Why are some prostate cancers lethal, while so many others linger harmlessly for years? How can a drug instilled in the bladder adhere in pursuit of cancer cells rather than washing out with the urine? And how can we study the multitude of possible interactions between a cancer drug and people’s diverse immune systems?
Yale Urology translational research scientist Darryl Martin, PhD, is tackling questions like these with a bench-to-bedside team intent on finding better genitourinary cancer treatments. Trained in cancer molecular biology, Dr. Martin has developed innovative tools like drug-ferrying nanoparticles and mice that carry both the tumor and the immune cells of a specific human cancer patient.
Dr. Martin leads a team of surgeons, pathologists, medical oncologists, chemists, biologists, radiologists, and machine-learning engineers. “Our department has invested in the science to help the clinical aspect,” Dr. Martin said.
In 2019, Martin’s team reported their discovery that a membrane protein called GP130 is rampant in aggressive and dangerous forms of bladder cancer. This protein is involved in some tumors’ resistance to chemotherapy, and inhibiting its presence makes cancer cells less prone to survive and metastasize, Dr. Martin found.
To block GP130, his team created nanoparticles laden with small interfering RNA (siRNA)—genetic molecules that can disrupt specific out-of-control gene-expression pathways. In a mouse model, the nanoparticles shrank tumors by nearly three-quarters.
These nanoparticles hold promise, too, in overcoming complications with intravesical therapy, a method in which a bladder cancer treatment agent is introduced directly into the bladder. Unfortunately, these agents tend not to adhere to the bladder wall or penetrate the surface layer of cells. Their contact with the tumor is brief, quickly washing out with the urine. Dr. Martin developed a nanoparticle shrouded in a viscous carbohydrate called Chitosan that is derived from the shells of crustaceans. He then loaded the nanoparticle with an siRNA that targets Survivin, a protein that allows tumor cells to live too long, and with another protein that penetrates cells. The newly created nanoparticle succeeded in penetrating bladder cells, decreasing Survivin levels and inhibiting growth of the cells.
“By encapsulating a treatment, these materials could actually stick to the wall,” Dr. Martin explained. “This allows the amount of time of exposure to be extended so it doesn’t wash out right away—it has a chance to stay and release a therapeutic agent over time.”
So far, the Martin lab has found promising results with particles that interact with cells in superficial bladder cancers. The bigger challenge is to develop a generation of nanoparticles that can penetrate deeper layers of the bladder and target more aggressive cancers. Nanoparticles also hold promise for treating prostate cancer. When Dr. Martin studied biopsies from Smilow Cancer Hospital patients with prostate cancer, he found that a receptor called Claudin is upregulated in the higher-grade cancers.
Claudin makes up part of the tight junctions that link adjacent cells, and Dr. Martin’s team was able to design a nanoparticle that targets it. They hooked iron oxide and fluorescent molecules onto this particle. They then demonstrated that the particle not only hones in better on the cancer site, but also allows for highly specific MRI and fluorescent images.
“The dream is that we could have imaging materials and therapeutic materials in one nanoparticle,” Dr. Martin explained. “It could illuminate the tumor and start releasing therapeutics to that site.”
Disease progression, the process by which an early-stage or indolent cancer can turn malignant, is still poorly understood. Dr. Martin is working to untangle the pathways and genes involved in this tipping-point aspect of tumor behavior.
A key part of the explanation, he suspects, lies in how each tumor is affected by its immediate surroundings, or microenvironment. The microenvironment comprises everything from blood vessels to collagen and enzymes to immune cells. Each may influence what a tumor does next. But studying the immune system’s influence on tumors is hampered by the fact that researchers rely on mice that lack an immune system.
In response, Dr. Martin and his colleagues are developing a mouse model that can better simulate these complexities. After isolating both immune cells and cancer cells from a single patient, they are transplanting these cells to generate immune-competent mice. The idea is to observe interactions between the patient’s immune system, the tumor and its microenvironment, and various therapeutic agents.
Eventually, researchers could build a library of such mouse models, each with a slightly differing cancer and immune-system variation that could allow for more tailored cancer treatment. As with all the Martin lab’s projects, the mouse model’s goal is near-term clinical relevance. “Patient care is going to depend on what type of research can be done in the lab,” Dr. Martin said. “The ultimate goal is to improve patient care at the end of the day.”