Two cancer geneticists make the case for moving beyond tumor sequencing studies.
A call to action to build a better map of cancer’s genetic vulnerabilities
Over the last several years, researchers at the Broad Institute of MIT and Harvard and the Wellcome Sanger Institute, UK have led an effort to systematically identify the genes and proteins that cancer cells heavily depend on for survival. These molecules, known as dependencies or vulnerabilities, could be promising targets for new precision drugs. This project, called the Cancer Dependency Map (DepMap), is mapping genetic vulnerabilities and drug sensitivities of hundreds of types of cancer, starting with laboratory experiments in cancer models such as cell lines and organoids.
DepMap leaders recently penned a commentary in Nature that urges the scientific community to move beyond pure sequencing-based studies and create a more comprehensive map of dependencies for cancer research. They called on institutions and researchers to come together to probe all 20,000 genes and test 10,000 drugs and drug candidates in 20,000 cancer models.
Two of the co-authors, Jesse Boehm and Mathew Garnett, spoke with us about their work, their Nature article, and what the future holds for cancer research. Boehm is the scientific director of the Broad's DepMap project and an institute scientist at the Broad. Garnett is a group leader at the Sanger Institute.
Why do you think it’s time for researchers to focus on cancer vulnerabilities and not just keep sequencing more tumors?
JB: Currently, sequencing data can help physicians choose the right therapy for about 10 to 25 percent of cancer patients. But those data alone aren’t enough to help the vast majority of patients. We need a companion dataset that assesses not just the genetic mutations within tumors, but also all potential molecular vulnerabilities.
MG: That dataset can help us achieve a variety of goals. One is to help clinicians use today’s drugs more effectively and identify opportunities to use those drugs in new cohorts of patients where their activity is not currently appreciated. Another goal is to be able to clearly delineate which drugs will not help patients so they aren’t unnecessarily treated with therapies that will yield no clinical benefit. Finally, we also want to significantly expand the repertoire of cancer drug targets in order to help those patients who are not well served by the precision medicines we have today.
The DepMap team has been working on a pilot project to demonstrate the power of this approach. What have you learned?
JB: We’ve learned that scale is incredibly important for getting the right answers. That means ensuring all tumor types, genotypes, and patients of all ethnicities are represented. It also means that it isn’t necessarily enough to just observe a potential drug target once in your data — you really need scale to draw robust causative relationships between the genetic makeup of a tumor and its vulnerabilities.
Another key lesson is the importance of sharing. We’ve found there is tremendous interest in and demand for DepMap data. We believe it’s our obligation to provide the data to researchers everywhere without restriction.
MG: Importantly, our partners see the unique value that organizations like the Broad and Sanger can bring to the development of large-scale resources for the scientific community. It’s an exemplar of what cancer research will increasingly look like in the decades ahead: big questions require big commitments, and those commitments require new ways of working across institutions.
What are the next steps for your team and for the scientific community?
JB: Our opinion piece in Nature is a call to action. We’re rallying others to the cause.
At the same time, we haven’t yet sorted out all of the ways that others could join the effort. There are outstanding questions in how we might move forward, and we’ve begun to articulate some of those — for example, how to bring immune cells to bear on the DepMap, how to reduce costs through miniaturization of the technologies we use, and how to use new gene editing technologies. A lot of innovation is needed.
MG: This is the start of a dialogue about the value of a comprehensive cancer dependency map and how it could be created through a collective, community-wide endeavor. We hope the community will come forward in the spirit of collaboration to truly make a difference for cancer.
What has the response been like so far to your piece?
MG: We’ve gotten a range of responses so far. We received inquiries from clinicians who are excited to contribute samples. And we’ve also heard from patients and patient groups who are interested in us generating data to help answer questions about their own types of cancer. We’ve also been contacted by scientists, including computational scientists and technology experts, who are excited by the challenges and opportunities of creating a cancer dependency map. We’ll spend the next month or so aggregating all the ideas and then come up with a consensus on how to move forward in the coming months.
You’ve been working on the DepMap for several years. Why put out this call now?
MG: There is a convergence of new tools and technologies that is allowing us to understand gene function at a scale and resolution that was not possible before. At the same time, the decreasing cost of various genomic technologies means we can interrogate the genomes, proteomes, and metabolomes of tumor cells at increasing scale.
JB: Beyond this evolution of technical capability, we are in a remarkable moment. In response to the coronavirus pandemic, we’ve seen the extraordinary impact of scientific teamwork in creating a handful of vaccines in just nine months — something many people thought was impossible.
Some cancer patient communities are left wondering: ‘Do cancer researchers act with this same level of urgency, as thousands of people continue to die of cancer every day?’ That has really thrown down the gauntlet for cancer research, because if we can make such rapid progress in battling this novel coronavirus, shouldn’t we be able to make similar progress for cancer? As cancer researchers, that’s a really difficult question to ignore.