Personalizing Cancer Therapy: physicians, mathematicians and engineers together simulate advanced cancer treatments

If you ask Dr. Marissa Nichole Rylander about the myriad factors influencing cancer cells, the names of dozens of growth-promoting proteins, signaling pathways, angiogenic factors and other players trip rapid-fire off her tongue. Undaunted by this biochemical brew, the tissue-engineering expert uses input from physicians at M.D. Anderson Cancer Center and ICES colleagues to create intricate simulations of tumors that are informing computational advances in the understanding of cancer.

“My lab is highly multidisciplinary, doing its best to partner with computational experts and clinicians to confirm that the 3-D systems we develop are physiologically relevant and will lead toward meaningful clinical outcomes,” says the associate professor of mechanical engineering, who recently joined ICES’ Center for Computational Oncology (CCO). “Those sorts of interactions are really important to make progress against cancer.”

Watch a video on Dr. Rylander's work.

To move the treatment needle, Rylander draws on degrees in mechanical and biomedical engineering from The University of Texas at Austin and a laser-like determination to develop the most meaningful biological replications of tumors and of other dynamic cellular structures. Her laboratory’s 3-D tumor models of liver, breast and other deadly cancers are being used to refine computational models developed by Thomas Yankeelov and other CCO faculty using the Texas Advanced Computing Center and other resources. The ultimate goal? Providing predictive, patient-specific information about a tumor’s behavior to drive personalized treatment plans.

“You only get one shot at selecting a patient’s initial treatment,” Yankeelov, who directs the CCO, says, “and if we had a theory that could reliably select the best therapy, that would be a major step forward for precision measurements.” He adds that the cross-disciplinary cancer modeling effort relies heavily on Rylander’s engineered tumor models. “She’s one of the leaders in the field,” he adds, “and has coupled those 3-D modeling approaches with microscopy so you can quantitatively measure changes in key characteristics of cancers over time.”

Rylander, the Werner W. Dornberger Centennial Teaching Fellow in Engineering, is no stranger to nuanced research. For her doctorate, she studied how prostate cancer cells thwarted laser-heat treatments in the lab of UT’s Ken Diller, professor of mechanical engineering and biomedical engineering. The multi-disciplinary work required considering all angles: how tumors in animal models were shielding themselves from laser irradiation by expressing heat-protective proteins; how those heat shock proteins behaved in 2-D tumor systems exposed to elevated temperatures; and how well computer models quantified the distribution of temperature and heat-protective proteins during laser treatments in Houston for dog models of cancer to inform care decisions.

“Innovative” is how ICES Director Tinsley Oden tags Rylander’s thesis approach. “She participated in coding and numerical analyses for the computer models, and helped with understanding treatments that were occurring in real-time at M.D. Anderson so we could get dynamic feedback on our model predictions.”

Since she completed her Ph.D. in 2005, mathematical models of tumors have become increasingly sophisticated. So too have the technologies Rylander uses to probe cancer cells and the microenvironment surrounding them (called the extracellular matrix).

She joined UT’s faculty in 2014 after eight years on faculty at Virginia Tech, and creates and analyzes 3-D tissue structures to uncover which cues prompt cancer cells to change their molecular makeup in ways that foster proliferation, the disease’s spread to new organs (metastasis) or other characteristics.

“Her experimental work in the lab actually delves into counting cells and differentiating between cancer and healthy cells and other cellular structures,” Oden explains.

Depending on the organ studied, her multi-scale models may include growth-promoting factors, immune cells, and stem cells within the chamber that houses a 3-D tumor. Blood vessels, either resembling a garden hose or as branched structures, pass through the tumor tissue. She may also engineer a tumor as one organ in a string of organ “beads” along a blood vessel. For instance, a breast cancer study could include mimics of bone, lung or brain tissue components as separate “beads” downstream of the 3-D tumor since breast cancer often metastasizes to those tissues.

Rylander can adjust the experimental real estate in many ways, such as altering the concentration of different cell types, the properties of the surrounding, gel-like extracellular matrix, or how much fluid courses through a tumor’s blood vessels to mimic the blood pressure of real tumors. Once she has combined the appropriate bio-building blocks, she can let a 3-D system run for weeks while analyzing spatial and time-dependent processes such as cancer cells’ effects on the rigidity of their extracellular matrix.

She draws on fluorescent confocal imaging and other real-time approaches to quantify protein and gene differences that exist between cancererous and normal cells. The cellular landscape of the 3-D mimics is also continually cross checked, using MRI and other imaging approaches, against the same type of tumors in animals and tumor tissue from Houston-area patients. “We can institute all kinds of complexity,” Rylander says of the 3-D models, “but what matters is what’s necessary to replicate the kind of features and behavioral responses we see within real tumors.”

The tech-heavy research has personal meaning for her. “My cousin’s little boy died of leukemia, which inspired my dream to eradicate cancer,” Rylander admits, “and my sister was very ill when she was young and doctors initial diagnosis was leukemia, so I’ve been touched very closely.”

Having that backdrop helps because replicating the intricate world of tumors involves multiple baby steps. To nudge endothelial cells into forming a simple blood vessel tube for use in 3-D studies took a year, she notes. The tubes provide highways for transporting nutrients, drugs and other factors that tissues can pull from the blood, and as a dumping place for cellular waste products.

She has also focused on creating a biologically relevant soup of naturally occurring molecules as the 3-D extracellular matrix (instead of the common, synthetic-matrix approach). “As we start to increase the complexity of all of our 3-D systems,” she says of the cancer-engineering field, “it becomes more and more evident how important the microenvironment is.”

Her personal motivations also help sustain a resolve to extend the value of the 3-D models. That includes testing whether nanoparticles function well as taxis to target chemo drugs more selectively to cancer cells. “With any type of therapeutic delivered into the bloodstream, you may only get – if you’re lucky – one percent of it to the tumor, so effective transport of a drug is a highly challenging problem,” she notes, adding that a drug’s toxicity and transport to different organs can be studied dynamically in her more complex 3-D systems.

Regardless of the focus, when Rylander or her students need a boost, she organizes a trip to M.D. Anderson. “We go there and we walk the halls of the wards where the patients are and look them in the eyes,” she says. “It remotivates you – the fact that there’s such a human element to this.”

She also conducts tissue-engineering studies of processes such as inflammation and the regeneration of skin tissue, while helping guide the careers of future multidisciplinary researchers. Her successes have garnered her five faculty awards, including a Y.C. Fung Young Investigator Award from the American Society of Mechanical Engineers. In addition, as the biotransport committee chair of the Summer Biomechanics, Bioengineering and Biotrasnport Conference, she organizes national sessions and workshops on cutting-edge bioengineering topics, and assists in recruiting minority and disadvantaged engineering students.

Rylander recalls being the sole female in some of her undergraduate engineering classes in the 1990s, and understands what it’s like to feel different. “Having the strong mentoring programs we offer helps,” she notes.

Her team approach and successful career speaks volumes too, Yankeelov says. Oden agrees, adding, “Nichole’s excitement about the potential of this kind of translational work is infectious.”

By Barbra A. Rodriguez

Posted: Nov. 8, 2016