How Scientists at Sylvester are Learning to Outrun Cancer Resistance
Summary
- Sylvester researchers are uncovering how cancer adapts to treatment and how resistance might be anticipated and disrupted.
- From liquid biopsies to metabolomics and epigenetics, Sylvester scientists are mapping the biology behind treatment resistance.
- By studying how tumors evolve under pressure, Sylvester investigators are laying the groundwork for more durable, precise cancer therapies.
Cancer knows how to survive and adapt.
A tumor shrinks. A scan looks promising. Then, quietly, the disease finds a way around the treatment. This cycle is one of oncology’s most persistent challenges: treatment resistance or the ability of cancer cells to rewire, survive and return despite targeted drugs, chemotherapy or immunotherapy.
At Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, scientists know that cancer’s greatest weapon isn’t mutation. It’s anticipation.
Through NIH-funded basic science, translational research and disease-focused collaboration, Sylvester researchers are uncovering how tumors adapt under therapeutic pressure, and how those adaptations might be anticipated, intercepted or reversed. This reflects a model increasingly central to national cancer research leadership and is part of the University of Miami’s commitment to addressing the world’s most complex health challenges through interdisciplinary, translational research, driven by Sylvester’s standing as the only National Cancer Institute-designated cancer center in South Florida.
Real-Time Tumor Evolution
One reason resistance is so difficult to cure is timing. By the time a therapy stops working, the cancer has already changed.
In advanced prostate cancer, tumors evolve continuously under treatment, accumulating mutations that help them survive. In one study, Sylvester investigators tracked fragments of tumor DNA circulating in patients’ blood to observe how those changes unfolded in real time, revealing how cancer adapted treatment by treatment.
“If we only test once, we’re trying to navigate a storm using last season’s forecast. Serial testing lets us see the fronts forming, not just the damage afterward,” said Chinmay Jani, M.D., chief fellow of hematology and oncology at Sylvester.
The findings underscore a fundamental shift in cancer care. Resistance is not a late‑stage surprise. It is often a predictable response to selective pressure, unfolding quietly long before visible clinical progression.
This ability to track cancer evolution as it happens is reshaping how leading cancer centers think about durability.
Systems-Level Resistance
If resistance has an archetype, pancreatic cancer may be it. Despite decades of effort, pancreatic tumors remain notoriously difficult to treat. One reason is their ability to activate alternate growth and survival pathways. Shut down one route, and the cancer finds another.
At Sylvester, investigators have shown that the surrounding tumor microenvironment of immune cells, supportive tissue and signaling molecules plays an active role in shaping the success or failure of pancreatic cancer therapies.
“Pancreatic cancer is highly adaptive. Even when we successfully target one pathway, tumors can rely on surrounding stromal and immune cells to help them survive and resist treatment,” said Nipun Merchant, M.D., founding director of the Sylvester Pancreatic Cancer Research Institute and the Alan Livingstone Professor in the DeWitt Daughtry Family Department of Surgery.
Rather than focusing on a single target, research teams are increasingly examining how tumor cells are influenced by interactions with surrounding cells and how resistance emerges as a systems‑level response.
Sylvester researchers have also identified immune‑driven signaling circuits that contribute to a treatment‑resistant microenvironment, pointing toward new treatment strategies.
“Treatment resistance in pancreatic cancer is an orchestrated, multi-dimensional process involving more than just tumor cells. Unless we tackle the interwoven networks between immune and stromal cells in the tumor microenvironment, even the best tumor cell-targeted therapies will have finite success,” said Jashodeep Datta, M.D., co-leader of the gastrointestinal site disease group, assistant director of transdisciplinary research, DiMare Family Chair in Immunotherapy and associate professor of surgery at the Miller School.
Spatial Plasticity and Identity
In some cancers, resistance is less about mutation and more about identity and location.
In glioblastoma, an aggressive brain cancer, Sylvester researchers used advanced spatial technologies to examine tumors cell by cell in their original locations. The work revealed a striking pattern. Cancer cells that disperse away from tight clusters become more plastic, more adaptable, more aggressive and more closely associated with treatment resistance.
Plasticity gives cells flexibility. In cancer, that flexibility becomes a clinical liability.
“When cells break away, they’re not just moving. They’re changing what they’re capable of. That flexibility is exactly what makes glioblastoma so relentless,” said Anna Lasorella, M.D., co‑director of the Sylvester Brain Tumor Institute and director of the Precision Medicine Initiative at Sylvester and professor of biochemistry and molecular biology at the Miller School.
The findings suggest that, while chemotherapy and radiation are essential, they may also reshape tumors in ways that leave behind the most adaptable, treatment‑resistant cells. This could be a possible explanation for why glioblastoma so often returns. Recent research also reveals a dynamic landscape shaped by genetics, epigenetics and the tumor’s surrounding immune environment.
“We’ve treated glioblastoma like a single enemy. But it behaves more like an ecosystem, pockets of cells with different rules for survival,” said Antonio Iavarone, M.D., director of the Sylvester Brain Tumor Institute and deputy director of Sylvester and professor of neurological surgery, biochemistry and molecular biology at the Miller School.
This shift toward ecosystem-level thinking is increasingly shaping how leading cancer centers approach therapies.
Resensitization Strategies
Rather than subtle adaptation, some cancer cells survive by ignoring internal damage signals altogether.
In studies of chemotherapy resistance, Sylvester researchers uncovered a surprising vulnerability. Blocking a key regulatory protein, p300, forces damaged cancer cells into a state of uncontrolled activity. This builds up stress inside the cells, which collapse and become sensitive again to treatment.
“Resistance is often framed as strength. Sometimes it’s overconfidence. If we can force cancer to keep reading damaged instructions, it can collapse under the weight of its own chaos,” Ramiro Verdun, Ph.D., research professor of hematology at the Miller School, said.
The work offers a new way of thinking about resensitization: exploiting, rather than overpowering, resistance. Epigenetics, the study of chemical signals that determine which genes are turned on or off, offers another possibility.
At Sylvester, cancer epigenetics researchers are studying how these disruptions contribute to treatment resistance and how they might be reversible. Because epigenetic alterations are not permanent, they offer a potential path to restoring sensitivity in resistant tumors.
“Cancer driver mutations are permanent, but derailed epigenetic mechanisms in cancer can be reversible, giving new opportunities to overcome or prevent resistance,” said Lluis Morey, Ph.D., associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics, John K. and Judy H. Schulte Chair in Genetics and basic science leader for Sylvester’s breast cancer site disease group.
Metabolic Forecasting
Cancer resistance also leaves a chemical trail.
While genetics explains what could happen in a cancer cell, metabolomics reveals what is happening in real time. The field focuses on metabolites, small molecules produced as cells generate energy, repair damage and respond to stress. At Sylvester, researchers are increasingly using metabolomics to understand why patients with the same diagnosis can respond so differently to the same treatment.
Working at the intersection of metabolism and epigenetics, 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, studies how disruptions in cellular metabolism influence gene regulation, aging and cancer behavior. By mapping metabolic byproducts in blood, tissue and tumors, investigators can gain insight into how efficiently cells are functioning and how cancer cells may be adapting.
“Metabolism doesn’t just support cancer growth. It communicates with diet, the environment and the genome in ways that shape how cells respond to stress, therapy and time,” Dr. Lombard said.
This work reflects a growing recognition that metabolism is also a driver of treatment response and resistance, adding another layer to precision oncology and offering the potential to design therapeutic or lifestyle-based interventions better matched to an individual patient’s biology.
Cellular Traffic Control
Some resistance mechanisms come down to logistics.
At the center of one such mechanism is XPO1, a protein responsible for transporting molecular cargo out of the nucleus, the cell’s command center. Cancer cells can hijack this export process to remove critical regulatory proteins from the nucleus, allowing malignant cells to survive.
With support from a five‑year, $1.92 million NIH award, Justin Taylor, M.D., associate professor of hematology, member of the Translational and Clinical Oncology Program and The Pap Corps Endowed Professor in Leukemia, is studying how XPO1 goes awry in cancer and how blocking that process might restore vulnerability.
“When you think about resistance, it’s easy to focus on what cancer builds. XPO1 is about what cancer removes: critical signals that are meant to stay in the nucleus. If you change the traffic pattern, you change the outcome,” Dr. Taylor said.
Staying Ahead of a Moving Target
Across cancers, resistance is not a single switch flipped at diagnosis. It is a moving target shaped by evolution, environment and therapy itself.
At Sylvester, researchers are responding with real‑time monitoring, systems‑level biology and precision targeting, alongside rethinking how cancer survives. Understanding resistance is just the beginning. By decoding how cancer adapts in real time, University of Miami researchers are helping to redefine durable treatment. In a field where the disease is always evolving, leadership belongs to those who can see what’s coming next.
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Tags: brain cancer, cancer epigenetics, cancer research, Dr. Anna Lasorella, Dr. Antonio Iavarone, Dr. Chinmay Jani, Dr. David Lombard, Dr. Jashodeep Datta, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Justin Taylor, Dr. Lluis Morey, Dr. Nipun Merchant, Dr. Ramiro Verdun, epigenetics, genetics, glioblastomas, hematology, metabolics, pancreatic cancer, pathology, prostate cancer, Sylvester Brain Tumor Institute, Sylvester Comprehensive Cancer Center