Sangeeta Goswami, MD, PhD, is an assistant professor in the departments of genitourinary (GU) medical oncology and immunology at the MD Anderson Cancer Center. She joined MD Anderson as a medical oncology fellow and then became a faculty member in September 2018. She has made a career for herself as a physician-scientist, leading early-phase clinical trials to improve treatment options for patients with kidney and bladder cancers. She is also a national leader in mentoring women scientists.
GU Oncology Now spoke with Dr. Goswami about her dynamic career path, the clinical trial work she leads that is revolutionizing our understanding of mechanisms of resistance to immune checkpoint therapy, and the value she places on mentoring the next generation of women scientists.
Why did you become a kidney and bladder cancer specialist? What was your inspiration to practice GU oncology?
Dr. Goswami: My inspiration stems from a combination of my clinical and research interests. I joined MD Anderson as a medical oncology fellow in 2013 after my internal medicine residency at the University of Pittsburgh Medical Center. As a first-year medical oncology fellow, I was required to rotate through every department. When I rotated in the Department of GU Medical Oncology, I had some amazing clinical mentors, and the environment lent itself to some excellent collaboration. It was during that time that I began to see kidney and bladder cancers as more than simply kidney and bladder cancers; I realized just how heterogeneous these malignancies were.
As an MD and PhD with a background in immunology, my natural instinct was to join the laboratory of Dr. Padmanee Sharma—a significant mentor in my journey—during my fellowship. I studied mechanisms of resistance to immune checkpoint therapy, and I was able to explore what would become my greatest research interests: Why do only a subset of patients with kidney and bladder cancers respond to immune checkpoint therapy? Why do they often show initial response yet develop resistance?
My time in the lab was a great opportunity to bridge my clinical expertise with my research interests. For these reasons, I decided to become a GU medical oncologist, and I have been an MD Anderson faculty member since September 2018.
Can you describe the clinical trial work you have done to date? What is your most meaningful contribution to the field, and what do you have ongoing?
Dr. Goswami: The discovery science project that I started in the laboratory as a medical oncology fellow eventually became an investigator-initiated clinical trial. One of the mechanisms that drives changes in the tumor microenvironment is epigenetic pathways. I was intrigued by these changes, and at the time, there were a few papers on epigenetic changes in T cells but only limited research on how epigenetic pathways in T cells have a direct impact on the efficacy of immune checkpoint therapy. Some research showed that T-cell signaling can induce an enzyme called EZH2, so we at the lab asked a very fundamental question: If T-cell signaling can induce this particular enzyme, what happens to T cells when you give immune checkpoint therapy? We took a reverse translational approach by examining patient samples and attempting to understand what those samples could tell us. We were able to see that for patients who received anti-CTLA-4 (ipilimumab), their EZH2 expression was apparent.
We took this translational observation into the lab and performed a series of mouse experiments to understand what EZH2 does to T cells. In sum, we found that EZH2 is an adaptive resistance mechanism. We then asked, what if we inhibit EZH2? How would that impact the efficacy of immune checkpoint therapy? We combined an EZH2 inhibitor with anti-CTLA-4 therapy in mouse models and saw improved survival of those tumor-bearing mice.
Those preclinical data encouraged us to lead a clinical trial, which is currently ongoing at MD Anderson. We are treating patients with metastatic stage IV kidney and bladder cancers, as well as aggressive variant prostate cancer, with a combination of an EZH2 inhibitor plus anti-CTLA-4 therapy. In addition to collecting the clinical data, we are also collecting patient biopsy samples at baseline and after 2 cycles of anti-CTLA-4. The goal is to see safety and efficacy of this combination in a clinical setting, but also to understand how this combination can change the tumor immune microenvironment in patients with these 3 different tumor types.
Another important research study we have ongoing is attempting to better understand predictive biomarkers for patients who are likely to respond well to immune checkpoint therapy, which comes with its own unique adverse events.
We’ve begun this research by, again, diving into the tumor microenvironment. We first found a specific genomic alteration, ARID1A, that is an epigenetic modulator. Patients who have this mutation seem to respond better to immune checkpoint therapy. Then, when looking at the immune microenvironment, we found that baseline expression of a specific gene, CXCL13, correlates with improved outcomes after immune checkpoint therapy. Thus, we were led to ask whether combining ARID1A mutation and high CXCL13 expression could be used as a predictive biomarker. Additionally, we performed experiments in the laboratory to understand the mechanism by which ARID1A and CXCL13 modify the tumor microenvironment.
Currently, I am leading a prospective biomarker clinical trial in bladder cancer that enrolls patients with ARID1A mutation. Enrolled patients receive pretreatment biopsy and then nivolumab every 4 weeks. Response to therapy will be evaluated and grouped based on ARID1A mutation status plus CXCL13 level in the pretreatment tumor tissue.
Overall, this has been an enriching experience to assess the biological correlates in patient samples and form the hypotheses, which are then tested in the laboratory to understand the mechanism(s) to design biologically informed clinical trials. It is perhaps the most important thing I do to improve the outcomes for my patients.
To whom or what would you credit your interest in translational research?
Dr. Goswami: My interest in translational research is owed mostly to my time under the mentorship of Dr. Padmanee Sharma. Since I’ve known her, she has been a large proponent of utilizing clinical samples to take the discovery science route to understand mechanisms. Since the advent of immune checkpoint therapy, there have been thousands of clinical trials that took the approach of using promising results in one cancer type to justify investigation in another cancer type but then realizing, after spending millions of dollars, it doesn’t work.
I’ve followed Dr. Sharma’s lead in taking a more sensible, reverse translation approach to designing clinical trials. This, coupled with my keen interest in discovery science and epigenetics, has led me down the path of conducting translational research for combination therapy and predictive biomarkers.
How would you describe your experiences as a mentee and a mentor, and what are you doing at MD Anderson to pay it forward, particularly with women scientists?
Dr. Goswami: I have 7 brilliant women working in my lab who I have been closely mentoring. In the past, I have been a mentor to different graduate students. Even when I was a fellow, I mentored summer students, graduate students, other fellows, and post-docs. But now, in my own lab in the Department of Immunology, I have 3 post-docs and 4 students (research technicians) under my mentorship. I cannot stress enough that this is the most fulfilling part of my job because it’s raising the next generation of scientists.
Historically, representation of women in medicine and science hasn’t been large, but this is changing. Although the number of women in the United States who are going into medicine and science is increasing, we still do not see many women leaders in medicine and science. Department chairs, cancer center directors, and so on are still male-dominated positions. Equal representation in leadership positions has yet to take shape.
I’m proud to say that at MD Anderson, we are making a conscious effort to make sure there is equal representation, equal visibility, and equal opportunity based on gender. Thus, it is my duty as a woman leader within my institution to mentor other women and shape them into the leaders they can be. I feel very strongly about this responsibility.
Furthermore, I encourage and remind my mentees that someday they have to be a mentor. Nowadays, in science, everything is so collaborative; engineering, data science, and medicine are all coming together under 1 discipline. We have to foster and embrace this collaborative spirit. To cure cancer, we cannot work in silos, especially in relation to gender. Between men and women, we each bring our own strengths to the table. Thus, in my mind, it is equally important to collaborate as it is to bridge the gender gap in science. That is why I do what I do.