Luigi Perelli, M.D., Ph.D.

Biography

During my medical training, I recognized the critical need to understand the complex pathophysiological phenomena driving cancer evolution and malignant transformation. This insight fueled my decision to dedicate my scientific career to advancing therapeutic strategies tailored to the molecular and cellular dynamics of cancer.

My medical school training at the Catholic University of the Sacred Heart, Rome, Italy, was of extraordinary importance for my career in research: I completed my medical degree with full marks (110/110), participated in workshops and internships organized by the university and the hospital, tutored new medical students, and strengthened my motivation to become an independent scientist in cancer biology. During my internship in the Hematology Department, I assisted patients affected by hematological malignancies, which sculpted my passion to understand the biology of neoplastic diseases by studying molecular pathway dysregulation, its relevance for whole-organ physiology, and its contribution to tumor pathophysiology.

Thus, I joined Dr. Ruggero De Maria’s translational research laboratory, where I contributed to several research projects characterizing the role of extracellular vesicles as pivotal messengers of colorectal cancer stem cells. We showed that CD147 is directly involved in exosome release during colorectal CSC differentiation, which in turn enhances the pro-tumorigenic potential of the surrounding cancer cells (PMID: 31973205, 31967331, 32872424). During this period, I significantly expanded my skills in the fields of cell biology and molecular biology, while designing my own research project focused on the detection and characterization of extracellular vesicles in the exhaled breath condensate of patients affected by chronic obstructive pulmonary disease. Our group was the first to detect exosomes in this biological fluid, and we found a clinical correlation between the number of exosomes detected and the severity of the disease. This discovery holds enormous clinical potential for the early detection of respiratory tract neoplasms, moving from the concept of “liquid biopsy” to one of “fluid biopsy.” I published these findings as a co-first author of a manuscript now published in European Respiratory Journal (PMID: 33795323), one of the top recognized journals in respiratory medicine.

Moved by the idea that basic research will impact the lives of cancer patients, I decided to continue my studies focused on a deep and comprehensive view of the molecular mechanisms governing tumor evolution, thus providing me with sufficient knowledge to contribute to impactful discoveries. After earning my medical degree, I joined the PhD program in Oncological Sciences at the Catholic University of the Sacred Heart, where I designed a project focused on dissecting the molecular determinants of disease progression and metastatic evolution of renal cancers. This project required me to apply breakthrough technologies to develop new model systems in cancer. I collaborated with Dr. Giannicola Genovese at the UT MD Anderson Cancer Center (MDACC), who is a brilliant and innovative investigator in the field of genomic engineering, functional genomics and metastatic disease. Thanks to the prestigious Ermenegildo Zegna Founder’s Scholarship, I joined Dr. Genovese’s lab and created a bridge between my university in Rome and MDACC.

During my PhD, I gained unparalleled expertise in designing and performing experiments with CRISPR/Cas9 genomic engineering, both in vitro and in vivo, and generating sophisticated genetic tools for longitudinal tracking of cancer cells. Because my independent research will require multidisciplinary approaches, establishing connections among scientists with different areas of expertise is an essential step in building a foundation that will ensure a successful career. At MDACC I actively engaged with the Genitourinary (GU) Medical Oncology Department research team, further strengthening my knowledge of GU malignancies by participating in efforts to address unmet clinical needs for renal medullary carcinoma (RMC), a rare renal malignancy with a paucity of clinical options. In this collaboration, I contributed to the molecular characterization and identification of the hallmarks of RMC. Specifically, we found that this rare disease is characterized by high replication stress and chromosomal instability with focal copy number alterations associated with activation of the cGAS-STING pathway, an actionable therapeutic target. Our evidence was published in Cancer Cell (PMID: 32359397). I further contributed to exceptional research articles and reviews on genitourinary tumors published in journals such as The Journal of Urology and Cancers. Finally, I completed my PhD thesis research project, “Interferon signaling restrains metastatic clones in renal cancer” in which we described the first somatic mosaic GEMM of metastatic renal cancer and advanced the field of genomic evolution of solid malignancies by demonstrating convergent molecular pathways toward the clonal selection of cancer cell populations with metastatic potential. This paper, where I am first and corresponding author, and published in Nature Cancer (PMID: 37365326).

While investigating the basic biological processes of renal cancers, I engaged in multidisciplinary collaborations with several groups at MDACC and other institutions worldwide. I discussed and presented my data to outstanding scientists, such as Dr. Giulio Draetta, Dr. Ross Levine, Dr. James Brugarolas, Dr. Samra Turajlic, Dr. Anirban Maitra, and many others. Of note, I had the privilege to collaborate with Dr. Ralph DeBerardinis group at the UT Southwestern where we described a critical metabolic switch during metastatic dissemination in kidney cancer; this work is now published in Nature (PMID: 39143213).

In a very short time, I strengthened my communication skills and participated as a speaker in numerous forums and symposia, such as the NIH/NCI 2022 Oncology Models Forum, the MDACC Research Townhall, and the Leading Edge of Cancer Research Symposium 2022. I co-authored various posters presented at international cancer research meetings, such as the SIC Annual Meeting 2022, the upcoming AACR Annual Meeting 2023, Cold Spring Harbor Meetings, and 2019 ASCO Annual Meeting. I participated in weekly joint lab meetings and journal clubs with the Departments of Genomic Medicine and Cancer Biology at MDACC. During these activities I met very enthusiastic scientists and was introduced to research activities regarding the therapeutic vulnerabilities and molecular evolution of pancreatic cancer. I studied the role of ARID1A loss in sensitizing pancreatic cancer cells to HSP90 inhibition, opening new potential therapeutic avenues. This work resulted in a co-first author paper now published in Cancer Research (PMID: 33158812).

I have been interested in understanding the evolutionary trajectories of pancreatic cancers, and the biological roots of its aggressive clinical behavior. For this reason, I lead a research project focused on the role of cell plasticity and transcriptomic heterogeneity in unleashing the genomic evolution of this disease. Thanks to incredible network of scientists and collaborators, I have been able to publish as first and corresponsing author a manuscript in Nature detailing the lineage-restricted evolutionary routes of pancreatic cancer and the effects of cell plasticity in the selection of highly aggressive metastatic clones.

My overarching, long-term career goal is to become an independent investigator in the field of cancer biology and dissect the molecular checkpoints necessary for the emergence of human malignancies. My broad research interest in oncology focuses on dissecting the biological and molecular mechanisms driving malignant transformation of normal cells to provide new information for cancer prevention and interception. Thus, I expect that studying the early steps of carcinogenesis and the biomolecular forces driving the clonal expansion of cells with malignant potential will provide new information critical for deciphering the general biology of tumorigenesis, and in the context of cancer predisposition syndromes. To this goal, I have embarked in the generation of cutting-edge technologies enabling the study of somatic clonal expansions of tissues harboring germline driver mutations at single cell resolution.

The CPRIT will be ideal to establish my independent career as an investigator in cancer biology. If awarded, I will establish my unique niche by leveraging CRISPR/Cas9 genome editing tools to investigate different biological relevant model systems to dissect malignant transformation in cancer predisposition syndromes. This award will be essential to generate a new line of research while applying for independent grant opportunities to potentiate functional genomic tools to conceptually advance our understanding and treatment of human cancer.