Interview with Prof. David A. Gewirtz: Exploring Breakthroughs in Cancer Drug Resistance and Treatment

On November 4, 2024, the editorial team of Cancer Drug Resistance sat down with Prof. David A. Gewirtz, a leading scientist in oncology research and an esteemed member of the journal’s Editorial Board. As a professor in the Department of Pharmacology and Toxicology at Virginia Commonwealth University, Prof. Gewirtz has dedicated his career to investigating the biochemical and molecular mechanisms that drive tumor responses to antitumor drugs and radiation. His research spans critical areas such as cellular senescence, autophagy, and the mitigation of chemotherapy-induced toxicities, with an emphasis on breast and lung cancer. Prof. Gewirtz was named to Stanford Elsevier Top Scientists List of the world’s best scientists for 2024 in September of this year.

Prof. David A. Gewirtz’s lifelong commitment to oncology research has driven impactful discoveries across multiple areas of cancer therapy, particularly in understanding how cancer cells respond to antitumor drugs and radiation. Inspired by a childhood fascination with science, he eventually focused his postdoctoral studies on cancer, discovering that while treatments can induce cell death, they also cause temporary growth arrest, which can lead to tumor dormancy - a concept that reshaped discussions about the reversibility of senescence in cancer cells. Through his work, Prof. Gewirtz has pioneered research on cellular senescence, autophagy’s dual roles in treatment sensitivity and resistance, and ways to reduce chemotherapy-related toxicities. His collaborations aim to address adverse effects like neuropathy and cognitive dysfunction, and his insights into autophagy have opened new possibilities for developing more effective treatments. He advocates for challenging existing paradigms and encourages young scientists to publish unexpected findings, underscoring the value of curiosity in advancing cancer research.

Below, Prof. Gewirtz addresses specific questions in this exclusive interview:

Q1. Could you share what initially drew you to research in the field of oncology, particularly focusing on the biochemical and molecular effects of antitumor drugs and radiation?

A: Well, I've been doing this for a long time, so explaining exactly how I entered this field would take a while. Let me take you back to when I was 10 years old, in fifth grade. I remember reading a science magazine article about an experiment where researchers injected tumor cells into plants, and the plants produced antibodies against those cells. I found that fascinating, and I think it drove me to pursue cancer research when I became an adult and a PhD student.

Although my PhD wasn’t focused on cancer, my postdoctoral work was, and that set the course for my career. In our early work on antitumor drugs and radiation, we used clinically relevant doses in cell cultures, which wasn’t always common in the literature. We noticed a certain amount of cell death, often attributed to apoptosis, but we consistently saw that cells would arrest - meaning they’d stop growing temporarily - and then recover, a phenomenon we linked to senescence.

Convincing the scientific community that senescence is reversible has been challenging. Our research suggests that in patients, this could contribute to tumor dormancy and, potentially, disease recurrence. This line of thinking was initially controversial, especially since Leonard Hayflick, who recently passed, published a seminal paper 50 years ago stating that senescence is irreversible. However, we and others have shown that cells can indeed escape from senescence.

Q2. Your work on the regulation of senescence arrest is particularly fascinating. What are the key mechanisms you've identified that influence senescence in breast and lung cancer cells, and how might this knowledge lead to new therapeutic strategies?

A: We’ve explored chemotherapy and radiation-induced senescence across several solid tumor models, including prostate, head and neck, lung, and breast cancers. ABT-263, or navitoclax, has emerged as a potent senolytic, though its clinical application is challenging due to toxicity issues. This drug targets the anti-apoptotic BCL-XL and BCL-2 pathways, offering proof of concept.

Interestingly, there are senolytics in aging-related research that work effectively against age-related pathologies but not in therapy-induced senescence in tumors. Drugs like dasatinib and quercetin don’t produce significant effects on therapy-induced tumor senescence, likely because senescent tumor cells upregulate proteins such as BCL-XL and BCL-2. There’s still a long way to go, and it would be ideal if we could identify safe and effective senolytics from aging pathology research for cancer therapy.

Q3. In your studies on autophagy, you have noted its dual role in both sensitivity and resistance to treatment. Could you discuss how understanding this duality could influence the development of more effective cancer therapies?

A: The role of therapy-induced senescence in tumor and microenvironment response is complex. Most studies have used immune-deficient animals, so we don’t fully understand the immune system’s role in this context. Senescent cells produce a range of cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP). Some elements of SASP are immunosuppressive, while others seem to activate immune responses.

Whether the immune system recognizes and eliminates senescent cells is still uncertain, but it's relevant to understanding disease recurrence. This raises questions about the immune system's role in maintaining tumor dormancy and why, over time, senescent cells might "wake up," contributing to recurrence and metastasis, which is often fatal.

Q4. Your research also addresses the mitigation of antitumor drug toxicity. What advances have been made in understanding the mechanisms behind these toxicities, and how do you envision improving patient outcomes in this area?

A: Collaborating with other researchers in our department, we've studied various chemotherapy-induced toxicities like peripheral neuropathy, renal toxicity, "chemo brain," and delayed-onset diarrhea from specific drugs. The mechanisms behind these toxicities are not fully understood, partly because different chemotherapy drugs can cause similar toxic effects through diverse pathways.

In animal studies, we’ve identified some agents that mitigate these toxicities in mice. However, translating findings from mice to humans is challenging—success rates are below 10%. Still, this work is foundational, and even if only one in ten potential treatments succeeds, it’s progress. There are many reasons why drugs may fail in human applications, including genetic, metabolic, and distribution differences, but we continue to investigate potential solutions.

Q5. Congratulations on being named among the “World’s Top 2% Scientists 2024.” How has this recognition impacted your work, and what message do you hope it sends to the broader scientific community?

A: Honestly, I don’t think it will change much in terms of my day-to-day work, though it’s always nice to be acknowledged. I'd like to use this moment to offer some advice to young scientists. First, don’t be afraid to question existing paradigms and remember that published research isn’t always definitive. I also emphasize to my students the importance of publishing all data, even if the results seem negative or unexpected. Often, unexpected findings lead to the most significant discoveries if you have the insight to explore them.

Full Interview Video [Embedded Auto-Generated Subtitles]

Through this insightful interview, Prof. Gewirtz sheds light on the future of cancer therapies, particularly in understanding and overcoming drug resistance—a cornerstone of his life’s work.

Editor: Louise Pan
Language Editor: Catherine Yang
Production Editor: Maggie Zhang
Respectfully Submitted by the Journal Editorial Office of Cancer Drug Resistance