This month, we shine a spotlight on Dr. Nancy Gordon and her groundbreaking work at MD Anderson Cancer Center, where her lab delves into the biology of osteosarcoma. With a career shaped by a deep connection to her patients and a drive to bridge gaps between clinical care and research, Dr. Gordon has become a leading voice in pediatric oncology. From aerosolized therapies targeting pulmonary metastases to innovative approaches in NK cell therapy, her lab is tackling tough challenges in osteosarcoma treatment. We learn about Dr. Gordon’s journey, the pioneering projects of her lab, her vision for the future of osteosarcoma research, and how her passion and expertise are driving hope and progress for osteosarcoma patients.
What inspired you to pursue a career in pediatric oncology?
My journey into pediatric oncology began during medical school, where I was captivated by the challenges and complexities of the field. The intricacies of hematologic and oncologic diseases fascinated me, but it was the prospect of contributing to advancements and cures that truly motivated me. Recognizing the limitations of medical resources in my home country, I sought training in the United States to immerse myself in cutting-edge research and treatments.
During my pediatrics residency, I discovered a special connection with patients diagnosed with osteosarcoma. These patients quickly became my favorite to care for, inspiring me with their resilience and reinforcing my desire to pursue a career dedicated to solid tumors. I found myself drawn to their stories, their strength, and the opportunity to make a meaningful impact on their outcomes, which ultimately defined the direction of my future career.
My fellowship in Pediatric Hematology/Oncology at MD Anderson Cancer Center further solidified this path. Under the mentorship of Dr. Eugenie Kleinerman, I developed a deep passion for research focused on osteosarcoma. The combination of hands-on laboratory research and clinical exposure opened my eyes to the transformative potential of translational science in improving outcomes for pediatric patients. My early work targeting the “Fas” protein in osteosarcoma provided valuable insights into metastasis and opportunities for therapeutic intervention.
Today, as an established investigator, I continue to focus on research-driven innovations, including clinical trials and novel therapies, to improve survival and quality of life for children with cancer. The foundation of my career has always been inspired by the patients I met during my residency and fellowship, particularly those with osteosarcoma, whose courage and determination continue to fuel my commitment to advancing the field.
Pediatric oncology is not just a profession for me. It’s a mission to create better outcomes and offer hope to families facing these devastating diseases.
The Gordon Lab focuses on understanding the biology of osteosarcoma. Can you share how your interest evolved and led to a focus on osteosarcoma?
From the outset of my fellowship, I was deeply passionate about osteosarcoma patients, even while maintaining an openness to exploring other aspects of the specialty. During my residency, I had already developed a strong connection with these patients, which solidified my interest in this disease. Upon joining the Pediatric Hematology/Oncology Fellowship at MD Anderson Cancer Center, I discovered that the only pediatric lab with a specific focus on osteosarcoma was led by Dr. Eugenie Kleinerman, a renowned expert in the field. Despite the institution’s vast resources and the opportunity to collaborate with adult sarcoma specialists, my interactions with multiple sarcoma experts consistently pointed me toward Dr. Kleinerman’s lab.
Dr. Kleinerman provided unparalleled opportunities for growth and learning. She recognized the unique challenges faced by fellows new to research and facilitated the creation of a research training course led by one of her PhDs. This course offered invaluable hands-on experience in laboratory techniques, bridging the gap between clinical training and scientific investigation. These early experiences not only built my confidence in the lab but also deepened my appreciation for the critical role of understanding disease biology in advancing patient care.
Through my work in Dr. Kleinerman’s lab, I gained a deeper understanding of the molecular mechanisms underlying osteosarcoma. This scientific insight, combined with my clinical passion reassured me that my focus on osteosarcoma was the right choice. The lab provided a dynamic environment where I could explore the interplay between science and clinical application, laying the foundation for my current role as an Investigator.
The Gordon Lab’s mission to unravel the biology of osteosarcoma is a direct evolution of this journey. My early exposure to both the clinical and research aspects of this disease shaped my commitment to improving outcomes for osteosarcoma patients by focusing on the biology that drives disease progression and therapy resistance.
Could you provide an overview of the current research projects in your lab? How do these projects aim to address critical gaps in our understanding or treatment of osteosarcoma?
The Gordon Lab is committed to addressing critical challenges in osteosarcoma by developing innovative therapeutic approaches and deepening our understanding of disease biology. Our research projects are diverse yet interconnected, each aiming to bridge significant gaps in treatment and improve patient outcomes. Here is an overview of our current focus areas:
a. Aerosolized Therapy to Target Pulmonary Metastases
The lungs are the primary site of metastasis and the leading cause of mortality in osteosarcoma. We are investigating the use of aerosolized therapies, including chemotherapy and immunotherapy with cytokines like IL-2, to directly target the lungs. This approach not only enhances therapeutic delivery to the site of metastatic disease but also reduces systemic toxicity. By focusing on localized treatment, we aim to significantly improve survival rates while minimizing adverse effects.
b. Mechanisms of Therapy Resistance and the Role of Autophagy
Therapy resistance remains a significant barrier to successful osteosarcoma treatment. Our lab is particularly interested in autophagy, which plays a dual role in cancer, promoting survival under stress and potentially contributing to therapeutic resistance. We are working to elucidate how autophagy is regulated in osteosarcoma and whether it can be manipulated to enhance therapy efficacy. Additionally, we aim to identify biomarkers that differentiate between therapeutic response and resistance to autophagy inhibition, which could guide more personalized treatment strategies.
c. Natural Killer (NK) Cell Therapy
NK cell therapy holds great promise for osteosarcoma, and we are exploring multiple strategies to enhance its efficacy:
- Epigenetic Modulation: Investigating how modifying gene expression can improve NK cell functionality.
- CAR-NK Development: Leveraging chimeric antigen receptor (CAR) technology to enable NK cells to directly target osteosarcoma antigens.
- Tumor Microenvironment (TME) Manipulation: Developing agents to overcome immune suppression within the TME by targeting molecules like TGF-β or altering the acidic/hypoxic conditions that inhibit immune cell activity.
d. Novel Imaging Technologies to Study NK Cell Dynamics
We are utilizing cutting-edge imaging modalities to track NK cells in real time and study their interactions with the tumor. These technologies allow us to assess metabolic and perfusion changes induced by therapy, providing valuable insights into the biology of NK cells and their therapeutic potential. This work is critical for optimizing treatment strategies and understanding the mechanisms underlying therapeutic response.
e. Correlative Studies from Clinical Trials
Our lab plays a key role in conducting correlative studies for ongoing Phase I/II clinical trials. Many of these trials are direct extensions of our preclinical work, while others are collaborative efforts with clinical faculty. These studies help bridge the gap between bench and bedside, offering critical data on the efficacy, safety, and biological impact of novel therapies in patients.
Each of these projects targets a fundamental aspect of osteosarcoma treatment—improving therapeutic delivery, overcoming resistance, enhancing immune-based strategies, and translating laboratory findings into clinical practice. Together, they represent a comprehensive effort to tackle some of the most pressing challenges in osteosarcoma and improve outcomes for patients.
Immunotherapy has faced significant challenges in osteosarcoma. In your view, what are the most pressing obstacles, and what innovative strategies hold the most promise for overcoming them?
Immunotherapy, despite its transformative impact on many cancers, has faced significant barriers in osteosarcoma. These challenges stem from several unique characteristics of the disease:
- Limited Effectiveness of Immune Checkpoint Inhibitors: Unlike in other cancers, immune checkpoint inhibitors like anti-PD-1/PD-L1 therapies have shown minimal efficacy in osteosarcoma. This is largely due to the immunologically “cold” nature of the tumor, characterized by low levels of immune cell infiltration and a lack of sufficient immune activation.
- Immune Cell Penetration in a Solid Tumor: Osteosarcoma, as a solid tumor, presents significant physical barriers that hinder immune cell trafficking and penetration into the tumor microenvironment. This limits the effectiveness of immune-based therapies that rely on robust tumor infiltration.
- Poorly Defined Surface Antigens: The lack of well-characterized osteosarcoma-specific antigens makes it challenging to develop targeted immunotherapies, such as monoclonal antibodies or chimeric antigen receptor (CAR)-based strategies.
- Tumor Heterogeneity: Osteosarcoma is a highly heterogeneous disease, with significant variability both within a single tumor and across patients. This diversity complicates the development of therapies that are broadly effective across the patient population.
Innovative Strategies to Overcome These Challenges: To address these obstacles, several innovative strategies hold promise for advancing immunotherapy in osteosarcoma:
- Discovery of Novel Immune Checkpoint Inhibitors: Precision medicine approaches and molecular analysis of patient samples can help identify new immune checkpoint molecules that may be relevant to osteosarcoma. Targeting these novel pathways could unlock more effective immunotherapeutic options.
- Improved Understanding of Immune Resistance in Solid Tumors: Focused studies on the mechanisms underlying the poor response of solid tumors to immunotherapy are essential. Insights from these studies can guide the development of combination therapies that enhance immune cell activation and infiltration.
- Tracking Immune Cells to Assess Trafficking and Persistence: Utilizing advanced imaging and molecular tools to track immune cells in real time can provide critical information about their trafficking, penetration, and persistence within the tumor microenvironment. This data can inform strategies to improve the delivery and efficacy of immune-based treatments.
- Counteracting the Immunosuppressive Tumor Microenvironment: Innovative approaches to modify the tumor microenvironment (TME) are essential. These include:
By addressing these challenges through innovative strategies, we can pave the way for more effective immunotherapy approaches that overcome the unique barriers posed by osteosarcoma, ultimately improving outcomes for patients with this aggressive disease.
You’ve collaborated with leading experts in the field, including Dr. Eugenie Kleinerman. How has mentorship influenced your approach to research and leadership in the scientific community?
Mentorship has profoundly shaped my approach to research and leadership in the scientific community, and my collaboration with Dr. Eugenie Kleinerman has been especially impactful. Under her guidance during my fellowship, I not only acquired technical expertise but also gained a deeper appreciation for the importance of mentorship, collaboration, and translational research in advancing the field of osteosarcoma.
Dr. Kleinerman provided me with invaluable opportunities to grow as a leader early in my career. She entrusted me with directing the research training course for clinical fellows, a responsibility I held for over seven years. This experience allowed me to mentor other fellows, fostering their transition into the laboratory environment while honing my own leadership and organizational skills. Additionally, she encouraged me to carve out my own niche within her lab, empowering me to pursue independent research questions. This trust and support were instrumental in helping me evolve into an independent investigator with a clear research focus.
Through her example, Dr. Kleinerman taught me the importance of creating a supportive and inclusive environment where junior researchers can thrive. Her dedication to mentorship extended beyond guiding research projects—she inspired creativity, persistence, and the ability to think critically about complex problems. She also demonstrated how to bridge the gap between laboratory discoveries and clinical applications, a translational mindset that continues to drive my work today.
As a leader and mentor in my own lab, I strive to follow her example by fostering collaboration, encouraging innovation, and providing opportunities for others to grow. By empowering the next generation of researchers, I aim to inspire them to pursue bold ideas and contribute meaningfully to the advancement of pediatric oncology, just as Dr. Kleinerman has inspired me.
As you look toward the future of osteosarcoma research, what developments are you most hopeful about? Where do you see the potential for transformative progress in the coming years?
The future of osteosarcoma research is incredibly promising, driven by advancements in our understanding of the disease and the integration of innovative therapeutic approaches. I am particularly optimistic about developments in immunotherapy and cell-based therapies, which have the potential to transform patient outcomes. While challenges remain, lessons learned from sequencing analyses and new insights into tumor biology are illuminating pathways to overcome these barriers.
One exciting area is the identification of novel immune checkpoint targets through precision medicine and molecular profiling of patient samples. These discoveries can inform therapies tailored to the unique features of osteosarcoma, addressing its heterogeneity and poor response to current immunotherapies. In particular, cell-based therapies such as CAR-NK cells are advancing with strategies to enhance targeting capabilities, persistence, and efficacy within the immunosuppressive tumor microenvironment.
The use of combined approaches—integrating immune-based strategies with therapies like autophagy inhibitors or agents that reprogram the tumor microenvironment—holds great promise. These multimodal therapies can simultaneously tackle multiple resistance mechanisms, improving both the efficacy and durability of treatments.
Emerging research on the microbiome and its role in modulating systemic and local immune responses is another transformative area. By understanding how the microbiome influences therapy response and resistance, we can explore interventions that enhance the effectiveness of immunotherapy and other treatments.
The interface between osteosarcoma and energy balance, particularly the role of exercise, is also an exciting frontier. Exercise has been shown to modulate immune function, improve systemic metabolism, and enhance therapy response in other cancer models. Investigating how structured exercise programs can synergize with existing therapies could offer a novel and impactful approach to improving outcomes for osteosarcoma patients.
Finally, with continued advancements in sequencing, imaging, and computational tools, we are better equipped than ever to decode the complexities of osteosarcoma. These technologies will enable us to refine therapeutic strategies, personalize treatments, and ultimately achieve transformative progress in survival and quality of life for patients.
