Traditionally, cisplatin-based chemotherapy has been the standard treatment for bladder cancer patients who are able to tolerate this drug. However, responses have been limited, and durable outcomes rare. Over the past years, two phase-3 clinical trials studied the effects of combining immunotherapy with either chemotherapy or a new drug, enfortumab vedotin, to treat bladder cancer (more exact: urothelial carcinoma). With success, both studies show a significant increase in both overall survival as well as progression-free survival.

Medical oncologist Michiel van der Heijden from the Netherlands Cancer Institute (NKI) explains: “these results mark a milestone in bladder cancer research, providing the first evidence of a survival benefit of combination therapy involving immune checkpoint inhibitors over chemotherapy. This is an exciting development in our field, as these findings will thoroughly change the treatment landscape for advanced bladder cancer. It is a testament to the collaborative efforts of researchers, and most importantly, the resilience of all patients who participated in this study.”

Combining therapies

The CheckMate 901 trial investigated a new combination of the drugs nivolumab and gemcitabine-cisplatin and compared this to treatment with only chemotherapy. The results demonstrated that patients treated with both drugs showed a 22% reduction in the risk of death compared to patients only treated with chemotherapy. The findings also showed that the combination of nivolumab and chemotherapy led to a significant improvement in progression-free survival vs chemotherapy alone.

The results will be published in the New England Journal of Medicine at the same time as the presentation at ESMO.

During this ESMO presidential session, the results of another phase-3 in the same treatment line will be presented, featuring a novel combination of an antibody-drug conjugate with immune checkpoint inhibition, using Enfortumab Vedotin + pembrolizumab. This study found a statistically significant and clinically meaningful improvement in overall survival and progression-free survival as well. These results will be published in a scientific journal at a later time.

Both treatments are yet to be registered and approved in the Netherlands for health insurance coverage, meaning that they will not yet be readily available. In the US, the Enfortumab Vedotin + pembrolizumab is already available for a subgroup of bladder cancer patients, based on a phase 2 study.

Unique

Michiel van der Heijden is involved in both these trials, making it a special occasion for the NKI to have such a leading role in two large studies that can change clinical practice. “It is very special to give a presidential lecture during ESMO. I have not had this honor before and it may very well not happen again anytime soon. Last year was a very special occasion as well, as two NKI researchers, Myriam Chalabi and John Haanen, both presented their findings in the presidential session. Not many researchers have received this honor, making this a really unique moment for the NKI once again.”

Some cancers, however, can hijack these pathways for their own benefit. Susanna Stroik, PhD, and Dale Ramsden, PhD, both researchers in the Department of Biochemistry and Biophysics in the UNC School of Medicine and the UNC Lineberger Comprehensive Cancer Center, have pieced together the lesser-known DNA repair pathway, called polymerase theta-mediated end joining (TMEJ).

The pathway — which has been found to be upregulated in many patients with hereditary breast cancer, ovarian cancer, and prostate cancer, specifically those involving BRCA1 and BRCA2 mutations — has been laid out step by step in a published article in Nature, and the new knowledge could lead to new therapies for cancer.

“People with these breast cancer mutations, their cancers rely on polymerase theta’s repair pathway to keep the tumors alive and repair DNA damage in the cancerous tissue,” said Stroik, a postdoctoral researcher in Ramsden’s lab. “Now that we know more about this pathway, scientists could, in theory, produce a drug that could disrupt key pieces of the pathway in cancer cells, as opposed to using conventional chemotherapies that destroy healthy cells along with the cancer.”

Polymerase Theta’s Discovery

Out of all DNA repair pathways, TMEJ has been the most elusive. Richard Wood, PhD, a distinguished professor at University of Texas MD Anderson Cancer Center played a key role in the first characterization of polymerase theta in 2003.

Over the next 15 years, multiple labs, including the Wood, Ramsden, and Gupta labs (also at Lineberger Comprehensive Cancer Center), were able to link polymerase theta to DNA repair (TMEJ) and cancer. Sylvie Doublié, PhD, an alumnus of UNC-Chapel Hill and professor of microbiology and molecular genetics at the University of Vermont, then solved the first structure of polymerase theta.

Together, and with other scientists from Penn State and New York University, these researchers were dedicated to understanding precisely what steps are involved in TMEJ, and which of those steps polymerase theta does and does not perform.

With the help of these collaborators, Stroik was able to use a wide variety of cutting-edge experimental approaches to fill in the gaps in our understanding of the TMEJ pathway. Critically, she discovered that another polymerase, called polymerase delta, uses a buddy system with polymerase theta to assist it in this repair pathway.

A Unique Buddy System

Stroik’s research showed that polymerase theta is good at some things, but not others.

“It makes a lot of errors and it’s not capable of creating large swaths of DNA at once,” said Stroik. “What was so beautiful and kind of elegant about the whole discovery is that there are two different enzymes alternating between pathway steps and helping each other out.”

When a double stranded break occurs, both strands of DNA are cut at the same spot, much like scissors severing a braid of hair. Polymerase theta acts quickly, grabbing the two single strands of DNA, matching up the closest base pairs to the break, and holding them together.

However, this often leaves some residual flaps of single stranded DNA at the ends. Polymerase delta jumps in to cut the extraneous flaps, giving polymerase theta enough room to start synthesizing new DNA to fill in gaps in the DNA strands. Finally, polymerase delta jumps in one last time to help polymerase theta complete synthesis.

Stroik had another breakthrough finding: polymerases theta and delta are physically attached to one another. This new information could prove to be especially useful to drug developers hoping to create a new cancer treatment by drugging this interaction.

Cancer Treatment Potential

Since many cancers make use of the TMEJ pathway to keep tumors alive, many researchers have investigated creating drugs that can interfere with the pathway, essentially preventing cancer from repairing itself, leading to its eventual demise.

“Anytime you find new pieces of the pathway, you can ‘drug’ it,” said Ramsden.

Stroik and Ramsden’s new research will contribute to ongoing basic studies in polymerases theta and delta, while also aiding new cancer drugs called polymerase theta inhibitors, which are currently in clinical trials.

An Oregon Health & Science University study published in the journal Obesity found people who have a healthy weight use more energy during the day, when most people are active and eat, while those who have obesity spend more energy during the night, when most people sleep. The study also found that during the day, those with obesity have higher levels of the hormone insulin — a sign that the body is working harder to use glucose, an energy-packed sugar.

“It was surprising to learn how dramatically the timing of when our bodies burn energy differed in those with obesity,” said the study’s first author, Andrew McHill, Ph.D., an assistant professor in the OHSU School of Nursing and the Oregon Institute of Occupational Health Sciences at OHSU. “However, we’re not sure why. Burning less energy during the day could contribute to being obese, or it could be the result of obesity.”

Obesity is defined as having a Body Mass Index, or BMI, of 30 or more. Being overweight or obese increases the risk for health conditions such as high blood pressure and Type 2 diabetes.

Schedules and when people sleep, eat and exercise can also affect health, by either complementing or going against the body’s natural, daily rhythms. Every 24 hours, people experience numerous changes that are triggered by the human body’s internal clock. These changes normally occur at certain times of the day in order to best serve the body’s needs at any given hour.

McHill and the study’s senior author, Steven A. Shea, Ph.D., director of the Oregon Institute of Occupational Health Sciences at OHSU, focus their research on how circadian rhythms and sleep impact the human body. McHill leads theOHSU Sleep, Chronobiology and Health Laboratory.

While previous research has suggested circadian rhythm misalignment affects energy metabolism and glucose regulation, those studies have largely involved participants who have a healthy weight. To explore this further, McHill, Shea and colleagues organized a study that included people of different body sizes.

A total of 30 people volunteered to participate in the study, which involved participants staying at a specially designed circadian research lab for six days. The study followed a rigorous circadian research protocol involving a schedule designed to have participants be awake and sleep at different times throughout each day.

After each period of sleep, volunteers were awakened to eat and participate in a variety of tests for the remaining time of each day. One test had participants exercise while wearing a mask that was connected to a machine called an indirect calorimeter, which measures exhaled carbon dioxide and helps estimate energy usage. Blood samples were also collected to measure glucose levels in response to an identical meal provided during each day.

Next, the research team plans to explore eating habits and hunger in people who are obese, as well as those who have a healthy weight. That new study will also follow up on a 2013 study, led by Shea, that found circadian clocks naturally increase food cravings at night.

In a study of air pollution data in relation to markers of reproductive development in infancy, Rutgers researchers found certain pollutants may negatively alter anogenital distance, a measure of prenatal exposure to hormones.

“These findings suggest air pollution may interfere with normal hormone activity during critical periods of prenatal and early infant development, and we suspect that disruption may have long-term consequences for reproductive health,” said Emily Barrett, a professor in the Department of Biostatistics and Epidemiology at the Rutgers School of Public Health and lead author of the study published in the journal Environmental Health Perspectives.

Cross-sectional studies in adult men and women have shown that alterations in anogenital distance — the length between genitals and the anus — may be related to hormone levels as well as semen quality, fertility and reproductive disorders.

In animal studies, anogenital distance is used to determine developmental toxicity of pollutants. One measurable impact is on the reproductive system. When anogenital distance is reduced in male offspring, it’s a sign that a toxic exposure is interfering with fetal testosterone production, Barrett said.

Researchers have speculated that a similar relationship may exist in humans. To test their hypothesis, Barrett and colleagues used data from The Infant Development and Environment Study (TIDES), an ongoing longitudinal study of pregnant women and their children launched in 2010 in four U.S. cities: Minneapolis; Rochester, N.Y.; San Francisco; and Seattle. Anogenital distance at birth in children, and at one year for boys, was measured as part of the TIDES program.

These data were then compared with levels of nitrogen dioxide and fine particulate matter (PM2.5) — particle pollution 2.5 micrometers or smaller released during the burning of gasoline, oil, diesel and wood. An air pollution monitoring system administered by the University of Washington tracked pollution levels in the residential areas of TIDES participants during pregnancy.

By comparing these two measures, the researchers identified a link between exposure to air pollution during key developmental windows and anogenital distance.

For instance, higher PM2.5 exposure during the so-called male programming window at the end of the first trimester, when the male fetus typically receives a surge of hormones, was associated with shorter anogenital length at birth.

The researchers also observed that higher PM2.5 during mini puberty (a period in early infancy when hormone production is high) was associated with shorter anogenital distance in males at age one. These findings suggest there may be multiple points during early development that the reproductive system may be vulnerable to the impacts of air pollutants.

“PM2.5 is like a trojan horse,” said Barrett, adding that particulate matter can carry metals such as cadmium and lead, known endocrine disruptors. “When these disruptors interfere with the body’s hormones, the result could be lifelong impacts on our health, from cancer risks to impaired ability to conceive a child.”