This week, Science in Boston profiles Dr. Michael Wichroski (pictured). Dr. Wichroski is the Scientific Senior Director for the Mechanisms of Cancer Resistance Thematic Research Center at Bristol Myers Squibb. He shares insights about his recent publication in Science Translational Medicine and discusses what he sees for the future of translational medicine.
Can you provide a brief overview of your lab’s current research focus?
Bristol Myers Squibb’s presence in Cambridge brings together pillars of discovery, development and data across cancer, cardiovascular, immunology and neuroscience.
We recently opened the new R&D site at Cambridge Crossing—one of the largest sites that we have within research—where we focus on understanding the complexities of cancer resistance, with cross-functional scientific teams collaborating throughout the drug discovery and translational medicine continuum. Our Cambridge labs also focus on discovery biology, translational science and chemistry research, as well as other important functions for several diseases, including various immune-mediated conditions.
I sit within the Mechanisms of Cancer Resistance Thematic Research Center (TRC) where our Drug Discovery teams work with Translational Medicine groups to create therapies that target cancer-specific vulnerabilities where cancer cells can signal suppression of the immune system. By harnessing the immune system and exploring the tumor microenvironment, our teams use an interdisciplinary approach to discover innovative ways to treat cancer.
What is the significance of the findings in this publication?
Treatment resistance in cancer is a particularly challenging clinical problem and one that we are working to overcome. Checkpoint inhibition, especially PD-1 blockade, has demonstrated remarkable clinical success in the treatment of many cancers. However, there remain patients who do not respond (primary resistance) or have an initial response and then progress (acquired resistance) as tumors find ways to evade therapies, such as reducing T cell activity.
These findings describe how our translational phenotypic screening approach, where we screened more than 1 million small molecules, led to the discovery of first-in-class dual inhibitors of two different lipid kinases (DGKα and DGKζ). DGKα and DGKζ are difficult-to-drug therapeutic targets that play a central role in negatively regulating T cell receptor signaling, a crucial component of the body’s natural immune response to fighting this disease.
What differentiates this research is this is the first time an intracellular (existing inside the cell) checkpoint pathway of this magnitude has been modulated; other checkpoint inhibitors being evaluated in the clinic are extracellular.
In preclinical models, the DGKα/ζ inhibitors identified in screening demonstrated robust tumor regression in combination with both anti-PD-1 and anti-CTLA-4 therapy, reinforcing the value of our translational approach and discovery strategy.
Did anything in your results surprise you?
Our Mechanisms of Cancer Resistance research team was both surprised and impressed by how this cellular phenotypic screening approach enabled druggability of DGK. DGKα and DGKζ, which are the DGK enzymes we’d like to target in T cells, are part of a larger family of 10 DGK enzymes with various functions across human tissue. Before this research, it was not clear how we might achieve selective inhibition. In this case, the cells did the talking and showed us how to do it. This is illustrative of BMS’ broader approach to follow the science. We match therapeutic modality to molecular mechanism of action based on our deep understanding of the interplay, overlap and intricacies of cancer treatment, which is gleaned from decades of experience in oncology.
Is the application of your research a primary motivator for you? If not, would you share what is?
Our primary motivation is always to deliver innovative medicines that help patients prevail over serious diseases. In this case, our preclinical data suggests that DGKα/ζ inhibitor immunotherapy may provide significant benefit for cancer patients which is both exciting and rewarding for all involved. Drug discovery is always a challenge—like a puzzle whose solution may or may not be within the bounds of anything that’s been done before. In the Mechanism of Cancer Resistance group, we’re focused on the specific challenge of overcoming drug resistance, so breakthroughs like this one are all the more motivating. We’re looking forward to finding out more about DGK α/ζ inhibitor immunotherapy as clinical studies progress.
Where do you see this research going in the next five/ten years?
We’re excited to build on our legacy as pioneers of checkpoint inhibition as we continue to develop the next wave of cancer therapies. As part of our work to overcome resistance and improve outcomes for more patients, we are advancing multiple next-generation medicines based on our deep understanding of causal human biology and access to robust data sets that enable us to identify and modulate new targets in the treatment of cancer.
Our significant experience in I-O therapies allows us access to large translational medicine datasets, which we use to better understand the diseases we’re studying and associated resistance mechanisms. We’re continuing to advance the future of checkpoint inhibition, including multiple next-generation medicines that target CTLA-4, DGKα/ζ, NKG2A, TIGIT/CD96 and ILT4 (a myeloid checkpoint), and advancing novel combinations with other advanced platforms and modalities (such as cell therapies and protein degraders).
What do you think are the biggest challenges facing life scientists in your field today?
In the field of immuno-oncology, one of our biggest challenges is understanding why certain patients do not respond to or acquire resistance to some T cell checkpoint therapies. BMS researchers are committed to understanding these mechanisms and delivering novel medicines to expand both the breadth and depth of response to T cell checkpoint therapy. Ultimately, we have to tackle these challenges head-on in pursuit of better outcomes for patients.
You worked with numerous other scientists on this paper; how did you manage such a large collaboration group?
Successful drug discovery programs require contributions from and interactions with scientists across a broad spectrum of specialties. Effectively managing these interactions can indeed be a challenge. It is critical that we foster an environment of open communication, teamwork and accountability. In this case specifically, we were blessed with a highly motivated team that appreciated the impact we could have on patients with a dual DGK α/ζ inhibitor.
We benefitted immensely from our physical presence in Cambridge—since the Mechanisms of Cancer Resistance TRC and Translational Medicine groups are fully based here, we’re able to collaborate in person on this research.
It’s hard to find a team member who hasn’t been impacted directly or indirectly by cancer. So, when the stakes are this high, everyone understands how important it is to work together toward a common goal—helping to understand, overcome and successfully address cancer resistance. It’s why we come to work each day.
