Published April 6, 2017
Stanley A. Schwartz, MD, PhD, UB Distinguished Professor of medicine and pediatrics, has received a $749,000 grant from Kaleida Health to investigate the feasibility of targeting and treating metastasized prostate cancer with nanoparticles.
The goal of the project is to determine whether the engineered nanoparticles can deliver treatment directly to distant metastases without distributing toxic drugs into the blood, Schwartz says.
If so, the approach would increase the effectiveness of the therapy while reducing the “collateral damage” of side effects to healthy cells.
“A nanoparticle is big enough to carry a large payload but small enough to get to places in the body where larger particles couldn’t reach,” explains Schwartz, chief of the Division of Allergy, Immunology and Rheumatology.
“It’s like a bubble in which toxic drugs are concentrated and delivered to the target tissues without delivering them in general throughout the body.”
In addition to encapsulating chemotherapy, gene therapy and a targeting agent in the nanoparticle, Schwartz’s research team is collaborating with scientists in the Department of Chemistry to endow the nanoparticle with an MRI agent, which would make the tumors easier to locate and diagnose.
““Lighting up’ the tumors is the next phase of the research,” he says. “This would help you identify where the tumor is as well as the boundary between normal tissue and malignant tumor.”
This theranostic strategy — in which researchers combine diagnostic and therapeutic capabilities into a single agent — would allow clinicians to simultaneously detect and treat tumors, says Ravikumar Aalinkeel, PhD, research assistant professor of medicine, who is conducting the study with Schwartz.
“There may also be metastasis that hasn’t been recognized because it isn’t causing symptoms,” he notes.
“Our technology could pick that up as well.”
The UB research has implications for a range of cancers characterized by solid tumors, including breast, brain, kidney, liver, uterine and colon cancer.
The team’s theranostic approach, for example, could help detect pancreatic cancer, which is asymptomatic in the early stages, so often goes undetected until its late stages, when the prognosis is poor.
In the case of prostate cancer, Schwartz and his colleagues are tackling the most frequently diagnosed noncutaneous malignancy of men in the industrialized world. The U.S. has one of the highest rates of prostate cancer, with it being particularly lethal among African-American men.
Although radiotherapy — alone or in combination with hormone ablation therapy — has proved effective for patients with organ-confined prostate cancer, neither treatment has improved the poor prognosis of patients with metastatic prostate cancer, Schwartz says.
“The majority of cases of prostate cancer are carcinoma in situ, so they don’t go beyond the prostate,” he says. “In those cases, the approach is usually watch-and-wait and biopsy to try to get some idea of the nature of the localized tumor.”
“But when the tumor escapes the prostate and metastasizes, it’s a very different story. There’s really not much in the way of therapy for these patients, and the mortality goes from modest to quite significant.”
With the Kaleida grant, Schwarz’s team will refine the nanoparticle they have developed and investigate its effectiveness through further in vitro and in vivo studies, with an eye toward clinical trials.
In earlier phases of the research, Aalinkeel developed a combination therapy consisting of a monoclonal antibody that docks to the metastases and targets interleukin-8 (IL-8), a critical factor in the growth of prostate cancer.
In the next phrase, the researchers successfully inhibited the gene for IL-8 using RNA molecules. The nanoparticles — which are ultimately digested and eliminated from the body — prevented the labile RNA from degrading while delivering it to the distant metastases.
“We’ve shown that we can make the tumor shrink — and that was only with radiotherapy,” Schwartz says. “But we get a one-two punch by adding the chemotherapy.”
Placing the potent chemotherapeutic drug doxorubicin in the nanoparticles reduces its toxicity, Schwartz says, thereby limiting its potential side effects, which include cardiac damage.
UB is particularly well-suited to conduct the in vivo studies for this project because of Aalinkeel’s specialized expertise in orthotopic injections, Schwartz points out.
In similar animal studies, researchers typically inject the prostate cancer cells into the flank of immune-deficient mice. However, Aalinkeel is one of a few scientists capable of injecting the cells directly into the animal model’s prostate.
“When you see animal experiments, they’re often conducted in sites where the tumor does not develop, so if it metastasizes, it's not metastasizing from the prostate,” he says.
The orthotopic model, by contrast, features cancer cells growing in their natural location, replicating human disease with high fidelity.
“It's an important skill to have,” Schwartz says, “and we have it right here at UB.”