Current Research Projects

Tumor ploidy as a predictive biomarker of differential chemotherapy response

Triple-negative breast cancer (TNBC) can behave very differently from one person to another. Even when two patients have tumors that look similar, they may respond differently to the same chemotherapy. Right now, doctors do not have a simple way to know ahead of time which chemotherapy is most likely to work for each patient.

Our research asks whether a basic feature of cancer cells—the amount of DNA or chromosome content they carry, called ploidy—can help guide treatment choices. Some tumors have chromosome content close to normal, while others have many extra chromosomes. This difference may affect how well cancer cells survive different types of chemotherapy.

In early studies, we found a promising pattern: lower-ploidy tumors appeared more sensitive to gemcitabine, while higher-ploidy tumors appeared more sensitive to doxorubicin. In this project, we will grow TNBC tumors in mice, measure tumor ploidy using a routine laboratory test, and then treat the tumors with these drugs. We will compare how strongly each treatment slows tumor growth and delays progression.

If successful, this work could help identify which chemotherapy is best matched to a patient’s tumor biology, potentially reducing ineffective treatment and unnecessary side effects.

Associate Member, Integrated Mathematical Oncology Department 

I am a computational oncologist dedicated to developing mathematical and computational models to predict how chromosome-scale variation (karyotype variation) shapes tumor evolution and to leverage those predictions for adaptive therapeutic decision-making. Unlike point mutations, karyotypic alterations can shift the dosage of thousands of genes at once, enabling rapid exploration of phenotypic space under stress. My laboratory combines longitudinal experimental systems with mechanistic modeling to quantify how microenvironmental constraints reshape evolutionary landscapes and to identify conditions that steer tumors toward more clinically manageable trajectories. To support this work, we developed ALFA-K (Nature Communications, 2025), the first framework to infer context-dependent karyotype fitness landscapes directly from longitudinal single-cell data and to forecast the next karyotypic states accessible in a given environment. Using these inferred landscapes, we have begun to identify design principles for controlling evolution, including how whole-genome doubling (WGD) can flatten fitness barriers and how high chromosomal instability (CIN) can favor robust, mutation-tolerant attractor states over maximal-fitness states. Our preliminary results also indicate that resource limitation is a major selective force acting on WGD.

The molecular and environmental factors that permit breast cancer cells to survive neoadjuvant chemotherapy

Even though breast cancer treatments have greatly improved, the disease still comes back for many patients, and this is a major cause of death. Chemotherapy often shrinks tumors at first, sometimes dramatically. However, a small number of cancer cells usually survive. Over time, these cells recover, grow, and spread, forcing patients to undergo additional rounds of treatment. This can mean longer therapy, more side effects, worse outcomes, and a lower quality of life.

Our research looks at cancer as an evolving disease. Just as living organisms adapt to survive harsh conditions, cancer cells can adapt to survive treatment. After chemotherapy, the remaining cancer cells are few, weak, and under high stress. We believe this moment—when the cancer is at its smallest and most vulnerable—is a critical opportunity to wipe it out completely.

Currently, treatment often pauses after chemotherapy to let patients recover. Unfortunately, this pause also gives surviving cancer cells time to adapt and become more resistant. We propose instead to act immediately, targeting these weakened cells before they have a chance to regroup and cause the cancer to return.

Immunotherapy has been revolutionary for some cancers but has worked less well in breast cancer. One reason is that breast tumors often do not trigger a strong immune response. Our research shows that chemotherapy changes this. After treatment, surviving cancer cells become stressed and easier for immune cells to recognize.

We found that these stressed cancer cells are especially sensitive to natural killer (NK) cells, which can destroy abnormal cells without special markers. By giving immunotherapy right after chemotherapy, we believe it can work much more effectively. This approach could reduce recurrence, minimize treatment burden, and improve both survival and quality of life.

Co-Director, Center of Excellence for Evolutionary Therapy, Senior Member of Diagnostic Imaging and Interventional Radiology.

Bob received a B.S.E. in Bioengineering and Mechanical Sciences from Princeton University and an M.D. from the University of Pennsylvania. He completed his residency in radiology at the University of Pennsylvania where he also served as chief resident. Bob remains an active clinical radiologist specializing in body imaging.  While working at the Fox Chase Cancer Center after residency, Bob perceived that cancer biology and oncology were awash in data but lacked coherent frameworks of understanding to organize this information and integrate new results. Reaching back to his training in engineering and physical sciences, Bob recognized that cancer was a complex dynamic system (similar, for example, to weather) and that understanding the often non-linear interactions that govern such systems requires mathematical models and computer simulations.  As a result, most of Bob’s subsequent research has focused on exploring mathematical methods to understand the first principles and key parameters that govern cancer biology and treatment.  In 2008, Bob joined Moffitt as chair of radiology and convinced the leadership to add a group of mathematicians to the faculty and form the Integrated Mathematical Oncology (IMO) department. Now, numbering 8 faculty mathematicians and over 20 post docs and grad students, the IMO has catalyzed formation of several disease-oriented teams of oncologists, surgeons, pathologists, radiologists, mathematicians, physicists, cancer biologists, imaging scientists and evolutionary biologists.   These multidisciplinary groups are investigating virtually every aspect of cancer biology and therapy. In fact, IMO members are co-PIs of two ongoing clinical trials that use evolutionary dynamics and computational models to guide therapy. There is no other cancer center in the world that has so completely integrated mathematical modeling and computer simulations into basic science and clinical research.

Development of BFL-1 inhibitor in AML (Acute Myeloid Leukemia)

Acute myeloid leukemia (AML) is a fast-growing and serious blood cancer that mainly affects older adults. While new treatments have helped some patients, many people either don’t respond to these treatments or their cancer comes back after initially improving. When this happens, there are very few effective options left.

This project focuses on developing a new treatment for patients whose leukemia no longer responds to current therapies. Our research has found that resistant leukemia cells survive by turning on a “backup” survival switch—a protein called BFL-1. This protein helps leukemia cells avoid dying, even when powerful cancer drugs are used.

Importantly, BFL-1 is much less active in normal, healthy cells. That means targeting it may hurt cancer cells while causing fewer side effects, making it a promising and potentially safer target.

We have created a new drug that specifically blocks BFL-1. In our early studies, this drug was able to kill AML cells and make them sensitive again to treatments that had stopped working.

In this project, we will test how safe and effective this new drug is using advanced lab experiments and animal studies, including leukemia cells taken directly from AML patients. If these studies are successful, they could pave the way for clinical trials and eventually lead to a new, more personalized treatment option for AML patients who currently have very limited choices.

Associate Member, Department of Malignant Hematology.

Dr. Yun’s clinical interests include management of patients with hematologic malignancies with a focus on Acute Myeloid Leukemia (AML).  As a physician-scientist with clinical and basic research expertise in hematologic malignancies, his scientific career is dedicated to understanding and targeting molecular circuits that contribute to the development, maintenance, drug-induced cytotoxicity and resistance of Acute Leukemia.

Rational tuning of CAR T cells against osteosarcoma for enhanced activity and reduced toxicity

The survival outcomes for metastatic osteosarcoma (OSA) are dismal and have not improved in several decades despite multimodal treatment with surgery and chemotherapy. Genetic engineering of a patient’s T cells to express a synthetic receptor that binds to a tumor antigen, known as chimeric antigen receptor T (CAR T) therapy, has shown great promise in treating B cell malignancies but has yielded poor results against solid tumors like OSA. A major reason for therapeutic failure is the hostile tumor environment that weakens CAR T activity. Additionally, CAR T cells are associated with life-threatening toxicities given that their targets are not only expressed on tumor cells but also on healthy tissues. Thus, unlocking full CAR T cell potential against refractory solid tumors requires new technologies that can exquisitely tune and strengthen recognition of tumor targets while avoiding life-threatening side effects. To address these roadblocks, we propose to rationally design and fine tune CAR T killing while decreasing side effects.

Assistant Professor of Pediatrics, Division of Hematology & Oncology
UF College of Medicine

Paul Castillo, M.D., is an Assistant Professor of Pediatrics and physician-scientist of the T Cell Engineering Laboratory of the Pediatric Cancer Immunotherapy Initiative (PCI2) and the Brain Tumor Immunotherapy Program (BTIP) at the University of Florida (UF). He serves as a member of the UF Data Integrity and Safety Committee (DISC), UF College of Medicine Scientific Review Committee, and as liaison of the UF Health Cancer Institute Community Outreach Engagement Council.

He received his medical degree from the Universidad Peruana Cayetano Heredia, Lima, Peru. He completed his pediatric residency at the Riley Hospital for Children – Indiana University. Next, he trained in hematology-oncology with additional focus on stem cell transplantation and cellular therapy at the Texas Children’s Cancer and Hematology Centers – Center for Cell & Gene Therapy – Baylor College of Medicine. At the University of Florida, his translational efforts are focused on developing new pipeline technologies that include systemic activation of innate and adaptive immunity to synergize and enhance CAR T cell activity against metastatic osteosarcoma. His research has received multiple awards including the Hyundai Hope on Wheels Young Investigator award, the American Brain Tumor Association Discovery award, the Florida Department of Health Live Like Bella Discovery award, the Gabrielle’s Angel Cancer Research Foundation award, and an institutional KL2 award. His research endeavors are additionally supported by Stop Children’s Cancer, Inc.

Biomarker-directed repurposing of Omaveloxolone for treatment of colon and pancreatic cancers

Colon and pancreatic cancers are among the deadliest malignancies and respond poorly to available therapies. The Protein Disulfide Isomerase enzymes (PDIs) are overproduced in these cancers and play a central role in driving the proliferation and survival of colon and pancreatic tumors. Our multidisciplinary team identified a family of compounds termed DDAs that inhibit these PDIs, however extensive pharmacokinetic and safety studies must be completed before DDAs can be used clinically. A survey of current clinically used drugs revealed that RTA-408/Omaveloxolone, which is used to treat Friedrich’s Ataxia, mimics the anti-cancer effects of DDAs, but is more potent than DDAs and kills a broader array of colon and pancreatic cancer cells. Further, RTA-408 kills cancer cells through a specific Death Receptor termed FAS, nominating the presence of FAS in tumors as a predictive biomarker of the efficacy of RTA-408 against individual patient cancers.

Together, our preliminary studies suggest that RTA-408, or related compounds, may be rapidly translated into clinical use for treating colon and pancreatic cancers and that tumor levels of FAS may be used as a biomarker to identify patients who will maximally benefit from RTA-408 based therapy. Additionally, the potential anti-cancer synergy of combinations of clinically approved drugs that converge on the FAS Death Receptor to selectively kill colon and pancreatic tumors will be evaluated.

Associate Professor, Department of Pharmacology & Therapeutics
UF College of Medicine

Dr. Law is an Associate Professor and Vice Chair for Faculty Affairs in the Department of Pharmacology & Therapeutics in the College of Medicine at the University of Florida. He grew up in the foothills of the Appalachian mountains in southeastern Ohio, where he earned a B.S. in Chemistry from Ohio University. He earned a Ph.D. in Biochemistry from Purdue University, and went on to do postdoctoral training in Cancer Biology in the laboratory of Dr. Hal Moses at Vanderbilt University. Since joining UF, he and his wife, Dr. Mary Law, have run a research laboratory together and collaborate with other UF investigators, including Drs. Castellano and Heldermon, to develop mechanism-based experimental therapeutic agents effective against drug-resistant and metastatic cancers of the breast, colon, and pancreas.

Cathy D. Perry Trust: Microgel delivery of total tumor antigen for the treatment of malignant glioma
Glioblastoma

is one of the most aggressive and difficult brain cancers to treat, and new therapies are urgently needed. Our team has developed a new immunotherapy designed to help the body’s own immune system recognize and attack these tumors more effectively. This work builds on prior research supported by the Ocala Royal Dames exploring ways to improve cancer vaccines.
Our treatment, called microgel-chemokine-matrix (MCM), acts like a temporary “training center” for the immune system, similar to a lymph node. The treatment contains a soft gel that releases signals to attract important immune cells, including dendritic cells, which help teach the immune system what to target. Once these immune cells enter the gel, they are exposed to genetic material (mRNA) from the patient’s tumor packaged inside tiny fat-based particles. This process trains immune cells to recognize tumor-specific signals.

After activation, these cancer-fighting immune cells travel into the brain tumor where they attack cancer cells directly. The treatment also appears to change the tumor environment itself, converting immune cells that normally suppress the immune response into cells that promote inflammation and anti-tumor activity. MCM has already shown strong results in aggressive mouse models of glioblastoma. In addition, three pet dogs with naturally occurring glioblastoma were treated at the UF College of Veterinary Medicine with encouraging early outcomes. This project will test an improved version of MCM designed to better support future clinical testing in human patients with glioblastoma.

Professor, Department of Neurosurgery
UF College of Medicine 

Maryam Rahman, M.D. has the title of professor in the department of neurosurgery at the University of Florida (UF). Dr. Rahman received a bachelor’s degree in chemistry from Johns Hopkins University and attended medical school and completed a neurosurgical residency at UF. During her training she completed a two-year neuro-oncology fellowship under the direction of world-renowned scientist Brent Reynolds, PhD, studying tumor stem cells and their role in developing novel therapy for brain tumors. After residency, Dr. Rahman completed a surgical neuro-oncology fellowship at Johns Hopkins University.  

Dr. Rahman is dedicated to finding a cure for brain tumors. Her laboratory focuses on identifying novel immunotherapy approaches to overcome resistance in patients with brain cancer. Current projects include development of vaccines for the treatment of brain tumors and combining immunotherapy with MRI guided laser ablation. Dr. Rahman’s work is supported by grants from the NIH, the Preston A. Wells Jr. endowment and private foundations. Her translational research is actively being tested in human clinical trials. She has published more than 100 peer-reviewed articles, and presented at multiple conferences and events.