Targeting the Achilles’ heel of tumors using molecular pathways

New Zealand genomics researcher and professor Dr. Cristin Print was a house surgeon fresh out of medical school in Auckland, New Zealand in the early 1990s when he realized that medicine’s lack of understanding of how specific diseases worked was hindering the ability of clinicians like him to treat patients.

“I felt like I was mowing the lawns, doing the same thing every day, when I wanted to be designing the garden… trying to find better ways to attack disease. One of the biggest examples for me was cancer – why some people did far worse on some treatments than others – and how little we understood scientifically about how tumors grow.” As a result, he says, “the treatments were one size fits all, and I felt very frustrated that we couldn't personalize them.

That frustration transformed the trajectory of his career. Print made the leap from clinician to medical researcher, spending over a decade focusing on genomics research and bioinformatics. In particular, Print wanted to understand how molecular pathways become disrupted to cause disease, and in particular, cancer.

“We want to identify the Achilles’ heels of each patient’s cancer,” he says. “With thousands of complex molecules inside each cancer cell, we want to understand where the regulation of those molecules has gone wrong to allow cancer to grow out of control, and how we can bring it back into line using targeted therapies. We especially want to work out how tumors evolve to evade the immune system.”

Finding out how cells tick

Print, a father of three and keen outdoorsman, is a thoughtful and respected figure here on the 2nd floor of the grey and unpretentious 50-year-old medical school building. Print is more likely to be found behind a computer screen than a DNA sequencing machine these days, but he still enjoys the excited hum of the lab.

Print’s translational research lab works on analyzing tissues, cells and genomes of various tumors. “We're moving into a phase now when we can get a very deep and nuanced understanding of an individual cancers,” he says.

One of the powers of advanced pathway analysis is its ability to identify biomarkers—for example, genes that are mutated, highly expressed or demonstrate altered expression, in association with specific active pathways. “We often use advanced pathway analysis to try and understand—based on looking at how thousands of genes are expressed—how the downstream effects of mutations drive cancers. Sometimes biomarkers can be very useful to identify whether tumors are vulnerable to specific drugs and even to monitor over time when specific drugs become ineffective.”

QIAGEN Digital Insights analysis tools, such as QIAGEN Clinical Insights (QCI), used to analyze gene variants, and QIAGEN Ingenuity Pathway Analysis (IPA), used to analyze gene expression, have changed the pace at which Print and his team can turn data into insights.

Molecular pathway of disease

A major discovery in his lab, in collaboration with the labs of his colleagues, was Dr. Annette Lasham’s identification of a new oncogene (a mutated gene that positively contributes to the development of a cancer) called YB1 in breast and ovarian cancer. “Without advanced pathway analysis, we’d never have detected this and would never have been able to start developing drug agents that could potentially be used in the future as a targeted therapy,” he says.

QIAGEN IPA relies on manually curated content from the QIAGEN Pathway Knowledge Base, and uses powerful algorithms to identify the most significant pathways, potential novel regulatory networks and causal relationships, among other insights. Such tools have enormous value because they offer an “up-to-date and exponentially growing pool of knowledge,” Print says. “This software also makes that knowledge base readily accessible to our collaborators, who aren't quite as nerdy as us, and don’t have the time to scour literature to validate findings,” he laughs.

“The beauty of these different software tools is that they really speed up our process of understanding,” Print says. “It’s like when you’re out on a walk in the wilderness and you think you’ve seen the top of the hill. You get there, and then there’s an even bigger hill above it. The deeper we look at molecular pathways in disease, the more we see and the more we need to look.”

Beyond cancer, Print has used advanced pathway analysis to understand endometriosis (“one of the greatest unsolved diseases of our modern age”), endothelial cell function, immune response and stem cell growth.

Fostering health equality

Making sure personalized disease treatment is available to people historically neglected by medicine is another of Print’s goals. He and his colleagues have begun to recognize that the explosion of genomics information available in international databases, and the increasing sophistication of tools to mine it, has the potential downside that it could widen an already massive health equity gap, especially in indigenous populations.

“In New Zealand, we’re very aware that Māori and Pacific people have a huge inequity in survival outcomes for cancer and many other diseases,” Print says. “We need to ensure that current research doesn’t generate further inequity in the future.”

This means genomics research in New Zealand is co-led by Māori, who regard their genetic information as a precious taonga (treasure). It’s for this reason that Print is co-lead researcher of Rakeiora, a genomics program in partnership with Māori researchers, clinicians and community leaders to lay a path for safe and effective use of indigenous genomic information that contributes to health equity. It’s a model being increasingly adopted internationally for indigenous populations.

“The funny thing is, when you have your own genome sequenced, you start to think in a very similar way to your Māori friends and colleagues,” he notes. “You realize that everything is long term. Your genome doesn't belong to you. It belongs to your parents and many generations in front of you and behind you. And we're starting to think in that way in some of our research.”