The biology of cancer

Glioblastoma recurrence and clues to blunt it

Radiation therapy after surgery is the primary treatment for most glioblastoma patients. “Ionizing radiation works quite effectively, up to a point,” said Sandeep Burma, PhD, professor of neurosurgery and biochemistry and structural biology at the Mays Cancer Center.

“Surgical resection of the tumor improves survival by approximately six months. Adding ionizing radiation extends survival to a year or even more. Unfortunately, the tumors always recur, and once they do, they are generally not responsive to therapy,” said Burma.

Burma and a team of investigators at the Mays Cancer Center are studying companion treatments to see if any can eliminate this Jekyll and Hyde property of ionizing radiation. The team’s research, first published in Cancer Research, suggests that the irradiated margin of healthy brain cells becomes a fertile microenvironment for cancer regrowth.

The role of senescence

If a cell is old, stressed or damaged by radiation, for instance, it may enter a state in which it can no longer divide. This is senescence. Senescence normally serves as an anti-cancer barrier by preventing such damaged cells from proliferating. But during the last decade, it has become clear that senescent cells can accelerate cancer progression by spewing tumor-promoting factors.

“When we irradiate a brain tumor, normal cells like astrocytes in the vicinity of the tumor senesce and just sit there, spitting out growth factors that seem to drive tumor recurrence,” Burma said.

Radiation therapy of glioblastoma traditionally targets not only the tumor, but a two- to three-centimeter margin of normal brain tissue around it. This is done because glioblastoma cells are so infiltrative. Burma and his colleagues now believe that the irradiated margin of healthy brain cells becomes a fertile microenvironment for cancer regrowth.

Clearing out senescent cells

The team also administered agents to clear senescent cells. This treatment, still in its infancy, is called senolytic therapy, and it is being tested in Alzheimer’s disease, COVID-19 lung disease and a host of other disease conditions.

“In our study, we showed that by using senolytics to clear senescent cells after radiation, we can slow down the growth of implanted tumor cells and improve survival,” Burma said.

Findings suggest that following radiation, adjuvant senolytic therapy could be a one-two punch against glioblastoma recurrence.

Eventually, a radiation-senolytic combination could be an answer long sought by oncologists, families and patients alike to blunt glioblastoma recurrence.

Studies show promise for improving bladder cancer survival

Bladder cancer is the fourth most-common type of cancer in men. In patients with high-grade cancer in the lining of the bladder — also called non-muscle invasive bladder cancer — cancer often comes back within a year following standard treatment. Although there are several approved treatments, none have significantly improved survival rates without serious side effects.

In a study published in The Lancet Oncology, Mays Cancer Center urologic oncologist and study site principal investigator Robert Svatek, MD, and his team evaluated a novel immunotherapy called nadofaragene firadenovec (NF) gene therapy that may offer new hope.

“This product is remarkable as one of the first virus-delivered gene therapies to treat cancer,” Svatek said. “NF is a virus that has been altered to transport a genetically modified protein called interferon alfa-2b. Once in the bladder, interferon alfa-2b prompts the cells in the lining of the bladder to make more of this protein to fight cancer, strengthening the body’s immune response.”

By piggybacking the protein and delivering it with a virus in a liquid placed in the bladder through a catheter, the protein is contained in the bladder for an hour — long enough to provide a significant immune response.

“NF has fewer and less serious side effects than other treatments approved for this type of cancer. NF also allows patients to avoid surgery to remove the bladder, which is the next treatment to consider if the current standard treatment fails,” said Svatek.

About 75% of bladder cancer cases are classified as non-muscle invasive, which means the cancer affects the tissue lining the inner surface of the bladder, but not the bladder muscle.

According to the study, 53.4% of participants receiving NF were free of cancer at three months and 45.5% of patients continued to be cancer-free for at least 12 months.

The phase 3 study included 153 patients from 33 U.S. institutions, including the Mays Cancer Center. Svatek and his team will continue to follow patients for four years to learn more about how they respond long term.

Understanding survival discrepancies

In another study published in Bladder Cancer by researchers at the Mays Cancer Center, bladder cancer was found to be more aggressive and more advanced in residents of South Texas than in many parts of the country.

According to the study’s findings, the disease is also deadlier in Hispanics and women, regardless of where they live nationwide.

For this study, the research team compared bladder cancer cases in the Texas Cancer Registry with cases in the Surveillance, Epidemiology, and End Results (SEER) program. SEER, which collects data on cancer cases from various locations across the U.S., does not include Texas statistics.

“Although South Texas and Texas had lower bladder cancer incidence rates than SEER, the region and state had significantly worse five-year survival rates for bladder cancer compared to SEER. This was regardless of gender,” said the study’s first and corresponding author Shenghui Wu, MD, PhD, assistant professor of population health sciences at UT Health San Antonio.

“We also found that Latinos, both men and women, had lower incidence but worse survival than non-Latino whites in each geographical area,” Wu said. “And women had significantly lower bladder cancer incidence but worse survival rates than men, regardless of race or ethnicity, in each area.”

Svatek, a study coauthor, said the findings reveal the complex variations among diverse groups in their responses to cancer. The Texas population, which is 40% Hispanic, “is uniquely different than the rest of the United States in the biology of bladder cancer,” Svatek said. “It means we really need to understand what is going on locally and study our patients to understand why there is a difference.”

Smoking contributes to bladder cancer development, but other factors aren’t known. The study authors note that residents in South Texas have lower per capita personal incomes; higher rates of unemployment, poverty and lack of insurance; lower educational attainment; less access to health care services; and higher obesity prevalence than the state as a whole, all of which may uniquely impact both incidence and survival rates for cancer patients.

Detecting cancer’s spread before it happens

Cancer that spreads to another area of the body is typically less treatable as the primary tumor from which it has originated. Survival from metastatic disease is generally poor.

But what if a daily or weekly blood sample could monitor each patient’s risk of metastasis, indicating the need for aggressive therapy before cancer spread is established?

That’s the goal of researchers at the Mays Cancer Center. In the journal Cancer Research, authors including Maria E. Gaczynska, PhD, and Pawel Osmulski, PhD, report that blood-borne seeds of cancer, called circulating tumor cells (CTCs), have specific properties that can be measured.

For example, CTCs are sticky and glom onto other cells called macrophages while hurtling through the bloodstream. Macrophages are infection-fighting cells that can be either pro- or anti-inflammatory.

The study, conducted in human prostate cells provided by the Mays Cancer Center, indicated that the presence of macrophages, along with properties such as stickiness, can be an accurate biomarker of risk for metastasis.

“What is completely new, what we found here, is that both pro- and anti-inflammatory macrophages can be bad for the patient,” Gaczynska said. “Both can help circulating tumor cells to survive.”

“Actually, this is like a crystal ball,” said Gaczynska. “When we are looking at the nanomechanical properties, and when we are asking how many macrophages there are, we can tell if this patient is at risk of metastasis very soon.”

The finding about the role of macrophages in cancer is a key building block discovery.

“Because the majority of cancer patients die of metastasis, this is of very high medical relevance,” Osmulski said. “The interactions between CTCs and macrophages can be the target of anti-metastasis drugs.”

Current studies use an atomic force microscope at UT Health San Antonio and are technically demanding, but the researchers seek to streamline the process to make it a bedside diagnostic.

Read more stories from our 2022 Annual Report.