Previewing the Future of Bladder Cancer Research and Care

Over the past decade, the clinical management of bladder cancer has seen remarkable advancements due, in part, to a better understanding of bladder cancer biology that has led to more targeted therapies as well as the introduction of effective immunotherapies. Dan Theodorescu, MD, PhD, director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, said that those advancements and what lies ahead will be just some of the key topics covered at the upcoming American Association for Cancer Research (AACR) Special Conference in Cancer Research: Bladder Cancer: Transforming the Field in Charlotte, North Carolina from May 17-20.

“Laboratory discoveries have also led to increasing integration of next-generation ‘omics’ technologies into clinical management including next-generation cell-free DNA panels, droplet digital PCR, and/or analysis of circulating or urinary tumor cells,” said Theodorescu who will serve as one of the conference’s cochairs. “Coupled with continued development of novel targeted small-molecule and biological treatments, as well as immunotherapies, these advances are shifting how we manage the bladder cancer patient with the expectation that the recent improvements in overall survival and quality of life will continue their upward trend.”

Still, bladder cancer is the ninth most common cancer worldwide with more than 600,000 cases diagnosed and more than 220,000 fatal cases in 2022, according to the International Agency for Research on Cancer.

“Despite all our advances approximately half of our patients with advanced and metastatic bladder die,” Theodorescu said, “so clearly more work remains to define who these patients are and what makes their disease resistant, so far, to our current therapeutic modalities.”

Theodorescu along with his fellow cochairs—Lars Dyrskjøt, PhD, professor in the Department of Clinical Medicine – Department of Molecular Medicine at Aarhus University Hospital in Denmark; Donna Hansel, MD, PhD, head of the Pathology & Laboratory Medicine division at the University of Texas MD Anderson Cancer Center; and Tahlita Zuiverloon MD, PhD, assistant professor at the Erasmus MC Urothelial Cancer Research Group in The Netherlands—have helped develop a program for the conference that spans the gamut of recent research on liquid biopsies, novel treatment approaches, artificial intelligence, and more working to address the challenges this disease still poses.

We spoke with Theodorescu and Dyrskjøt about the upcoming conference and what most excites them about the current research in this field.

How will the evolution of bladder cancer research be reflected at this meeting? 

Dyrskjøt: With novel analysis tools and novel treatment options, research in bladder cancer is evolving towards better understanding of disease mechanisms, especially immunotherapy response (such as with the therapeutic vaccine Bacillus Calmette-Guérin and immune checkpoint inhibitors). Furthermore, we are getting closer to using biomarkers to guide treatment decisions in bladder cancer with liquid biopsy analyses, for example. These areas will be discussed throughout the meeting. 

Theodorescu: We have also seen sequencing and gene expression studies that have revealed heterogeneity within and across tumors. These studies have shown that several distinct molecular signatures/subtypes exist that might predict disease progression and therapeutic response, which could eventually inform clinical decision-making. However, most recently, single-cell and spatial technologies have challenged the definitions of subtypes and will likely form the basis of new subtyping strategies.

I believe the advent of artificial intelligence will allow a further leap forward in cancer research and clinical practice by allowing us to discover molecular and disease patterns that we have not previously been able to see. This will drive new clinical diagnostics, prognostics, and therapeutics. Taken together I see these advances leading to a tectonic shift in how bladder cancer patients are characterized and how this information is translated into remarkably better therapies in the next decade.

What unique or interesting approaches to bladder cancer are you most excited about that will be covered at the conference?

Dyrskjøt: I am very excited about all the interesting research that will be presented in the areas of immune-tumor interactions and how to understand disease progression and treatment response based on multiple molecular and cellular parameters. I think that once we get a better understanding of this complex interaction we will discover novels ways of guiding treatment—and possible novel treatment targets.

Theodorescu: An area that I find very exciting is the intersection of sex, gender, race, and ethnicity with tumor biology, prognosis, and therapeutic response across all stages of disease, including non-muscle invasive, muscle invasive, and metastatic disease and across all the therapeutic modalities. I am also excited by advances in immunotherapy—especially the combination of immune-based therapies with chemotherapy and targeted agents of all types including small molecules and antibody-drug conjugates—and how these will impact all stages of disease.

What drew you to your own current area of research in bladder cancer?

Dyrskjøt: My focus is on basic understanding of disease biology and immunology and to use this knowledge to develop novel biomarkers for guiding treatment decisions. We have been working on molecular subtype analysis in non-muscle invasive bladder cancer (NMIBC) for several years now and have also contributed significantly to the field of circulating tumor DNA (ctDNA) in muscle invasive bladder cancer (MIBC). Currently, we are conducting a clinical intervention trial (TOMBOLA) to demonstrate the use of ctDNA to guide treatment decisions in MIBC.

Theodorescu: Since inception, our laboratory has been involved in the discovery and development of novel drivers and biomarkers of cancer prognosis and therapeutic response. For example, two recent topics of interest in our lab include the demonstration that mutiomic data can be more useful than single omic data in the prognostication of cancer. This coupled with the use of artificial intelligence has allowed us to demonstrate effectiveness for a proof of principle of a platform technology, called the Molecular Twin. In principle, this can be applied across multiple cancer types and would allow the discovery of better prognostic panels and therapeutic targets.

The other area is the study of the impact of sex and gender in cancer. For example, it was previously reported that more than 40% of men over the age of 70 have a detectable loss of the Y chromosome, a condition known as mosaic loss of Y chromosome (mLOY). This condition has been associated with increased death rates in patients with solid and hematological malignancies, cardiovascular disease, and neurological diseases. Our lab has been fascinated by this finding for five years. 

We evaluated if mLOY in bladder tumor tissue drives tumor progression and if so, the mechanisms underlying this. In this study, we found that mLOY in tumors indeed drives tumor progression and does so by creating an immune suppressive tumor microenvironment. We also showed that mLOY tumors exhibited a superior response to anti-PD-1 and anti-PD-L1 immune checkpoint blockade in mouse models as well as the ability of mLOY to stratify response to immune checkpoint blockade therapy in patients.

Because this study provides mechanistic insights, our current research is centered on using these insights to base novel predictive biomarkers and therapeutics for improving cancer immunotherapy.

What do you hope attendees walk away with from the meeting?

Theodorescu: Few conferences cover the entire arc of bladder cancer from basic biology to survivorship at a level of faculty excellence that we have here. Ultimately, the diverse educational needs of all attendees will be met. Physicians and health care professionals will learn about the latest advances in this disease and about the fundamental biology that underpins those advances. Scientists will be exposed to the results of clinical applications of their work and will become aware of the “reverse translational” opportunities in this field. Young investigators will be exposed to data-rich discussions, allowing them to identify areas of interest and focus for their future work/specialization. And all attendees will preview the future of bladder cancer research and care, potentially encouraging them to participate in the evolution of the field.