Reverse translation, also known as bedside-to-bench research, is an innovative approach increasingly recognized as pivotal for scientific advancement and potentially reducing health care costs.

The strategy involves the examination of patient samples, obtained during clinical trials, in laboratory settings to unravel the complex molecular mechanisms and functions of key proteins implicated in diseases.

"This research paradigm reverse engineers the traditional bench-to-bedside method, where laboratory discoveries are translated into therapeutic applications," said Keith Syson Chan, PhD, director of Translational Research in the Houston Methodist Department of Urology. "The integration of both approaches within the same institution has been shown to dramatically accelerate medical and scientific breakthroughs, particularly in our understanding of how diseases like cancer work at the molecular level."

In December 2022, Houston Methodist recruited Dr. Chan, who also serves as program lead of Innovative Therapeutics at the Dr. Mary and Ron Neal Cancer Center at Houston Methodist, to help push the frontiers of early-phase clinical trials and improve responses to chemoimmunotherapy among bladder and genitourinary cancer patients.

His appointment, supported by a $6 million Established Investigator Recruitment Grant from the Cancer Prevention and Research Institute of Texas (CPRIT), is expected to catalyze more collaborations within and outside of Houston Methodist.

Dr. Chan says the cyclical process of translating laboratory findings to clinical settings — and vice versa — can significantly shorten the timeframe for achieving critical clinical milestones.

His translational research team, which acts as a bridge between basic science and clinical research teams, collects tissue samples from patients enrolled in clinical trials. These samples enable robust laboratory tests and further hypothesis generation, potentially leading to more efficacious phase III clinical trials.

As a cancer biologist, Dr. Chan has traditionally focused on inducing programmed cell death in cancer cells. His recent research highlights an understudied aspect of cell death biology that can influence therapeutic responses.

His team found that dying cancer cells release factors that affect the remaining cancer cells and the immune tumor microenvironment.

"This could reshape our understanding of how chemotherapy and immune checkpoint blockade therapy work, with the potential to significantly reduce tumor burden," Dr. Chan commented.

In April 2023, Dr. Chan shared these novel insights at the Cancer Moonshot Seminar Series, organized by the National Cancer Institute, showcasing the importance of understanding the tumor microenvironment's intricacies.

He advocates for a holistic reverse translation approach that dissects the interactions between cancer cells, stromal cells and immune cells and illuminates how these interactions contribute to therapy resistance.

"Our laboratory has evolved to adopt a comprehensive perspective, where we examine the interplay between cancer cells, fibroblasts and immune cells using cutting-edge technologies like single-cell RNA sequencing and spatial biology profiling," Dr. Chan explained.

This collaboration with the Methodist Systems Biology team, led by Dr. Stephen Wong, provides an all-encompassing view of the tumor microenvironment, crucial for developing effective treatment strategies.

Chan's team is also investigating molecular markers that define different cancer cell states, which could serve as prognostic markers for subtyping bladder cancer into clinically relevant categories.

As part of an international consortium dedicated to improving outcomes, Dr. Chan's goal is to refine bladder cancer classification and explore how these subtypes correlate with treatment responses.

Dr. Chan's commitment to collaboration within the Neal Cancer Center exemplifies the potential of integrating bench-to-bedside and bedside-to-bench research.

This integrative approach has the potential to bring about substantial improvements in health care delivery, clinical decision-making and the development of more effective drug combinations, ultimately advancing precision medicine therapies for bladder cancer patients and reducing unnecessary costs associated with failed treatments.

The American Cancer Society estimates there will be 82,000 new bladder cancer cases in the U.S. in 2023 and 16,000 deaths. Men are three times more likely than women to be diagnosed, and it ranks as the fourth most common cancer among men.

For more on how reverse translation is advancing precision medicine at Houston Methodist, click here.