per year in the U.S., the incidence of this disease is on the rise and the prognosis is often poor for those with advanced disease. Obesity raises the risk of this kidney cancer. But, interestingly, renal cell carcinoma patients with obesity tend to have better outcomes than those without. The reasons behind this so-called “obesity paradox” are unclear, but it points to the involvement of metabolism.
All cancer types have altered metabolism and altered lipids, but the fact that clear renal cell carcinoma cells entirely fill up with fat molecules is unusual. Only one other cancer, a rare form of ovarian cancer, does the same. Dr. Welford’s team will lead a project aiming to better understand kidney cancer’s unique characteristic.
In initial studies, Dr. Welford and his colleagues found that lipid accumulation seems to protect cancer cells from certain kinds of stresses, giving them a growth advantage. They’ve also captured renal cell carcinoma’s “lipidome,” the molecular profiles of every kind of lipid molecule present in these cancer cells. They’ve found two different types of lipid profiles so far, one of which correlates with better patient outcomes and the other with worse outcomes.
“That led us to the hypothesis that the lipid content is very significant to these tumors, and that if we could alter it, we might be able to change the prognosis of patients with those tumors,” Dr. Welford said.
Through the award, they will generate lipidomes from 150 different samples from Sylvester kidney cancer patients to understand the variability in lipids naturally present among patients and investigate whether any of these variations correlate with factors such as BMI or smoking status.
Delving into the Details Behind BMI
In another project, Dr. Crane and her colleagues will assess the impact of body composition on kidney cancer. While obesity is linked to higher rates of renal cell carcinoma, it is typically measured by body mass index, or BMI, a blunt measure that may not always reflect the true variability among people’s bodies.
To understand how body composition affects renal cell carcinoma outcomes, the researchers will use a large database built by Dr. Merchan and his colleagues. The database comprises clinical information, including imaging and pathology data from more than 800 Sylvester kidney cancer patients dating back to 2010. This database has one of the highest proportions of Hispanic patients of any kidney cancer dataset. The researchers will use this database to explore how body composition, including proportions of fat and muscle, correlates with treatment outcomes.
Can Timing of Meals Influence Treatment Response?
The researchers are also exploring how circadian rhythms affect kidney cancer outcomes. Obesity and cancer can impact our internal clocks. Using stored tumor samples from the database, Dr. Crane, Dr. Merchan and colleagues will ask whether the expression of certain circadian clock genes is altered in renal cell carcinoma tumors.
Circadian rhythms are also tightly tied to metabolism. Emerging research suggests that the timing of our meals can regulate or dysregulate our internal biological clocks. Specifically, late-night eating or eating too close to bedtime can confuse our inner clocks and may lead to negative health outcomes. Although it’s early days in the field of circadian science and cancer treatment, Dr. Crane has seen some promising results in patients with metastatic breast cancer by shifting their eating patterns to earlier in the day. Limiting late-night eating seemed to lessen side effects from certain types of treatments in these patients.
In the new project, Dr. Crane, in collaboration with Dr. Merchan, will lead a pilot study of 30 newly diagnosed advanced renal cell carcinoma patients to test whether time-restricted eating changes their response to treatment. Participants will be instructed to stop eating by 8 p.m. and wait 14 hours before starting to eat the next day.
“There is emerging evidence suggesting that our internal time clocks may be critically important for timing and responses to treatment and to some extent, treatment toxicities,” said Sylvester’s Director of Cancer Survivorship and Supportive Care, Frank Penedo, Ph.D., who is a co-investigator on the project along with Dr. Merchan. “We know one’s metabolism can play a role in cancer initiation, progression and treatment response, and this highly innovative study will assess whether time-restricted eating can favorably impact treatment outcomes.”
Circadian Genes
Dr. Lombard is leading a project within the award to delve further into the role of the circadian clock in kidney cancer. He and his colleagues will look at sirtuins. These genes affect our bodies’ metabolism, fat tissue and internal clocks, among other biological processes. By genetically engineering kidney cancer cells in the lab to eliminate different sirtuin genes one at a time, they’ll gain insight into whether and how these genes influence the cancer’s growth and survival.
They’ll also explore sirtuins’ effects on the cancer in preclinical models, as well as measure hundreds of metabolites in samples from all three projects of the award.
“We’re going to try to generate some unifying themes and really figure out what these interventions do at the level of metabolism,” Dr. Lombard said.
Dr. Lombard’s and Dr. Welford’s studies on metabolism and dietary interventions in preclinical studies with kidney cancer will also inform Dr. Crane‘s research on time-restricted eating in humans facing the disease, as well as future potential dietary studies.
“To me, this is very exciting and a good example of how, individually, we’re all good, but we’re great together,” she said. “The kinds of questions we’re going to be able to answer in this project, we couldn’t answer alone.”
Tags: Cell Metabolism, Dr. David Lombard, Dr. Jaime Merchan, Dr. Scott Welford, Dr. Tracy Crane, kidney cancer, lifestyle medicine, nutrition, renal cell carcinoma, Sylvester Comprehensive Cancer Center