Leading oncologist says working in bubbles must go and teamwork is essential to achieve a cure for metastatic cancer

Patricia LoRusso, President of the American Association for Cancer Research (AACR), gave Agência FAPESP an exclusive interview during a visit to Brazil. She spoke about the importance of attracting early-career researchers to oncology, the future of clinical cancer research, and potential new discoveries in the field.

By Maria Fernanda Ziegler | Agência FAPESP – “Early-career scientists should know there’s no better time for cancer research than now,” says Patricia LoRusso, President of the American Association for Cancer Research (AACR). This is no exaggeration. She has witnessed huge advances in discoveries in tumor biology during her own career.

“This is a very exciting time for oncologists. Cancer research has achieved many discoveries since the human genome was sequenced a couple of decades ago. But we still have a long way to go, and we must join forces in order to continue advancing,” she says.

LoRusso has more than 30 years of experience in medical oncology, drug development and Phase 1 clinical trials, resulting in 14 cancer drugs approved by the United States Food and Drug Administration.

During a visit to attend AACR on Campus Brazil, an event held in partnership with the University of São Paulo (USP) on February 19-23, LoRusso talked to Agência FAPESP about the importance of attracting young researchers to the field, the future of clinical cancer research, and potential new discoveries in the field.

Agência FAPESP – Cancer researchers have made many discoveries in recent years. Nevertheless, it appears that much remains to be investigated. Is that because cancer is a very complex disease?
Patricia LoRusso – It’s true that this is a very exciting time. We now have many tools to extend our understanding of cancer. Many discoveries concerning the biology of the disease have been made since the human genome was sequenced a couple of decades ago. However, I think the reason we haven’t yet achieved all our goals is multifactorial. Although our understanding of the disease has advanced a great deal, cancer is far more complex than what we know. The second point is that the drugs we’ve developed are capable of targeting only one or at most two cancer hallmarks [the set of functional capabilities acquired by human cells that are crucial to the formation of malignant tumors]. Tumors have many hallmarks, and different tumors display different hallmarks as the disease progresses. Another important aspect has to do with work in the laboratory. We need to understand cell culture and in vivo models [humans and animals], but we also need to find out what happens to patients during treatment. Another complexity involves the capacity to offer patients clinical trials so that we can study the problems relating to cancer and do reverse translation, which means understanding what happens to patients from an analysis of samples. So we are indeed faced with multiple complexities. There are many challenges to be addressed as we move between the laboratory bench and the clinic via translational medicine. Right now we’re merely developing the tools for translational medicine. We have yet to understand how to use these tools, without going from one to the other at random. Part of the understanding of cancer treatment is knowing when to treat it. The timing is crucial. The differences that occur in a tumor are associated with the exact point at which it begins to be treated.

Agência FAPESP – One of the main aims of the AACR on Campus program and the Center for Research and Convergent Technologies in Precision Oncology recently opened at USP is to attract and support early-career researchers. Why is this a concern?
Patricia LoRusso – Cancer is a strong enemy. It’s smarter than us at the moment because it’s multifaceted. That’s why we need to get all our troops into the field. In this setting, we need to support early-career scientists and junior faculty because the future of cancer research is in their hands. It will be up to them in future to understand the disease better than we do now so that it can be treated more effectively. Without this support, we could lose the next generation of physicians and scientists who will take the research forward.

Agência FAPESP – At the start of your career, cancer treatment consisted basically of attacking the tumor. It now seems to have acquired more layers, does it not?
Patricia LoRusso – Yes, there are many layers to cancer treatment. Also, we should bear in mind that cancer isn’t linear. As an enemy, it’s a continuum [a series of sequential elements with differences between the first and last elements]. However, I think the main enemy in this case may be the exact moment at which the cancer cell emerges in the organism, or perhaps even before that. We need to understand how to prevent cancer.

Agência FAPESP – You have said understanding why drugs don’t work is as important as understanding why some drugs do. Could you elaborate?
Patricia LoRusso – Yes, that’s extremely important. We develop drugs on the basis of the biology of the disease and on the basis of a hypothesis. Trials involving human beings, however, often take into account what has been observed in activities and systems in preclinical models. And we expect this to work. But how can we know what to do after a test if we don’t understand why a drug doesn’t work? In most cases, when a clinical trial is negative, it’s the end of the line. No one looks at the samples taken from the patients who took part in the trial in order to understand why it didn’t work. But as I said before, cancer is a continuum, and when a clinical trial has a negative outcome, part of the continuum may be resistance to the drug. Like responses to treatment, drug resistance has several facets. It’s important to understand this. When a drug works, we seek to understand the different mechanisms through which this happens. But if we want to develop truly personalized cancer treatment that targets the tumors of individuals, it’s equally important to understand the mechanisms involved in the response to and resistance to a drug, especially when the cancer is metastatic. How are we going to treat patients with a new line of drugs if we don’t understand what’s going on with the tumor?

Agência FAPESP – You often speak about next-generation drugs. Where are we heading in this regard?
Patricia LoRusso – Well, it depends. Right now we’re developing molecularly targeted drugs based on genetic signatures. But how functional are these signatures? How can we know whether these genes are in fact significant and do something that results in tumor growth? We don’t know much about this yet. That’s why tools like proteomics are so important to this race for novel drugs and to an understanding of the biology of the disease. With these tools, we can analyze molecular functionality and identify the differences. And we can create strategies and combine treatments. Nevertheless, there are still many unanswered questions in cancer treatment. Not just questions about a class or type of drug. We need to work with a huge number of drugs on the basis of a huge amount of knowledge we already have to understand the biology of the disease. This is why we’re still a long way away from curing metastatic patients. In my view, it isn’t possible to say right now that the next generation of drugs will be this or that class, or entirely novel drugs. We can’t make that kind of prediction. We need to look continuously for different drug classes. It’s also possible that the next generation will be a combination of several drugs, given that the biology of cancer is so complex.

Agência FAPESP – How can novel technologies help scientists design clinical trials?
Patricia LoRusso – Some of these new technologies are helping us understand what makes tumors grow, for example, and this knowledge may enable us to intervene effectively. This is the case for technologies like proteomics and transcriptomics, especially an approach known as spatial transcriptomics [which maps gene expression patterns in the tumor microenvironment and associates them with the development of therapies]. When we use these technologies, we don’t necessarily have to have a hypothesis. In these cases, you look at the data and you can see what’s making the tumor grow. As a result, the approach changes because you have a deeper understanding of the biology of the disease. It’s no longer important, for example, to focus solely on extending the repertoire of T cells to attack the tumor and prevent it from growing – the tumor probably even has its own T cells, which aren’t working for some reason. Instead, we try to find out what’s wrong so that we can make the mechanism right again.

Agência FAPESP – Do you believe it will be possible to treat metastatic cancer effectively and even cure it in the near future?
Patricia LoRusso – That’s my dream, yes. Would you like to know what I think we should do to make it come true? In cancer research, we have different groups pursuing the same goals but working in bubbles. We need to puncture the bubbles and get researchers working with physicians, patients and translational scientists. That would extend our understanding of the disease much farther. Not by chance, it’s exactly what we’re trying to do right now. I believe the AACR on Campus program is a way for the AACR to try to understand how we can help assemble teams that work together.