What’s New in Research: June 2022
Pandemic Disrupted Cancer Clinical Trials, But Enrollment and Activation Are Recovering
The COVID-19 pandemic substantially disrupted clinical trial activities in oncology, but enrollment and activation have both begun to bounce back, according to a prospective study of therapeutic clinical trials conducted at two large academic medical centers. The research team, which included investigators from the Brigham, found a major decrease (46 percent) in patient accruals early in the pandemic. But the team also reported a progressive recovery and a return-to-higher than normal levels by June 2021. From 2019 to June 2021, the two centers studied had added 467 newly activated clinical trials. The authors note that the sharpest decline in enrollment during the pandemic was seen among academically sponsored trials, and racial disparities were seen among people taken off trial.
“An important consideration is the fact that academically sponsored trials might have been more prone to disruptions during the pandemic because they can be more resource-intensive and often require research biopsies and frequent visits by patients to the clinic,” said co-first author Ziad Bakouny, MD, an internal medicine resident at the Brigham.
Read more in Annals of Oncology.
Investigators Identify a New Candidate Therapeutic Target for Parkinson’s Disease
The human brain is lipid rich. Lipids and fatty acids contribute to many important cellular processes. Alpha-synuclein — a protein that plays a critical role in Parkinson’s disease (PD) — is known to interact with and alter the balance of lipids and fatty acids. Investigators from the Brigham and Harvard Medical School are exploring how to rebalance fatty acid metabolism in the brain to find new therapeutic approaches for PD and related conditions. Their previous work has led to the identification of an inhibitor of an enzyme called stearoyl-CoA-desaturase, which is now being tested in human clinical trials. In a new study, they identify LIPE, a lipase that degrades triglycerides to produce fatty acids, as a candidate therapeutic target. Inhibiting LIPE reduced the formation of clusters of α-synuclein inclusions and other characteristics associated with PD in patient-derived neurons. LIPE reduction also alleviated neurodegeneration in a C. elegans model of α-synuclein toxicity.
“Our research led us to become increasingly aware of the role lipid and fatty acid balance may play in Parkinson’s disease,” said co-corresponding author Saranna Fanning, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham. “Ultimately, we hope this lipid-related target will have promise as a small-molecule therapy for Parkinson’s disease.”
Co-corresponding author Dennis Selkoe, MD, also of the Ann Romney Center for Neurologic Diseases at the Brigham, added, “The identification of LIPE inhibition and a unique co-regulation of fatty acid synthesis and degradation pathways are further evidence that targeting fatty acid metabolism holds promise for Parkinson’s disease.”
Read more in npj-Parkinson Disease.
Newer Class of Type 2 Diabetes Drugs Decreased Risk for Hospitalization for Heart Failure
In cardiovascular outcome trials among adults with type 2 diabetes (T2D), sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have shown therapeutic promise, including reduced risk of hospitalization for heart failure compared to placebo. However, SGLT-2i have mainly been evaluated as a second-line treatment — metformin is generally given as a first-line, antidiabetic treatment. In a new study, researchers from the Brigham compared cardiovascular outcomes among adults with T2D who initiated first-line treatment with either metformin or SGLT-2i. For the study, 8,613 patients treated with SGLT-2i were matched to 17,226 patients treated with metformin. The authors found that patients receiving SGLT-2i showed a similar risk for myocardial infarction, stroke, and all-cause mortality, and a lower risk for hospitalization for heart failure compared with patients who received metformin. The risk for adverse events was similar except for an increased risk for genital infections compared with those receiving metformin.
“Our results suggest that SGLT-2i may be considered as first-line treatment for patients with T2D and cardiovascular disease or who are at increased risk for cardiovascular events,” said lead author HoJin Shin, BPharm, PhD, of the Division of Pharmacoepidemiology and Pharmacoeconomics. “However, more evidence from randomized clinical trials or observational studies will help us to identify patients who would benefit most from using SGLT-2i as first-line type 2 diabetes treatment.”
Read more in Annals of Internal Medicine.
Treatment for Myelodysplastic Syndrome by Hypomethylating agents (HMA) May Activate an Oncogene
Hypomethylating agents (HMA) are currently used as a first-line treatment for patients with myelodysplastic syndrome (MDS), and increasingly in other diseases, but their mechanism of action is not clear. HMAs may affect many genes and could potentially activate an oncogene — a gene that contributes to the development of cancer — but this has not been clearly demonstrated to date. To test this, investigators from Brigham and Women’s Hospital, Harvard Stem Cell Institute and collaborators studied how HMA affects known oncogenes. They found that HMA activated the oncofetal protein SALL4 in up to 40 percent of patients with MDS, leading to poor patient survival, even in patients in clinical remission. The findings may apply to other cancers and diseases in which HMA are being used.
“SALL4 is an embryonic stem (ES) cell gene and leukemic stem cell factor, and it belongs to a new class of oncofetal gene. Gain-of-function SALL4 transgenic mice develop MDS and acute myeloid leukemia (AML), as well as liver tumors. Loss-of-function studies demonstrated that SALL4 is essential for the survival of cancer cells, including leukemic cells by regulating multiple survival pathways. Our data suggest that MDS patients receiving HMA treatment should be monitored for demethylation and upregulation of oncogenes such as SALL4, which we found are linked to poor outcomes, and these patients should be provided with an additional combination therapy,” said lead author Li Chai, MD, of the Brigham’s Department of Pathology.
The Chai lab has been working on SALL4 since 2003, and Chai has led a research program centered on SALL4 function, mechanism, structure and targeting. Given the gene’s unique oncofetal expression pattern, she and her collaborators have initiated a ground-breaking SALL4-based approach to classify and target cancer, and their previous work has shown the feasibility of targeting this ES cell gene in cancers (Yong KJ, et al NEJM, 2013, Liu B, et al PNAS, 2018, Yang J, et al Cancer Research, 2021).
Read more in The New England Journal of Medicine.
Further Evidence that mRNA Vaccination Against SARS-CoV-2 is Safe During Pregnancy
Many public health initiatives today are focused on protecting vulnerable populations against the novel coronavirus and recommend that pregnant women routinely receive mRNA vaccines to prevent maternal and fetal morbidity as well as mortality. To gather more data on vaccine safety and any effects on the fetus, researchers at the Brigham sought to understand if any Spike protein from the virus can accumulate or undergo translation in the placenta post-vaccination. The group identified 48 patients receiving one or two doses of an mRNA SARS-CoV-2 vaccine during gestation and subsequently quantified the expression of the Spike protein in preserved placental tissue. In doing so, they discovered that all placentas in the study and their corresponding negative control groups did not express the Spike protein. Moreover, the six placentas with the shortest vaccination-to-delivery intervals were tested for SARS-CoV-2 Spike RNA and were negative. Both observations provide further evidence that mRNA vaccines are safe for the growing fetus.
“Our findings were derived from pregnant patients in real-life conditions and underscore the portended safety of mRNA vaccination during pregnancy,” said senior author Carlos Parra-Herran, MD, from the Department of Pathology. “We are now eager to continue understanding the safety of mRNA vaccines during pregnancy in order to expand vaccination efforts and better protect our vulnerable populations,” added lead author Andres Santos MD, PhD, also from the Department of Pathology.
Read more in Modern Pathology.
High Social Vulnerability Predicts Worse Long-Term Outcomes After Traumatic Injury
Traumatic injuries — such as physical injuries resulting from a car accident, fall, gunshot or stabbing — are one of the most common causes of impairment and disability worldwide. A team of investigators led by Juan P. Herrera-Escobar, MD, MPH, of the Brigham’s Center for Surgery and Public Health, found that living in an area with higher social vulnerability is strongly associated with worse mental and physical health outcomes after a traumatic injury. Areas with high social vulnerability are those with higher poverty and unemployment rates, lower income, higher proportion of racial/ethnic minority groups and people with limited English-speaking ability, more households without vehicles, and crowded housing, among other factors. The team leveraged data from the Centers for Disease Control and Prevention’s (CDC’s) Social Vulnerability Index (SVI), a data-driven tool used to inform decision about COVID-19 vaccine allocation.
“These findings suggest that community-level social factors play a significant role in recovery after injury,” said Herrera-Escobar. “The CDC’s SVI could serve in trauma as a branch point in determining referral to a standard set of post-discharge support services and interventions, such as mental health services, assistance with return to work, and rehabilitation services such as physical therapy, occupational therapy.”
Read more in Annals of Surgery.