'Born to Be Bad'

Cancer Researcher Christina Curtis Presses for Answers on the Origins of Tumors

Christina Curtis, PhD

Through all the discoveries that cancer researcher Christina Curtis, PhD, has made so far, there has been one big-picture question driving her forward. It has preoccupied Curtis since she was a curious high school student who lost her grandfather to the disease.

How does a tumor begin?

While scientists proved decades ago that cancer begins with genetic mutations that allow malignant cells to develop different characteristics than other cells, the exact process of how the tumor begins—and which cells acquire those mutations—is still poorly understood, says Curtis, associate professor of oncology and genetics, director of breast cancer translational research, and co-director of the Molecular Tumor Board at the Stanford Cancer Institute.

“What does it take to form a cancer?” Curtis asks. “We’re beginning to have the tools and technologies, both experimental and computational, to start to address that. There’s so much potential.”

To discover the origins of cancer, Curtis and her colleagues are working to trace the life cycle of a tumor, beginning with the first error in a cell’s DNA, to the point where it spreads, or metastasizes, to other organs. The Curtis laboratory analyzes patient tumor samples, creates virtual tumors that simulate the process in a human being, and grows miniature versions of organs—called organoids—on which the scientists can use CRISPR gene-editing technology to introduce alterations that are common in certain cancers and observe what it takes for a tumor to develop.

A New Era in Breast Oncology

While Curtis has made contributions across a number of areas in oncology research, she may be best known for her discovery of 11 genetically distinct subgroups of breast cancer. This work, published in Nature in 2012, has formed a key pillar of the Curtis lab’s work, culminating in a landmark 2019 Nature paper showing that four of these subgroups have a high risk of late metastasis and collectively account for about 25% of women whose tumors express the estrogen receptor and not the HER2 receptor. In some cases, the recurrence comes decades after the women thought they were cured.

Allison Kurian, MD, MSc, professor of oncology and of epidemiology and population health and director of the Stanford Women’s Clinical Cancer Genetics Program, says she can’t think of another scientist who has made such advances in the field of breast oncology so early in their career.

“Dr. Curtis is a brilliantly original thinker whose work has already begun to have a transformative impact on the field of breast oncology,” says Kurian. “Late recurrence of favorable-diagnosis, hormone receptor–positive breast cancer is a problem of tremendous importance, affecting thousands of women annually. Dr. Curtis’ discovery of molecular drivers of this disease offers excellent potential for the development of targeted therapies.”

"Dr. Curtis is a brilliantly original thinker whose work has already begun to have a transformative impact on the field of breast oncology"

This work has led to a Department of Defense–funded clinical trial, of which Curtis is the principal investigator, together with George Sledge, MD, professor of oncology, to test new therapies for these high-risk breast cancer patients. The trial is being led by Sledge and Jennifer Caswell-Jin, MD, assistant professor of oncology, who trained in Curtis’ lab. It will be the first of what Curtis believes will be many trials that could help usher in precision medicine for this biomarker-defined group of cancer patients.

The Quest Becomes Personal

Curtis knows from personal experience that these discoveries can’t come fast enough. In 2017, when Curtis was in the throes of deep thinking about the problems of metastasis and late-stage cancers, her parents were diagnosed with different cancers one month apart. Her mother lived just three and a half months; her father recovered, but Curtis worries about recurrence.

The experience pushed Curtis to place even more focus on tracing a tumor’s starting points.

She was the mother of two young children, facing two parents sick with cancer, and it was all happening so fast.

We were doing research on late-stage cancers—and had made really important insights there—but the whole experience impressed on me a renewed need to intercept earlier,” Curtis says. “It’s not enough to detect a tumor when it’s already metastasized.”

Seeds of Metastasis Start Early

The lab’s recent findings have reinforced the message that metastasis can happen earlier than previously suspected.

One study, published in Nature Genetics, expanded on Curtis’ 2019 discovery that some tumors are “born to be bad.” She and colleagues coined the term after observing that in most patients with metastatic colorectal cancer, the cancer cells spread to distant organs, like the brain or liver, years before the initial tumor was diagnosed.

In the new paper, she and her collaborators showed that early metastasis can happen in breast and lung cancer too, two to four years before the first tumor is detected—illuminating the need for improved strategies to detect cancers earlier. What’s more, their findings illuminated the need to consider the timing and types of therapy to avoid the emergence of drug resistance.

While these are not easy messages to convey, and more research is needed, “they open our eyes to the need to study patient tumors sampled during the course of therapy, and to anticipate resistance,” Curtis says. “The seeds of metastasis can be sown early, and we need to study the continuum of disease with this in mind. It can empower the field to address some of those harder questions, particularly as new technologies are at hand.”

Recently, Curtis and colleagues also identified a long-sought-after biomarker for women with early-stage, newly diagnosed, HER2-positive breast cancer. Up to 50% of patients with HER2-positive tumors, which produce too much HER2 protein, have residual cancer following treatment.

“Many clinical trials have been designed with the goal of asking, ‘Is there a new biomarker that would predict which women would respond to therapy, above and beyond the fact that they have HER2 amplification?’ and the field has struggled,” Curtis says. “It’s unfortunate, because here’s a place where we have multiple FDA-approved drugs, and we could either combine them to increase a women’s response, or we could give targeted therapy and leave out the chemo and spare this patient the additional toxicity. So we really need predictive biomarkers.”

In a study that deployed a completely new technology called digital spatial profiling to look at 40 different tumor and immune proteins in tumor tissue samples before and during preoperative therapy, Curtis and colleagues found what they were looking for. Patients who had higher levels of an immune marker called CD45 after just a single cycle of HER2-targeted therapy tended to have a dramatic response to treatment, while those with lower levels did not. The findings were published in April 2021 in Nature Cancer.

The next step will be to design a clinical trial that tests these findings.

“If it validates, this has the potential to transform patient care,” Curtis says. “We would be able to personalize therapy with this approach—for example, by eliminating chemotherapy use in a subset of patients who do not require it.”

A Dedicated Mentor

Besides her notable scientific contributions, Curtis is known as a “deeply collaborative” colleague and “gifted lecturer, with exceptional skill in mentoring young investigators,” Kurian says. In particular, Curtis, who had few female mentors when she trained in computational biology, has made an effort to create an environment where women feel supported. Today, more than half of the scientists in her lab are female.

“I’ve had the opportunity to train many stellar trainees that have gone on to be faculty and lead new breakthroughs,” Curtis says. “It’s been really important to me to try to cultivate a laboratory where everybody felt that they had an equal footing, and especially make sure that female scientists felt they could do this whether they wanted to have a family or not.”

Caswell-Jin says she felt lucky to work in Curtis’ lab.

“She is an extraordinary mentor,” Caswell-Jin says. “She cares deeply about the science we work on together and about the potential for it to translate to the clinic to improve people’s lives. She loves helping us grow from trainees in her lab to colleagues and collaborators.”