Advancing Cures and Developing the Next Generation of Lymphoma Researchers

Growing up in Spoleto, Italy, Laura Pasqualucci, MD, loved classical music. While her appreciation for music led her to attend a conservatory to study the art form, it was ultimately her adoration for medicine that inspired her to
dedicate her career to studying pathology. As a child, Pasqualucci visited the emergency clinic where her father worked, and the intellectual complexity and humanitarian aspects of medicine drew her in. Medicine runs deep in
Pasqualucci’s family. Her father was a physician, her mother a pharmacist, and several family members were doctors as well.

Encouraged by her family to pursue whatever interested her, medicine or not, Pasqualucci gravitated toward
clinical medicine, nonetheless, and completed her residency in hematology at the University of Perugia Medical School in Italy. Pasqualucci was drawn to the pathology of this physiological system and was especially interested in the events that initiate disease and in understanding why certain patients respond to therapy while others don’t.

At the same time, this field provided rich patient contact and the ability to be there to support people who are
coping with a diagnosis that can be challenging to face. In 1997, Dr. Pasqualucci received a fellowship to conduct
research abroad from the Italian Association for Cancer Research, which brought her to New York. Since then, she has worked as a researcher and professor.

Transitioning to Basic Research

While she misses seeing patients, she has thrown her considerable intellect and experience into research and
currently works on critical projects in the study of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma,
the two most common lymphoma diagnoses, as Professor of Pathology & Cell Biology in the Institute for Cancer
Genetics at Columbia University. She also serves on LRF’s Scientific Advisory Board (SAB) where she helps the
Foundation seeks out the most innovative and promising lymphoma research projects for support. Additionally,
Dr. Pasqualucci is passionate about helping to mentor the next generation of basic and translational researchers and has done so through LRF’s Lymphoma Scientific Research Mentoring Program – a first-of-its-kind program for junior scientists focused on lymphoma and CLL research.

When Dr Pasqualucci first entered the lymphoma research field in 1997, she was both excited and a bit intimidated. The culture of lab work is different from clinical practice. She had a lot of knowledge to catch up on but said she was happy to do the work. Dr. Pasqualucci is keen to remind prospective researchers who may lack a lot of lab experience that they can make the change, too. “If you have passion and curiosity, you can catch up very quickly,” she says.

As a researcher, core aspects of malignant hematology appeal to Dr Pasqualucci. The easy access to tissues to
work with – blood cells – means there’s a rich environment for interrogating the deep roots of the disease and
gaining insights into what drove these cells to become malignant. She also adds that the increasing success rate
of new treatments is gratifying, and she is inspired by the prospect of her research continuing to provide the basis for improving patient outcomes.

“Every three minutes somebody in the U.S. is diagnosed with a form of blood cancer. There are still several
unmet clinical needs, and my main goal is helping to fill those gaps.”

Harnessing the Immune System

Dr Pasqualucci’s initial work involved the study of normal germinal center B cells, a specialized lymphocyte population that is crucial for the body to achieve effective immune responses against foreign pathogens. Germinal center B cells are essential to the immune system, as they can modify their antibody genes through the process of somatic hypermutation and, by doing so, increase the specificity of the antibodies for the foreign pathogen. Only a few cells that succeed in this process are ultimately selected to exit the germinal center and fight off pathogens by secreting antibodies. When this process goes awry, however, it can lead to cancer.

“This difficult work is clearly worth the effort,” says Dr. Pasqualucci.

When she joined the laboratory of Dr. Dalla-Favera in New York (also a past member of the LRF SAB), Pasqualucci discovered that hypermutation can affect other genes beyond the antibody genes, and that this
process malfunctions in lymphoma, leading to the aberrant targeting of multiple genes. This key finding opened new paths for investigation into how mutations can contribute to the development of lymphomas, and it remained a major interest in her research. Indeed, a joint effort with Dr. Dalla-Favera, who remained a main collaborator in
the genetics of B cell lymphoma, led to the discovery that this mechanism targets specifically the non-coding regions of these tumors’ DNA. Non-coding regions don’t produce proteins but are essential for regulating gene activity. They are also particularly challenging to study.

Dr. Pasqualucci’s work has led to mapping out mutations across the entire genome and a better understanding of
how these mutations can deregulate other key genes. This discovery has revealed new disease drivers that could serve as targets for therapy and new areas of investigation in lymphoma research more broadly. Among the genes hijacked by germinal center-derived lymphomas, Pasqualucci found several “epigenetic modifier genes.” These genes are like the conductors of an orchestra, who don’t play an instrument themselves but tell other genes when to start and when to stop playing or instruct them to play louder or to remain silent, therefore, changing the overall symphony of the cell without changing the notes.

The ultimate goal is to identify vulnerabilities of the cancer cell that could be leveraged for more effective, less toxic treatments. Pasqualucci and her colleagues are working to better understand how cancer cells can manipulate their environment to avoid immune system interference.

Dr. Pasqualucci notes that it is important that we work on a comprehensive understanding of lymphoma cells,
their microenvironment, the epigenetic factors beyond the DNA sequence that influence gene expression, and
also the patient’s genetic makeup. Having a complete picture of cancer development helps us develop more
effective therapies.

Patients are Always Top of Mind

Dr. Pasqualucci is always aware of the real-time link between her work and patients.

She would like patients to know that they can contribute to the field of lymphoma research by participating in
correlative studies during trials and by consenting to the use of biosamples, especially tissues that might otherwise be discarded.

“There are still patients who do not respond to current approaches, and there are lymphoma types where cure rates are very low. We need to understand the heterogeneity of this cancer,” she said. “This community is relatively small, but it’s critical that we advocate for them.”

Pasqualucci remains deeply involved with LRF due, in part, to its tight focus. “LRF is a particularly unique organization because of its Scientific Advisory Board and review process. It’s all experts in lymphoma, so it’s
different from many other foundations.”

One of Dr Pasqualucci’s non-research projects is to increase the number of researchers studying lymphomas.

“LRF is a phenomenal venue to identify important new areas of research – and up-and-coming researchers,” she said. “LRF’s mentorship program is valuable to new researchers because it exposes them to key aspects that may not be addressed during their training. The program also gives young researchers an opportunity to meet and work with leaders in the lymphoma field, which can be invaluable to their career growth.”