Basic Research: R01s – Drs. Todd Aguilera & You Zhang

R01 Spotlight – Todd Aguilera, M.D., Ph.D.

The number of locally advanced rectal cancer cases has been increasing for patients under 50 years old since the mid-1990s. With the five-year survival of high-risk locally advanced rectal cancer close to 71%, it is more important than ever to understand this disease and how it responds to treatment, so more effective approaches can be developed to combat it.

The standard of care currently comprises neoadjuvant radiation therapy and chemotherapy, with a push toward avoidance of surgery. Consequently, this thrusts immunotherapy into the spotlight as a potential therapeutic route for rectal cancer. However, there is still not enough known about its curative scope, which is why there has been an identified need for development of a tool that can help nominate ideal therapeutic techniques. To investigate this deficiency, UT Southwestern Medical Center has received a five-year NIH R01 grant titled “Early response to radiotherapy and immunotherapy in rectal cancer: An integrated molecular, cellular, and spatial approach,” led by Todd Aguilera, M.D., Ph.D., Assistant Professor of Radiation Oncology, CPRIT Scholar in Cancer Research, and Damon Runyon Clinical Investigator.

“There is a critical need to pioneer new treatment combinations so patients can be definitively treated with radiation and systemic therapy, avoiding invasive surgeries,” Dr. Aguilera says. “This grant will allow us to further improve and elevate the integrated approach we have developed to assess early biopsy tissue after short-course radiation therapy. We are using multiple advanced technologies and computational methods to uncover the complexity of the therapeutic response.”

Dr. Aguilera’s lab is performing single-cell RNA sequencing and multiplexed immunofluorescence, as well as using deep learning techniques to study immunologic responses in tissues collected from the INNATE trial, which randomized patients to receive a novel immunotherapy added to standard therapy. The endeavor’s hope is that these findings will shed light on how to immunologically target colorectal cancer and combine radiation therapy and chemotherapy with immunotherapy, facilitating the development of a new and more effective treatment strategy for patients with rectal cancer.

R01 Spotlight – You Zhang, Ph.D.

In patients with primary and metastatic liver cancer, radiation therapy is becoming a front-line treatment technique with highly effective results. An advanced and specialized form of radiation therapy, stereotactic body radiotherapy (SBRT), is increasingly used for these cancers because it is more potent at killing cancerous cells and delivering superior tumor control and survival benefits. One drawback of using this technique is that often a larger-than-needed volume is treated with radiation, exposing healthy liver tissues to potential radiation damage. This is attributed to several reasons – in particular, breathing-induced motion – as well as difficulties in visualizing liver tumors from surrounding normal tissues in X-ray imaging that is used to locate the tumor.

To account for the uncertainties arising from these challenges, radiation oncologists tend to treat patients using a larger safety margin beyond the true tumor to prevent potential treatment misses at the cost of damaging surrounding normal tissues. Considering this, advanced imaging techniques that can localize the liver tumor and capture its motion are highly sought in radiation oncology to allow the radiation beams to precisely pinpoint the tumor and avoid surrounding tissues.

You Zhang, Ph.D., Associate Professor of Radiation Oncology, has received a five-year NIH R01 grant titled “Accurate 4D liver tumor localization for radiotherapy using contrast-agent-free X-ray imaging and liver biomechanical modeling” to investigate this issue. Dr. Zhang and his lab are currently in the fourth year of their research and are optimistic about their results.

“This proposal’s work will enable us to see what we currently cannot see for precise cancer treatment in the liver,” Dr. Zhang says. “A major challenge is that we currently cannot see these tumors because everything is so similar looking under X-ray imaging.”

This research aims to develop a technique where clinicians will be able to precisely locate liver tumors and visualize how they change in location and shape over time, allowing for timely treatment plan optimization and adaptation to ensure the radiation matches with the tumor. Through techniques such as 2D-3D registration and biomechanical modeling, Dr. Zhang’s group can use limited information – for instance, a few X-ray projections – to reconstruct volumetric images of the liver (and the tumors within) and capture their motion automatically without the requirements of manual tumor identification.

“Previously, a big challenge of this technique was limited efficiency due to its computational demand, making real-time application challenging,” Dr. Zhang notes. “Now, using GPUs and artificial intelligence-driven efficiency enhancement, we can have images and motions solved in less than 500 milliseconds, opening many new potential avenues.”

Furthermore, Dr. Zhang is planning to push the limit of this technique to achieve real-time imaging by using a single X-ray projection to capture the volumetric motion of the liver, the tumor within, and all surrounding normal tissues and organs. He is planning to collaborate with physicist Weiguo Lu, Ph.D., Professor of Radiation Oncology, to bring this technology into proton therapy, which can potentially offer more precise cancer treatment than the more commonly used photon therapy. The caveat is that proton therapy’s precision is highly affected by tumor and organ motion.

Drs. Zhang and Lu are envisioning development of an on-the-fly proton therapy delivery system that combines real-time 3D imaging, motion tracking, and simultaneous plan delivery optimization and adaptation to yield the full potential of proton therapy. The combined system will allow the ultimate form of precision in liver cancer treatment by combining the most advanced X-ray imaging technique and the most sophisticated plan delivery and adaptation strategy.