Cancer Evolution and Progression Focus of Studies

By Dirk Hoffman

The studies, funded by the National Cancer Institute, focus on bladder cancer and basal-like breast cancer, a very aggressive kind of breast cancer.

“The strength and innovation of the projects are that we combine machine learning, bioinformatics, tumor biology, and next-generation sequencing techniques to address some critical issues and unmet clinical needs in cancer research,” Sun says.

Sun is the contact principal investigator on “Prognostic Analysis and Progression Modeling of Basal-Like Breast Cancer Using Multi-Region Sequencing,” a five-year study totaling $3.2 million. Steven Goodison, PhD, of the Mayo Clinic, Jacksonville, Florida, is the co-principal investigator on the study.

On the other five-year, $2.5 million study titled “Disease Progression Modeling of Bladder Cancer,” Goodison is the contact PI and Sun is the co-PI.

Breast cancer is the most common cancer in women worldwide, and the fifth most common cause of death from cancer overall. As with many other cancers, breast cancer presents in a variety of forms and can be broadly divided into molecular subtypes.

Among them, basal cancer represents approximately 20% of primary breast tumors and is one of the most aggressive and deadly subtypes.

“While significant efforts have been made, the biological process of how basal cancer progresses to a malignant, life-threatening disease is not well understood, and the prognostication and treatment of basal cancer remain major challenges,” Sun says. “Specifically, there are currently no prognostic tests available that can assist clinical management, and nearly all basal cancer patients are classified as having a high risk of recurrence.”

Sun notes because the majority of basal tumors lack expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), there are presently no effective targeted treatment regimens available, and harsh, indiscriminate chemotherapy is the only treatment option.

“Consequently, a significant number of basal cancer patients are under- or over-treated,” he explains.

Building upon his lab’s previous work, Sun proposed a large-scale interdisciplinary research plan, which will use multi-region sequencing and advanced computational techniques to address some pressing issues and unmet clinical needs of basal breast cancer.

The researchers will perform molecular profiling of 300 primary basal tumors and 50 matched metastatic tumors they have identified from Mayo Clinic tissue banks.

“By using the obtained multi-region sequencing tumor tissue data, we will derive a prognostic evaluation system for basal cancer through multiple instance learning, and construct and validate a high-resolution progression model of basal cancer,” Sun says.

The researchers will also perform a large-scale analysis on a range of molecular data to systematically search for genetic determinants of basal cancer progression at both gene and pathway levels, which will provide insights into molecular mechanisms of tumorigenesis and enable them to identify potential therapeutic targets for basal cancer.

“If successfully implemented, this work will significantly advance the basal cancer research, and pave the way for applying similar strategies to study other deadly cancers,” Sun says.

In the other study, a large-scale interdisciplinary research plan is expected to derive a progression model for bladder cancer (BLCA).

BLCA is among the five most common malignancies worldwide. In the U.S. alone, new cases are estimated at 72,500 with estimated deaths at over 15,000, figures that are anticipated to increase in the near future.

“Classification of BLCA into multiple molecular subtypes has recently been proposed and has the potential to impact clinical management,” Sun says. “Nonetheless, significant biologic subgroup heterogeneity remains, and more work is needed before a unified classification system can gain wide acceptance.”

“More importantly, there is no understanding yet of the inter-relationships between subtypes. Insights into how subtypes are related and how cancer evolution influences the observed changes in molecular pathologic phenotype is the next level of analysis required and is our current focus,” he adds.

Sun says the work will inform a range of research directions that were previously unattainable.

“The derivation of a BLCA roadmap and the identification of pivotal molecular events that drive stepwise cancer progression will provide new insights into tumor biology and guide the development of improved cancer diagnostics, prognostics and targeted therapeutics,” he says.

“Annotated progression maps can also guide the design of clinical trials and animal studies to focus on pivotal points of cancer development, which may yield the best return with limited resources.”