Three projects from Brigham researchers have received Innovation Discovery Grants (IDG) from Mass General Brigham through a highly competitive grant program. Each has the potential to transform patient care and health care delivery by leveraging gene and cell therapy advancements. Investigators will respectively receive $100,000 toward ongoing development and future commercialization, based on the potential to improve health outcomes, meet articulated milestones and attract follow-on investment as assessed by independent industry experts.
The winning projects from the Brigham will power the search for new therapeutic agents to target a main driver of cancers, develop a better test for detecting potential pregnancy complications and advance a new therapeutic to take aim at brain cancer. The projects are led by Vidyasagar (“Sagar”) Koduri, MD, PhD of the Division of Hematology; Hope Yu, MD, of the Division of Maternal-Fetal Medicine; and Arpita Kulkarni, PhD, of the Division of Engineering in Medicine, respectively.
Development of KRAS Degraders in Cancer
More than 30 percent of human cancers are driven by mutations in the family of RAS genes. The percentage is even higher in some of the most difficult-to-treat forms of cancer: 95 percent of pancreatic cancers, 45 percent of colon cancers and 35 percent of lung cancers have mutations in KRAS, a member of the RAS family. Considering how common and critical mutations in KRAS are for cancers, the gene makes for a tantalizing target. However, RAS proteins are slippery — the proteins’ smooth surfaces make it remarkably challenging to design a drug that can bind to them. RAS proteins are considered by many to be “undruggable” — impossible to target with a therapeutic treatment — but Vidyasagar Koduri, MD, PhD, a fellow in the Kaelin lab, is galvanized by what others call impossible.
“RAS is considered the most intractable drug target there is — it’s resistant to so many of the tricks we usually use to build drugs against therapeutic targets,” said Koduri. “We’ve heard from drug companies that this is just too hard, and we’ll need to sit tight. But for us, the impetus is still there to find another way to target KRAS.”
Koduri draws inspiration from a discovery made in the labs of Benjamin Ebert, MD, PhD, and William Kaelin, MD. Ebert and Kaelin independently showed that lenalidomide works by directly binding to the crucial myeloma protein Ikaros. The lenalidomide-IKaros complex can then be detected by the ubiquitin-proteasome system, which degrades Ikaros by chopping it up — much like a woodchipper for proteins. Because myeloma cells depend on Ikaros for survival, this degradation process kills myeloma cells, and account for the efficacy of these treatments in myeloma.
“Ikaros is critical for the survival of multiple myeloma cells, just as RAS is critical for other kinds of cancer,” said Koduri. “Lenalidomide staples itself onto Ikaros to signal to the cellular machinery to dispose of the protein. Without lenalidomide, ikaros is invisible — but with it, it becomes targeted for degradation.”
Lenalidomide’s rediscovery was serendipitous. But Koduri’s goal is to develop a more systematic way to find drugs that could act like KRAS degraders — flagging the proteins for woodchipper disposal. He is developing a high-throughput screening platform that would allow researchers to search for potential agents.
“If you can’t inhibit a protein directly, finding a degrader could be a great solution,” said Koduri. “As we’ve seen in myeloma, this strategy holds the promise of turning cancer into a manageable disease.”
Predicting Placenta Accreta in Pregnancy
During her residency, Hope Yu, MD, who is a current third-year fellow in Maternal Fetal Medicine, was drawn to surgical obstetrics and helping women with high-risk pregnancies. One of the conditions she has seen in the clinic is placenta accreta spectrum, or PAS. PAS is a potentially life-threatening pregnancy complication that occurs in approximately 1 in every 1,000 to 2,000 pregnancies. PAS occurs when the placenta attaches abnormally to the uterus, making it difficult for the placenta to deliver and puts women at risk for hemorrhaging. It is one of the highest risk factors for maternal morbidity, and, though uncommon, it has increased in occurrence over the years. While severe forms of PAS are easily identified, less invasive cases may not be detected using ultrasound.
“If we could identify women who are at risk and ensure they deliver at a center that can provide the appropriate level of care, we could reduce morbidity by 80 percent,” said Yu. “Accurate, early detection could be lifesaving.”
Yu has been working with Thomas McElrath, MD, PhD, of the Division of Maternal-Fetal Medicine, to develop a panel of protein biomarkers associated with circulating microparticles that can be detected in a pregnant woman’s blood sample and could help identify patients who are at risk. The Innovation Discovery Grant will help Yu and her colleagues validate these biomarkers in a larger population.
This fall, Yu will stay on at the Brigham as a faculty member, working closely with Daniela Carusi, MD, the director of Surgical Obstetrics and the Abnormal Placentation Program in the Division of Maternal-Fetal Medicine. Since 2008, the program has cared for hundreds of women with complicated pregnancies, including 30 to 50 women yearly who have PAS. In addition to experts who can care for adult patients, the Brigham also has neonatologists who can help care for babies who are delivered early due to PAS.
“Moms should never feel like their lives are at risk in bringing a baby into the world,” said Yu. “Finding ways to help our patients who are at risk is what motivates me in my research.”
Taking Aim at Glioblastoma
As a cellular and developmental biologist, Arpita Kulkarni, PhD, studies the underlying biological mechanisms of health and disease with the ultimate goal of translating her findings into clinical impact.
“My mission and purpose with my research are to reduce human suffering and enhance the quality of life,” said Kulkarni. “This desire fuels my work.”
Kulkarni’s team is interested in finding effective treatments for glioblastoma multiforme (GBM), a lethal and treatment-resistant form of brain cancer. Traditional treatments for GBM (chemotherapy, radiation and surgical resection) have remained unchanged for decades, and the prognosis for GBM patients is grim. New approaches are being pursued, but some have failed in clinical trials and others have had highly variable outcomes in patients.
“Our aim is to address this huge, unmet medical need and change outcomes in patients with GBM,” Kulkarni said.
Kulkarni is part of a team that has identified Hsp90 as a clinical biomarker for GBM. Hsp90 is a molecular chaperone that helps stabilize other proteins — including proteins that may be required for tumor growth. Kulkarni and colleagues have engineered and patented a therapeutic that acts as an inhibitor of Hsp90. The new therapeutic is the first and only Hsp90 inhibitor that can cross the blood-brain barrier, induce tumor immunogenicity in models of GBM and other solid cancers and synergizes with cell therapies.
“Such a multi-pronged approach has never been taken before,” said Kulkarni. “Our envisioned technology is exponential, faster, cheaper, safer, more effective and accurate than currently available treatments.”
The therapeutic also has potential for translation as a drug delivery vehicle not just for GBM, but for other cancers as well. Kulkarni hopes that the new therapeutic will be a gamechanger for GBM and other cancers.