Advances in Hematologic Malignancies
Issue 9, Fall 2018
Why did you decide to work in oncology?
My strongest inspiration to become a physician scientist in hematology and oncology came from my mother, a theoretical physicist in Slovakia, who was diagnosed with lung cancer as a non-smoker a few months after I moved to the United States to start college.
She may have had an activating mutation in EGFR or ROS, or had a tumor responsive to immunotherapy — but this was years before any of these discoveries were made.
My experience with her ultimately unsuccessful battle with lung cancer solidified my interest in understanding the molecular basis of cancer, with a goal of developing more effective therapies. I was very fortunate to be mentored by a number of world
class physician-scientists in the field who nurtured my interests and supported me along the path of making this dream come true.
As an undergraduate student, I spent a summer working on the biology of chronic myeloid leukemia in the lab of Dr. George Daley, the current dean of Harvard Medical School, where I got the first real taste of academic medicine. Later, as a medical and
graduate student, I worked on basic mechanisms of hematopoietic stem cell self-renewal in the lab of Dr. Gary Gilliland, who inspired and enabled this dream further.
And finally, I found my scientific home during my postdoctoral studies in the laboratory of Dr. Benjamin Ebert (now chairman of Dana-Farber’s Department of Medical Oncology), where I studied genetics
of myelodysplastic syndrome and acute myeloid leukemia, and developed new models of myeloid malignancies.
Describe your area of focus. Why is this an area of interest to you?
My clinical and research focus is on genetics and epigenetics of myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). I am specifically interested in understanding how chromatin architecture contributes to transformation of hematopoietic stem cells and disease development. I have spent the past few years studying how mutations in the protein complex that facilitates
DNA folding, the cohesin complex, cause leukemia and how we could target them.
Why is this research important?
Understanding how epigenetic factors — which represent the majority of recurrently mutated genes in myeloid malignancies — contribute to cancer development, can open up completely new opportunities to target cancer cells. For example, cohesin gene mutations
represent a new class of genetic lesions that promise to offer unique biological insight into myeloid malignancies and new therapeutic opportunities.
What are the clinical implications for your research?
We have identified that cohesin-mutant AML cells have impaired DNA replication forks and DNA damage repair, and as a result accumulate DNA damage and are sensitive to inhibition with PARP inhibitors. In collaboration with my clinical leukemia colleagues
at Dana-Farber/Harvard Cancer Center, Dr. Jacqueline Garcia and I have developed an Investigator-Initiated Phase 1B clinical trial of the PARP inhibitor talazoparib to treat cohesin-mutant AML/MDS.
This trial should open in early 2019.
How does being a physician-scientist influence your research?
I attend on the adult clinical leukemia service twice a year and always find the experience incredibly motivating. Being a part of an amazingly diverse and accomplished adult leukemia group has enabled translation of some of our preclinical discoveries
to clinical studies, which has been very gratifying. Recently, when I was sitting down with a medical resident advisee of mine to discuss his career aspirations, I could not help but comment on what a privilege it was for me to do what I get to do
each day. I truly feel like I have the best job in the world, and yet I know there is much more to come.
What are you most excited about in your area of expertise? What holds promise for patients?
I am really excited about the new therapeutic options that are beginning to change the way we have treated MDS and AML over the past four decades. We now know most, if not all, of the recurrent genetic lesions associated with these diseases and are beginning
to make inroads into understanding the basic mechanisms that contribute to disease development. I remain very optimistic about our ability to take these findings and translate them to true patient benefit in the future.
What do you like to do when you’re not doing research/caring for patients? What do you do for fun?
I am an avid foodie and love experimenting in the kitchen and inviting others to share. Music, art, and dance have played a big part in my life. Playing piano relaxes me after a long day, and I enjoy going out to symphony. It feels like I have danced
my whole life but I truly enjoyed it during residency, when it became a great source of energy boost (and frankly, one of the few things I could do without falling asleep). My daily bike ride to and from work provides a time for much needed reflection
during our busy lives.
For more on Dr. Tothova, visit her researcher profile or the Tothova Lab website.