Carlos Caldas, M.D., FMedSci, has been a pioneer in genetics and genomics, studying the field just as it was coming into medicine in the 1990s. He is receiving a Brinker Award, Susan G. Komen’s highest scientific honor, for his contributions over the last 25 years.
He recently spoke with Komen about some of his most impactful discoveries and his distinct approach to studying a tumor’s ecosystem, not just the tumor, to better understand breast cancers.
Dr. Caldas is a clinician scientist and Senior Group Leader at Cancer Research UK Cambridge Institute at the University of Cambridge.
Q: Explain a little more about functional genetics and the work you’ve done and are doing to understand tumor biology.
A: I lead a functional genomics lab and we’re very interested in the DNA and RNA composition of the tumors, and also increasingly cellular phenotypes, tumor architecture – what I like to call the tumor ecosystem – and of course, the translational value of that. In other words, how can we take all of this information to better diagnose, better treat, better predict and better prognosticate breast cancer. I’m a physician scientist, which means I’m a medical oncologist and I still see patients. And I’m also a lab researcher, so I bring to the lab the perspective of the physician treating patients.
Q: When you graduated from Medical School 37 years ago, I’d have to think the study of genetics was in its infancy. How did you get into the field?
A: I graduated from medical school in Portugal, and I was always fascinated by Anglo-Saxon medicine, so after I graduated, I decided to do my postgraduate training at UT Southwestern Medical School in Dallas, Texas. So, I started my residency at UT Southwestern in 1988 at Parkland Memorial Hospital and at the VA. The training program at UT Southwestern was an amazing clinical program – very busy, you learned a lot and you had this absolutely second to none faculty. We did our morning report every day, then ward rounds after we admitted all of these patients, and around four or five o’clock in the morning, you would find the residents that really cared and were the top residents in the library reading Cell, Science or Nature articles on a topic relevant to one of the patients that they had seen.
And this is really when the revolution of molecular biology and molecular genetics were coming to medicine. And so, I was exposed to it. And besides receiving amazing clinical training, I was really working in a place that was the cathedral of translational medicine and molecular medicine. A member of the faculty, Dr Michael Brown, Nobel Prize winner in 1985, was my attending at the time and gave me a book called, “The Molecular Biology of the Cell,” and I decided then I wanted to go into oncology because cancer is the first disease where genomics and the molecular biology revolution were going to have an impact. Cancer is a genetic disease. A normal cell doesn’t become a cancer cell by magic; a normal cell is transformed into a cancer cell by accumulating mutations in its genome and then these mutations will screw up the wiring of the cell and the molecular mechanisms within it.
During my fellowship at Johns Hopkins University, I was working in a lab that had made amazing discoveries in tumor suppressor genes, mismatch repair deficiency, identifying mutations that are molecular markers in body fluids – at the time, researchers were detecting colorectal cancer by identifying mutations in the stool. I was working on identifying mutations in the stool to diagnose pancreatic cancer. At around that time and by looking at cell lines a new tumor suppressor gene was identified at chromosome 9p. I knew there had to be a tumor suppressor gene present there in pancreatic cancer, and within a few weeks we had identified multiple truncating mutations in P16 (a protein that slows cell division, resulting in many types of cancer). So, we put a paper together and got it published in Nature Genetics, and that was the beginning of my career in genomics back in 1994. And all that work on the P16 gene, was done with my own hands. Now we have machines that automate this and can sequence tumor DNA in an hour.
Q: And how did you find your way to breast cancer?
A: After I graduated from John Hopkins, my family and I moved back to Europe and relocated to the UK. I decided then I wanted to work on epithelial malignancies, and specifically a very common human malignancy. Breast cancer affects one in eight women, but it varies in each woman. You can have women who are cured and survive 25, 30 years, while others die very quickly. And I said, “There can only be one reason for this, it’s that not all breast cancers are equal. They must be different at the genomic level.” So, I said to myself, “This is what I’m going to study and tackle.”
And so, I immediately realized that if breast cancers are different and if they have different responses to treatment, it is because they are distinct genomic entities. And a tumor is not just the malignant cells, it’s also the tumor micro-environment. When we started my lab 25 years ago, I realized even back then, that tumors are ecosystems. They are tumor ecosystems of malignant cells and non-malignant cells. And so, we need to encompass all of this to arrive at a proper stratification and proper therapies. With cancer, I say, it’s not about the hammer, it’s about the nail. Treatment is the hammer; each tumor is the nail. I am more interested in studying the nails than I am in wielding the hammer.
Q: How does understanding that breast cancers are different affect the way we treat it?
A: Our big study was published in 2012 in Nature where we showed that breast cancer is not one disease, it is a constellation of 10 diseases, we now say 11 because we separate one subtype. After that I realized understanding the genome and transcriptome of the tumors is going to be really key.
This realization gave rise to the Personalized Breast Cancer Program at Cambridge University, where for every single consenting woman that we see with both early breast cancer and metastatic breast cancer, we sequence their tumor genome and transcriptome. As of mid-November, we have nearly 900 women recruited and now we can really understand the molecular landscape of their tumor and adjust and make treatment recommendations based on that and develop more therapies matching the treatment to the individual.
Q: You’ve seen the entire field of genetics begin and transform over the past decades, so what does the next decade look like for your work?
A: I want to really understand tumors as ecosystems. How is the tumor ecosystem established both at the primary and distant sites? Because that is what underlies tumor dormancy, the metastatic process, and treatment sensitivity and resistance. So, asking very fundamental questions about that, and in parallel, continuing to have a translational effort where we are looking for better predictions, better prognostication, better tumor monitoring with circulating tumor DNA, understanding the immune response, and more. Only this system level view will eventually lead to truly personalized precision cancer medicine!
