This post is the second in a series highlighting a selection of The Mark Foundation for Cancer Research’s scientific partners who have rapidly mobilized resources to confront the great challenges posed by COVID-19 (you can see the earlier post here). Dr. Shokat is a recipient of the foundation’s ASPIRE Award for a project titled “Priming Cancer Cells for Detection by the Immune System.”
Earlier in my career as a medicinal chemist, I had the chance to deploy skills in the race to discover and develop new drugs for hepatitis C. It was an exciting time scientifically. After over a decade of effort, breakthroughs were being achieved in rapid succession and treatments finally reached the status of cures for patients in need. Now, as Vice President of Scientific Research at The Mark Foundation for Cancer Research, I mostly think about accelerating scientific breakthroughs for cancer patients.
Right now, however, it is impossible to ignore the scientific challenges of finding new treatments for COVID-19. I find myself asking a number of questions: Will it take over a decade, or can the world move even faster this time? Is it realistic to believe we will have an effective vaccine in time to obviate the need for stronger antiviral treatments? Will the current cell-based methods for discovering drug candidates against SARS-CoV-2 ultimately produce treatments that work in patients? Will a cocktail of multiple direct-acting antivirals be the best path to maximum efficacy as it has been in HIV and HCV? And should we focus on targets in the human host, which are less subject to mutating around the treatment?
While our foundation plans to stay focused on our mission to better treat, diagnose, and prevent cancer, we’ve been inspired over the past couple of months by researchers from within the cancer community, including those well-steeped in pathway biology, biomarkers, chemical biology, and therapeutics discovery, who have turned their attention to the most prominent scientific problem of the day: how to treat and prevent SARS-CoV-2 infection.
In one recently published study by a global team of collaborators, including UCSF and UC Berkeley professor Kevan Shokat, a rapidly mobilized team science approach has led to a detailed network analysis at scale that systematically maps the interaction landscape (or “interactome”) between SARS-CoV-2 proteins and human proteins. This network analysis uncovered insights into SARS-CoV-2 biology and interactions with human proteins involved in a variety of host processes, such as innate immunity and RNA translation, that may represent therapeutic targets, as well as provided a context for hypothesis generation to study viral pathogenesis further. Of the 332 human protein targets the team identified that interact with the viral proteins with high significance, they discovered 63 for which there are approved drugs (29), drugs under clinical investigation (12), and/or preclinical drug candidates (28) known to modulate them. These protein targets were prioritized for inclusion in antiviral activity assays against SARS-CoV-2 infectivity and replication, and some very interesting hits were found in those screens, including protein biogenesis inhibitors and ligands of the Sigma1 and Sigma2 receptors. Follow up work on those hits is now actively underway.
A few things stand out to me about this study. One is speed. The tangible list of drugs and drug candidates assembled in a short amount of time (weeks) is an impressive and actionable outcome of the interactome network analysis studies. The network and pathway insights uncovered will also lead to new lines of biological investigation as the scientific community dives deeply into the unknowns of how SARS-CoV-2 interacts with its host at a molecular and cellular level. Another stand-out aspect for me is the global nature of this collaboration. As of the time of publication on April 30, plasmids expressing the viral proteins had been shipped to almost 300 laboratories in 35 countries. Antiviral assays have been executed in both New York at Mt. Sinai Hospital and Paris at the Institut Pasteur. The last, and most remarkable feature for me, is the connection of these efforts to cancer research. Viruses take over host cellular machinery to replicate, in many ways analogous to how cancer progresses, by co-opting normal cellular processes to proliferate and invade other tissues. Several pathways and processes identified in the study are also relevant in the cancer setting, including cell cycle, metabolism, epigenetics, and RNA translation. In fact, one of the lead authors of the study, Nevan Krogan, just last week published a follow-up paper in Cancer Discovery on the landscape of cancer proteins that are present in the SARS-CoV-2 viral protein interactome. In addition to Krogan and Shokat, other investigators who participated in this study, such as Davide Ruggero from UCSF and Trey Ideker from UCSD, also study cancer and no doubt are seeing and pursuing the obvious parallels.
To expand a little on the connection of this SARS-CoV-2 study to cancer, one of the most exciting hits identified in the drug screens was zotatifin (eFT-226). Zotatifin is an inhibitor of the eukaryotic translation initiation factor 4A (eIF4A), a helicase essential for translation of mRNAs with highly structured 5’ UTRs. Currently, zotatifin is in phase I/II clinical development for the treatment of patients with advanced pancreatic adenocarcinoma or with other solid tumors that have HER2, ERBB3, FGFR1, FGFR2, or KRAS mutations. Interestingly, eIF4A was validated as a target in the cancer context around a decade ago by Shokat and Ruggero. This history means that the tools for understanding this target’s biology are well established and can be readily repurposed for this new avenue of research.
I am encouraged to see both the leveraging of expertise from the world of cancer research to identify therapeutic discovery and development opportunities for fighting SARS-CoV-2 infections, as well as the scientific overlap between cancer and COVID-19 at the biochemical pathway and process level. While the current pandemic could be viewed negatively from one perspective as diverting the attention of global researchers away from cancer, we shouldn’t diminish the upside. Insights from efforts to uncover the fundamental biochemical processes and pathways that drive SARS-CoV-2 infection and viral replication will also inform our understanding of how cancer works and how it might be treated. On both fronts, it will be exciting to follow the breakthroughs that emerge in the weeks and months ahead.