Guenther Lab

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Guenther Lab

About Dr. Guenther

Dr. Lillian (Lily) Guenther recently joined St. Jude from the Dana-Farber Cancer Institute and will be a faculty member in the Division of Molecular Oncology. Guenther’s journey in medicine is one that has benefited from the convergence of clinical care and scientific discovery. Dr. Guenther earned her undergraduate degree at Brown University and her MD degree from SUNY Downstate College of Medicine. During medical school, she completed a research fellowship at the Howard Hughes Medical Institute/National Institutes of Health (NIH), which led to her engagement with osteosarcoma biology. Her exploration into this area facilitated a passion that has shaped her personal research work in osteosarcoma for many years. Dr. Guenther completed her fellowship under the mentorship of Dr. Kimberly Stegmaier at the Dana-Farber Cancer Institute, where she subsequently was an Instructor of Pediatrics at Harvard Medical School and an Attending Physician at Dana-Farber and Boston Children’s Hospital. With a clinician-scientist background, Guenther’s work has translational aspects in which patients help focus her research efforts, and her laboratory work challenges the way she thinks about patients. Her goal is to steer focused research efforts that lead to novel therapeutic developments for pediatric bone sarcomas.

This summer, Dr. Guenther was awarded the SARC Career Development Award which is geared toward fostering the development of innovative research via the cultivation of new ideas and career paths of early-stage, young physicians/scientists dedicated to defeating sarcoma. 

When did you know that you wanted to be an oncologist?

I am one of those bizarre people who knew what they wanted to be from a young age. I decided when I was about ten years old, as the oldest of four children and a frequent caregiver, that I wanted to go to medical school and become a pediatrician. In high school, I spent time over one summer, between shifts flipping burgers at a poolside snack bar, shadowing in a pediatric brain tumor clinic in New York City. I absolutely loved the patients and was inspired to want to care for them and their families during their cancer journeys. From that point on, my goal was a career in pediatric oncology.

How did you get interested in researching osteosarcoma?

Though I started my journey to medicine aspiring to be a clinician, by the time I was a medical student I was intrigued by the possibility of a career in scientific discovery. I was fortunate to be chosen as a Howard Hughes Medical Institute – NIH Research Scholar. This incredible program sponsored medical, dental, and veterinary students for a one-year research fellowship in a laboratory of their choice at the NIH campus in Bethesda, MD. One of the advisors of the program was Chand Khanna, a veterinarian, and seasoned osteosarcoma researcher, who introduced me early on to Lee Helman, his research collaborator, and a renowned expert in osteosarcoma biology. It was a great fit; I joined the Helman laboratory at the National Cancer Institute and quickly became fascinated with osteosarcoma biology and metastasis cell signaling. I knew then that I wanted to stay in this field. During my oncology fellowship and as a young faculty member, I was very fortunate to train with Dr. Kim Stegmaier at Dana-Farber Cancer Institute. She is a world expert in utilizing CRISPR screening and other high-throughput screening modalities to identify novel genomic dependencies in pediatric cancers. Though Dr. Stegmaier did not previously work on osteosarcoma in her laboratory, she is an incredible mentor who, from the get-go, supported my desire to apply her scientific expertise to osteosarcoma in order to make advancements in that disease. It was within the Stegmaier lab that I was able to develop the work that I will continue in my own independent laboratory at St. Jude.

What new technologies are you most excited about that you think will be a game changer for cancer research?

There is so much up and coming in cancer research right now that is compelling. I think that for osteosarcoma specifically, technologies to look at and classify the epigenome, such as ChIP and ATAC-seq, as well as assays interrogating gene methylation, are incredibly important for understanding what makes osteosarcoma tumors different from one another. CRISPR gene editing, which can be performed at genome scale, is obviously near and dear to my heart and I believe is a powerful way to look at non-mutated genes in cancer. This is very important, especially for pediatric tumors, including osteosarcoma. In addition, new chemical biology techniques, including advanced degrader-based technologies, are enabling the selective study of the function of individual proteins in cancer cells and opening the door to the possibility of therapeutic interventions for targets of interest that are traditionally difficult to manipulate.

Your line of work can be very all-consuming.  What are your tips for balancing work and family? 

This balance is certainly a work in progress for me (as is true for many physician-scientists!). As a female scientist with two young children, it has been incredibly important for me to be both fully in gear when I am working in the lab or in the clinic, as well as to be 100% present for my family when at home. I am eternally grateful to my supportive spouse without whom this tightrope walk would not be possible. I guess my tips would be to remember to cut yourself slack, give yourself time to do things you enjoy (and to find things you enjoy outside of work), and to not check work email while engaged in personal time as much as possible. Also, it is important to seek out mentors who model the work-life balance you aspire to have in your own life.

Describe your perfect day (outside of work!)

A picture-perfect day for me would be to spend the morning with my family at an ocean beach, enjoying the sea breeze, sand, and water. In the afternoon I would have a manicure/pedicure or a massage, and possibly a nap. I’d finish off the day by reading a good book or the New Yorker magazine outside under the late afternoon sun, and then have a delicious dinner and drinks with my spouse and maybe some friends.


What makes you excited/inspired to get to the lab each day?

Science is so fun! No two days in the lab are alike. There are highs and lows for sure, and research is certainly challenging.  But, at the end of the day, I always try to remember that the work has the potential to positively impact people who are going through the most difficult and unfair things I can possibly imagine in life. That’s what drives me through it all.

What (if anything) makes you most hopeful that a cure for osteosarcoma is in sight?

There is so much energy around osteosarcoma research right now! It is exciting that multiple young investigators are invested in working on this challenging disease. This enthusiasm, combined with the money from essential groups like MIB Agents that is being put towards sample collection model creation and characterization as well as patient genomics on and off clinical trials is really going to lead to significant changes and hopefully better cures in the next several years. I’m looking forward to being a part of it.

The Guenther Lab 

Osteosarcoma is a tumor with an incredibly complex genome, marked by mutations and diverse chromosomal rearrangements. Such genomic heterogeneity contributes to unique molecular drivers in individual tumors that can present challenges to effective treatment. Dr. Guenther’s ongoing research, which uses genome-scale CRISPR screening in cancer cell line models to examine critical non-mutated genes in the osteosarcoma cancer genome, has revealed that different elements of the DNA damage cascade may be important in different subsets of osteosarcoma. As the complex genome underlying osteosarcoma tumors seeks to replicate and proliferate, the DNA damage response cascade may play a critical role. A major theme of Dr. Guenther’s work at St. Jude will seek a deeper understanding of these DNA damage-related targets in osteosarcoma.

A major focus of the early efforts in the Guenther laboratory will be the preclinical validation of one such target, which is a helicase enzyme involved in replication stress response. Based on preliminary data, Dr. Guenther hypothesizes that osteosarcoma tumors that are more dependent on this gene may be more sensitive to certain types of DNA damage response or checkpoint inhibitors. Dr. Guenther’s work will concentrate on validating these findings in a variety of murine models and PDXs available at St. Jude. The validation of these models may lead to an understanding of whether this is a potential niche for osteosarcoma treatment in some patients.

The Guenther laboratory will also exploit genomic screening technologies in other ways, such as the identification of drug-drug combinations and drug-resistant mechanisms to targeted agents in bone sarcomas. The goal of this research is to validate novel combination strategies using in vitro and in vivo models, potentially leading to clinical trials.

The theme of Dr. Guenther’s research at St. Jude will center around the investigation of promising osteosarcoma dependency genes, including those involved in DNA damage repair. By understanding how these genes influence disease progression, she hopes to find ways to harness cancer cell vulnerabilities that will transform osteosarcoma treatment.

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