Jefferson Investigates: The “Obesity Paradox” & Cancer, Mechanisms Underlying Huntington’s Disease, & the Mitochondria in Liver Cancer
Exploring obesity and cancer outcomes; repairing abnormal DNA in Huntington’s Disease; targeting a mitochondrial protein in liver cancer.
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Does The “Obesity Paradox” Extend to Cancer Treatment?
It’s well-known that obesity is a risk factor for cardiovascular disease. But some research suggests that while people who are obese are more likely to develop cardiovascular problems, they’re also less likely to die from them. This counterintuitive finding is called the “obesity paradox”.
Thomas Jefferson University researchers wanted to see if the obesity paradox also applied to cancer. Their research suggests that obese patients fare better after immunotherapy treatment for solid tumors.
The study included data from over 18,000 cancer patients from the TriNetX healthcare database, half of whom were obese. The researchers compared survival rates after immunotherapy between obese patients and those with normal body mass index (BMI).
“We found that patients who were obese had improved overall survival almost across the board,” says Eric Mastrolonardo, MD, a 4th-year otolaryngology resident at Jefferson Health and first author on the paper.
“The study provides some evidence that obesity can be associated with improved responsiveness to immunotherapy,” says Joseph Curry, MD, Vice Chairman of Research at Thomas Jefferson University and the senior author on the study. “This finding is intriguing, but more research is required to understand why it might be.”
There are several theories concerning obesity’s role in immunotherapy effectiveness, including improved nutritional status or increased immune reserve. Past research in mice has proposed that obesity may be associated with better outcomes because obesity causes certain proteins to be expressed at higher levels, so immunotherapy drugs that affect those proteins have a more dramatic effect. However, this theory hasn’t been tested in humans. Continuing to tease apart why some people respond better to immunotherapy will be key to improving cancer treatment in the coming years.
“The advent of anti-cancer immunotherapy has been one of the most important cancer advances in recent decades, but only a fraction of patients actually respond,” Dr. Curry says. “We hope that this work points researchers towards new translational research and clinical trials, which can then be used to find ways to increase the number of patients who benefit from immunotherapy for cancer.”
By Marilyn Perkins
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A Key Protein Sheds Light on Huntington’s Disease
Huntington’s disease is a genetic disorder that kills nerve cells in the brain, causing people to lose their cognitive and motor abilities. New research led by Thomas Jefferson University researcher Anna Pluciennik, PhD is revealing the molecular pathways behind the disease. Along with graduate researcher Fenglin Li, research associate Ashutosh Phadte, and postdoctoral research fellow Mayuri Bhatia, she and the rest of her team found a protein complex that fixes abnormal DNA and could be a potential target for Huntington’s disease.
Huntington’s is characterized by an abnormal repeating sequence in the DNA. As people with Huntington’s age, this sequence gets longer, causing the strands of DNA to misalign, like a shirt with its buttons in the wrong holes. This misalignment creates extra loops in the DNA that make the DNA longer and longer. This in turn leads to the production of a toxic protein which eventually kills nerve cells.
Prior research showed small mutations in a protein called FAN1 could hasten or delay the onset of Huntington’s disease. Dr. Pluciennik believed FAN1 may play an important role in removing these extra loops of DNA, so the research team set out to test the theory.
Using an electron microscope to generate “pictures” of FAN1 interacting with DNA, the team found that the protein acted like a pair of scissors, snipping off extra loops of abnormal DNA. To do this, FAN1 teamed up with another protein, called PCNA, forming a stable complex. Dr. Pluciennik found the same mutations that were associated with earlier disease onset also impacted the stability of the FAN1-PCNA complex, making it less effective at removing extra pieces of DNA, like scissors with dull blades.
In addition to helping researchers understand the molecular basis of Huntington’s, this research positions the FAN1-PCNA complex as a promising therapeutic target.
“Based on our research, if you made the FAN1-PCNA complex more stable, or made more of the FAN1 protein, it could be protective and delay disease onset,” says Dr. Pluciennik, a member of the Sidney Kimmel Medical College.
By Marilyn Perkins
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Mitochondrial Protein May Improve Selective Liver Cancer Treatment
Hepatocarcinoma is the most commonly diagnosed form of liver cancer. It is an aggressive, fast growing cancer with a 5-year survival rate of only 15%. Thomas Jefferson University researcher Gyorgy Hajnoczky, MD/PhD, and his team recently found that a protein in mitochondria called VDAC2, may be a key player in making liver cancer cells more susceptible to cell death than normal liver tissue, offering a promising avenue for targeted therapy.
Dr. Hajnoczky’s group previously found that VDAC2 recruits another protein called BAK, a key regulator in mitochondria-dependent cell death. “The mitochondrion has a larger purpose than being the ‘powerhouse of the cell’,” says Dr. Hajnoczky. “They also play a role in maintaining a healthy cell population by facilitating the death of unhealthy cells.”
In the new study published in Nature Communications, the team led by researchers at Jefferson’s Mitocare Center, found that liver cancer cells have higher levels of VDAC2 compared to normal liver cells, making them susceptible to existing treatments targeting BAK-dependent cell death. Combining two pre-clinical drugs that target BAK shrunk tumors of liver cancer cells with high levels of VDAC2, while leaving normal tissues intact in mice. However, mice with tumors lacking VDAC2 did not respond to this treatment and showed cancer-cell growth.
“It may be that VDAC2 is the ‘Achilles heel’ of liver cancer, presenting a vulnerability that can be therapeutically exploited, while leaving normal liver cells intact,” says Dr. Hajnoczky, who is also a member of the Sidney Kimmel Medical College.
Although this research is exciting, it is still in the early stages. Dr. Hajnoczky and his team hope that future studies will reveal more about how VDAC2 is involved in primary and metastatic liver cancers, paving the way for effective therapeutic strategies for patients.
By Moriah Cunningham
