Researcher Spotlight: Marcus Ruscetti, PhD
How did your interest in science develop?
Both of my parents worked for over 30 years as scientists at the National Cancer Institute, studying the role of HIV and other human leukemia viruses in human pathogenesis. To see them translate their findings in the lab to potential treatments and cures for patients showed me that basic research could make a real difference in people’s lives. In addition, their diverse interactions with members of their laboratory, which they built into a home away from home, and with colleagues from around the world was inspiring and invigorating.
Did you start off as a cancer researcher? If not, what led you to work on cancer-related research topics?
My first two experiences in the laboratory involved researching mechanisms of viral pathogenesis and blood development (hematopoiesis). Though very different from my current research, these experiences provided me with basic training in how to develop scientific questions, form hypotheses, and conduct scientific research.
I first became interested in cancer research after taking a course on cancer biology during my third year of college. I was fascinated by the "cancer stem cell" hypothesis — the idea that certain cancer cells retain qualities of stem cells that allow them to evade drug treatment and evolve to form distant metastasis. The concept that tumors could revert back to developmental states and in a way lose their identity completely changed the way I conceptualized cancer. And with some of my background on blood development, I started to think about how developmental pathways and cancer could be intertwined.
Now, with the current interest in immune oncology and the success of immunotherapy in cancer treatment, I continue to connect the dots between my previous research in immunology and developmental biology and how they may apply to cancer through studying a specific tumor suppressor pathway (known as senescence) that in a way links these fields together.
What studies are you currently working on related to lung and other cancers?
My research group is trying to understand how to mobilize the immune system to target cancer. Our approach is to reactivate tumor suppressor pathways that are lost during tumor development, as a way to make tumors more visible and easier to target by the immune system. Specifically, we are trying to develop therapies to activate a tumor suppressor pathway (cellular senescence), which can cause tumor cells to express factors that allow the immune system to target them.
My previous work showed that a combination of therapies targeting the activity of an oncogene called KRAS could induce senescence in lung cancer and pancreatic cancer. We found that these drugs — the MEK inhibitor Trametinib and CDK4/6 inhibitor Palbociclib — could lead to immune-mediated tumor regressions and long-term survival in mice with lung tumors, and potentiate the activity of currently ineffective chemotherapies and immunotherapies in pancreatic cancer. We are working with clinicians to now test these combinatorial therapies in late-stage lung and pancreatic cancer patients that have limited treatment options.
Currently, we are using high-throughput sequencing technologies to dissect how senescence is regulated on a basic level in different contexts and understand which senescence factors are important for immune responses and for improved therapy outcomes in the setting of pancreatic cancer. Additionally, we are using drug screening approaches to identify new therapies that may induce senescence in other tumor types, including prostate cancers that also do not respond to current immunotherapies. Those therapies that are most promising will be tested in our suite of mouse cancer models in the preclinical setting before going on to be tested in human clinical trials.
What do you hope to learn from your research?
We hope these projects will advance our basic understanding of senescence as a tumor suppressor pathway and elucidate new ways to galvanize the immune system to target and eliminate cancer. The ultimate goal will be to translate this new knowledge into the development of small molecules and therapeutic strategies to treat patients with deadly lung, pancreatic, and prostate cancers.
What do you see as the most promising technology/techniques in cancer research right now?
Single-cell technologies — which include techniques to understand gene and protein expression of each single cell in a tumor and their spatial relationship to other cells — have become and will continue to be instrumental in our understanding of the heterogeneous interactions between tumor cells and the immune system. We can also now perform screens at the single-cell level to understand the heterogeneous responses to tumor cells to various cancer therapies. Finally, through the use of CRISPR/Cas9 and other genome editing technologies, we can more easily than ever manipulate and model different genetic alterations found in cancer in mice to understand their potential contributions to human disease and use such systems as preclinical models to test new cancer drugs before they go into the clinic.
Where do you see the future of cancer research going?
I believe cancer researchers will continue to explore the interactions between tumor cells and other cells in their environment and come up with innovative ways to target that cancer microenvironment as a means to enhance immune recognition of cancer. In addition to screening patient tumors for specific mutations, I believe that sequencing of other cell types in the tumor microenvironment and analysis of non-tumor biomarkers will allow for better stratification of patients likely to respond to given therapies. Specifically, I think that the burgeoning field of the microbiome and its interactions with tumors will further deepen our understanding of the heterogeneous immune and therapeutic responses in tumors observed between different cancer patients.
How has the cancer field changed or progressed over time?
The field of cancer genetics has progressed from looking at a few select cancer-associated genes to interrogating whole pathways and signaling networks, including changes in the epigenome and chromatin structure, that govern tumor evolution. Much of the knowledge on how tumors evolve has now been gained from large-scale genome sequencing studies performed on almost every tumor type. We also know much more about how DNA damage, chromosome instability, and altered metabolism in cancer contribute to tumor growth and metastasis, and how these can also be potential vulnerabilities in tumor cells that can be targeted therapeutically. But the most striking shift in the study of cancer biology has been the focus on how to engineer the immune system, and in particular T cells, to target and destroy cancer.
What is the impact of your research on the cancer community?
My basic research into understanding how tumors evade the immune system will contribute to new immune-based therapies for targeting some of the most aggressive solid tumors, including lung, pancreatic, and prostate cancers.
What inspires you?
Interacting and collaborating with amazing colleagues at my institute and around the world, mentoring and learning from trainees in my lab, and developing potential therapeutic strategies that could directly help patients suffering from human disease inspires me every day. To me I have the best job in the world.
What advice would you offer to a young student who’s considering becoming a cancer researcher? What are some challenges that young researchers should anticipate?
It is important to have knowledge of both the basic and clinical side of cancer research. Having the right models and working with the right colleagues and collaborators will help to elevate your research to the next level. Taking multiple approaches to tackle a question or hypothesis, and validating your findings in human systems, will be critical. Don’t be afraid to take chances, ask questions, and fail. There is a great deal of failure in research, and through this we learn some of our most important lessons. Be persistent. Though things may not work out the way you intended, in the end the science is the science, and be willing to follow it in whichever direction it leads.
Why do you feel it is important for patients with cancer to take part in medical research?
It is beneficial for cancer patients to participate in medical research from both the patient and researcher’s perspective. Patients can give valuable insight to researchers in terms of their treatment regimens and an understanding of the clinical course of their disease. It is also extremely inspiring to researchers to meet and interact with patients, the very people they are trying to help with their research! If patients are willing and able to, providing their tissue and blood samples for research use is vital for researchers to understand the complexity of human disease and validate their findings from the laboratory. For the patients, interacting with biomedical researchers and learning about their projects may introduce them to new treatment options and ways to help fund cancer research. In some instances, research performed on patient samples has revealed new drugs that those patients might benefit from and which they subsequently received!
What is your message to potential donors?
We know that the immune system has the potential to mediate cancer cures, but it only does so in a small group of patients. A better understanding of how tumors learn to evade the immune system will allow us to test new ways to target the tumor and the immune system simultaneously in order to mediate potential cures in more patients and in other common cancer types with limited treatment options, including lung, pancreatic, and prostate cancers.
About Marcus Ruscetti
Marcus Ruscetti, PhD, is an assistant professor in the Department of Molecular, Cell & Cancer Biology at the Umass Chan Medical School. Dr. Ruscetti earned a PhD from University of California, Los Angeles and received postdoctoral training at Memorial Sloan Kettering Cancer Center.
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