An M.D.-Ph.D. candidate in Georgetown University’s tumor biology program defended his dissertation, titled “Molecular Signatures of Treatment Responses in Tumors and Serial Liquid Biopsies in Patients with Metastatic Melanoma,” Jan. 16.
Sidharth Jain, the doctoral candidate, described a novel way to track melanoma progression and treatment response through blood draws. Skin cancer is the most common cancer in the United States, and melanoma is the most dangerous type because it has a relatively higher probability of spreading to other parts of the body. While mortality rates have declined over the past decade, melanoma can still be deadly if not found early.
Jain said this new method of monitoring melanoma, known as a liquid biopsy, is less invasive and more versatile than a traditional biopsy, since just one blood sample contains many informative substances.
“A single assay of liquid biopsy can provide many analytes,” Jain said at the event.
A liquid biopsy is a laboratory test on blood, urine or other bodily fluid that is used to measure tumor load, the number of cancer cells in the body at a given time. While cancer cells themselves are not found in the blood, cell-free DNA is, and thus can be used as a stand-in that reflects tumor load.
Cell-free DNA, or cfDNA, is genetic material that sheds into the bloodstream as cells die and are replaced. Physicians can use features of cfDNA to determine what type of cell it came from.
Methylation is one such feature. It is a chemical process that modifies regions of DNA so they are less available to be expressed in bodily functions. A DNA fragment’s pattern of methylation can help identify its origin, or “lineage.” For example, DNA from melanocytes — the type of skin cell that can turn into melanoma — is methylated differently than DNA from other skin cells.
Patrick McDeed, a doctoral candidate in biostatistics, helped Jain’s team map out methylation patterns in 21 cell types. They found largely parallel patterns between melanocytes and melanoma, meaning that the more melanocyte-lineage cfDNA there is in the blood, the more melanoma there is likely to be.
Jain said a decrease in cfDNA, observed as early as six weeks into immunotherapy treatment, predicted a better overall outcome.
“Our analysis showed there’s actually not a big difference in the tumor between patients who respond and patients who don’t respond to immunotherapy,” Jain said. “It takes a combination of not just what’s happening in the tumor, but also what’s happening around the tumor, what’s happening in systemic circulation.”
Jain completed his dissertation under the mentorship of Dr. Anton Wellstein, a professor of oncology and pharmacology at the Lombardi Comprehensive Cancer Center, a leading cancer research and treatment hub in Washington, D.C. Wellstein focuses on developing therapeutics by targeting features specific to cancer cells.
Wellstein said that, while past methods rely on specific, known DNA mutations to identify cancer cells, liquid biopsies and cfDNA uniquely rely on a cell’s lineage, making them more broadly applicable — even when a patient’s cancer does not match a particular mutation.
“This relies on the biology of the cancer itself,” Wellstein told The Hoya. “Sid used features of the normal cells, melanocytes — which can turn into melanoma — and used those molecular features to discover how much the melanoma load would be in a given patient.”
Natalie Thompson (CAS ’27), an undergraduate researcher in the Wellstein lab, said she appreciated how working on Jain’s project gave her an array of different skills, allowing her to better discern her research interests.
“I’ve gotten wet lab experience and coding experience,” Thompson told The Hoya. “I’ve tried everything out and I’ve seen what I like.”
Bella Huerta, the coordinator of Georgetown’s tumor biology program, said the program offers meaningful mentorship from faculty members and opportunities for students to take the lead on their biomedical education.
“The accessibility of our faculty and their commitment to our students’ success as individuals really stood out to me when I first joined the program,” Huerta wrote to The Hoya. “There’s a lot of space to take initiative and make the program what you want.”
Wellstein said he believes that research and clinical practice go hand-in-hand, as seen in Jain’s work and plans for the future.
“You will have all shades of gray of people who do science with medicine,” Wellstein said. “You bring those two sides together, either in yourself or you find someone you can work closely with.”
