Grand Challenge Winners Leveraging Intellectual Diversity

A yeast biologist, a medical oncologist, and an evolutionary theorist walk into a lab…. That's not exactly common; researchers with such disparate specialties don't often collaborate on the same projects. However, multidisciplinary expertise characterizes four teams investigating complex and long-standing questions with funding from the Cancer Grand Challenges program, sponsored by the NCI and Cancer Research UK (CRUK).

Launched in 2020, Cancer Grand Challenges identified nine research areas in which large-scale collaborative efforts might provide deeper insights and unlock new treatments (Cancer Discov 2021;11:OF1). In June, the NCI and CRUK announced the four winning teams that will each receive a 5-year, $25 million grant.

The length of the awards is not unusual, but the amount of money is, says Eileen White, PhD, of Rutgers University in New Brunswick, NJ. Apart from Cancer Grand Challenges, “there is no mechanism at NCI for combining that spectrum of expertise, from clinical to basic science, on a global scale to solve a problem,” she says.

White co-leads the CANCAN team, which will investigate cancer cachexia, the wasting syndrome that afflicts many patients with cancer. Her lab is one of the 14 in the United States and the UK trying to answer three fundamental questions: How does cancer change the body's metabolism and nutrient allocation to produce cachexia? What factors do tumors release to promote the condition? How do the nervous and endocrine systems go awry such that patients stop eating?

And because there are no FDA-approved cachexia treatments, the team aims to confirm their hypothesis that multiple cachexia subtypes exist, possibly pointing to targeted therapies.

The eDyNAmiC team, led by Paul Mischel, MD, of Stanford University in California, is drawing on expertise in yeast biology, medical oncology, evolutionary theory, and other areas to investigate circular extrachromosomal DNA (ecDNA). Discovered in the 1960s, ecDNA's connection to cancer is just starting to emerge. Recent work suggests that it fosters tumor development by amplifying oncogenes and promotes resistance to checkpoint inhibitors and other treatments.

The team's 14 labs will tackle questions such as how ecDNA forms, how it eludes the immune system, and whether it has any vulnerabilities that could be targeted by treatment. Researchers also want to know how ecDNA drives tumor evolution and leads to resistance.

“The speed at which cancers seem to evolve makes no sense,” says Mischel. ecDNA, rather than typical alterations to chromosomes, may explain “the rapidity of genetic change.”

The NexTGen team aims to develop chimeric antigen receptor (CAR) T cells to treat pediatric sarcomas and brain tumors. To date, CAR T-cell therapy has been approved for children with acute lymphoblastic leukemia only. Childhood cancers often carry few antigens recognizable to CAR T cells. That's why the group wants to identify novel antigens—not only proteins but also altered glycosylation patterns and the so-called dark antigens produced when tumors express normally silenced portions of the genome—on pediatric tumors.

Because the tumor microenvironment can suppress immune cells, it creates an obstacle to using CAR T cells to treat solid tumors. To address that limitation, the researchers aim to develop countermeasures to protect the cells and then launch multiple trials to test their approaches.

Knowing that cells can function normally even when carrying multiple cancer-causing mutations, the PROMINENT team wants to better understand what triggers carcinogenesis. The researchers hypothesize that an additional spark, such as a wound that fails to heal, is necessary to ignite abnormal growth. They want to identify risk factors that may promote the transition to cancer and uncover what stimulates the early stages of abnormal growth. To determine which cells carry mutations and where the cells reside, the scientists will analyze more than 4,000 tissue samples from mice, along with tumor and healthy tissue from more than 5,000 patients. With new information, they may conceive strategies to prevent mutated cells from becoming malignant.

These teams are just the first group of Cancer Grand Challenges winners. The NCI and CRUK will call for additional proposals in 2023 and 2025. –Mitch Leslie

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