What’s New in Research – February 2019
The Brigham is home to nearly 5,000 researchers, including physician-investigators, biomedical scientists, and faculty, who publish new research papers on a range of scientific and medical subjects. Below are brief summaries of a selection of our community’s most recent work. If you have an upcoming Brigham publication, please contact email@example.com.
Site of Care May Affect Patients’ Access to Palliative Treatment
Regardless of race or ethnicity, patients were 33 percent less likely to receive any palliative care for metastatic cancer at hospitals primarily serving minorities
For patients at the end of life, palliative care can prolong survival and improve the quality of life for patients with a life-threatening illness and for their families. But studies have found that racial and ethnic minorities are less likely to receive end-of-life palliative care than their counterparts. A new study conducted by investigators at Brigham and Women’s Hospital set out to understand why and has revealed that site of care may be a key contributing factor to this difference among patients with advanced, metastatic cancer. Their results are published in JAMA Network Open.
“There is a growing role for palliative care, and most physicians accept that many patients in the late stages of cancer should be referred to palliative care,” said corresponding author Quoc-Dien Trinh, MD, a physician in the Division of Urological Surgery and the Center for Surgery and Public Health (CSPH) at the Brigham.
“We knew that black and Hispanic cancer patients receive palliative care at lower rates than white patients, but until now, we didn’t know why. Was it just that doctors were not offering these services to their black and Hispanic patients? Or is there some other factor at play?” said first author Alexander P Cole, MD, also of the Division of Urological Surgery and CSPH.
In their study, Trinh, Cole and colleagues found that patients treated at some hospitals have only about two-thirds the odds of receiving palliative care compared to those receiving care at typical hospitals. These tend to be hospitals that disproportionately treat minority patients.
“We find that the site of care seems to be a key determinant of whether or not someone receives palliative care,” said Trinh.
The team conducted a retrospective, registry-based analysis of adults diagnosed with four types of metastatic cancer using data from the Participant Use Files of the National Cancer Database (NCDB). The team focused on men and women 40 years and older with metastatic prostate, non-small cell lung, colon and breast cancer—four common and lethal cancers. The main outcome measured was receipt of palliative care, such as pain control, surgical treatment, radiation therapy and systemic chemotherapy administered to alleviate symptoms but not to cure disease.
Investigators looked at the hospitals at which patients received care, calculating the proportion of minority patients (black or Hispanic) treated at each. Hospitals with the greatest proportion of minorities were considered “minority serving hospitals” (MSH). Hospitals that were not in the top 10 percent were considered “non-minority serving hospitals” (non-MSH).
The team found that of the more than 600,000 individuals with metastatic cancer studied, 21.7 percent received palliative care. Overall, 22.5 percent of white patients (106,603 people) received palliative care, while only 20.0 percent of black patients (16,435 people) and 15.9 percent of Hispanic patients (3,551) received palliative care. After adjusting for other variables, the team found that patients who received care at an MSH had two-thirds the odds of receiving palliative care compared with those who received care at a non-MSH, regardless of the patient’s race or ethnicity.
“Our mission is to reduce inequity in health care, and the first step in doing so is to raise awareness of these disparities,” said Trinh. “These findings suggest that there are significant racial and ethnic disparities in receipt of palliative care for patients with metastatic cancer and that these disparities are largely accounted for by the site of a patient’s care. Strategies that focus on improving palliative care use at minority-serving hospitals may be an effective strategy to increase the receipt of palliative care for minorities.”
Funding for this work was provided by the Brigham Research Institute Fund to Sustain Research Excellence.
Paper cited: Cole, AP et al. “Association of Care at Minority-Serving vs Non–Minority-Serving Hospitals With Use of Palliative Care Among Racial/Ethnic Minorities With Metastatic Cancer in the United States” JAMA Network Open DOI: 10.1001/jamanetworkopen.2018.7633
Exploring the Connection Between Hearing Loss and Cognitive Decline
Eight-year study reveals association that may indicate early stage changes in cognition
Hearing loss affects tens of millions of Americans and its global prevalence is expected to grow as the world’s population ages. A new study led by investigators at Brigham and Women’s Hospital adds to a growing body of evidence that hearing loss is associated with higher risk of cognitive decline. These findings suggest that hearing loss may help identify individuals at greater risk of cognitive decline and could provide insights for earlier intervention and prevention.
“Dementia is a substantial public health challenge that continues to grow. There is no cure, and effective treatments to prevent progression or reverse the course of dementia are lacking,” said lead author Sharon Curhan, MD, MSc, a physician and epidemiologist in the Channing Division for Network Medicine at the Brigham. “Our findings show that hearing loss is associated with new onset of subjective cognitive concerns which may be indicative of early stage changes in cognition. These findings may help identify individuals at greater risk of cognitive decline.”
Curhan and colleagues conducted an eight-year longitudinal study among 10,107 men aged ≥62 years in the Health Professionals Follow-up Study (HFPS). They assessed subjective cognitive function (SCF) scores based on responses to a six-item questionnaire administered in 2008, 2012 and 2016. SCF decline was defined as a new report of at least one SCF concern during follow-up.
The team found that hearing loss was associated with higher risk of subjective cognitive decline. Compared with men with no hearing loss, the relative risk of cognitive decline was 30 percent higher among men with mild hearing loss, 42 percent higher among men with moderate hearing loss, and 54 percent higher among men with severe hearing loss but who did not use hearing aids.
Researchers were interested to see if hearing aids might modify risk. Although they found that among men with severe hearing loss who used hearing aids the risk of cognitive decline was somewhat less (37 percent higher), it was not statistically significantly different from the risk among those who did not use hearing aids. The authors note that this may have been due to limited power or could suggest that if a difference truly exists, the magnitude of the effect may be modest.
The authors also note that the study was limited to predominantly older white male health professionals. This allowed for greater control of variability but further studies in additional populations would be helpful. In addition, the study relies on self-reported hearing loss and subjective measures of cognitive function. In the future, the team plans to investigate the relationships between self-reported hearing loss, change in audiometric hearing thresholds, and changes in cognition in women using several different assessment measures.
“Whether there is a temporal association between hearing loss and cognitive decline and whether this relation is causal remains unclear,” said Curhan. “We plan to conduct further longitudinal studies of the relation of hearing loss and cognition in women and in younger populations, which will be informative.”
This work was supported by grants DC 010811, UM1 CA167552, and UM1 CA 176726 from the National Institutes of Health.
Paper cited: Curhan, S et al. “Longitudinal study of hearing loss and subjective cognitive function decline in men” Alzheimer’s & Dementia DOI: 10.1016/j.jalz.2018.11.004
The Hitchhiker’s Guide to Defeating Glioblastoma
New approach using multiple microRNA ‘hitchhikers’ to weaken cancer cells in advance of standard therapy shows promise in preclinical models
In cancer therapeutics research, microRNAs—tiny strings of nucleotides that get churned out inside cells—have been a source of both excitement and disappointment. While preclinical studies have found that microRNAs play an important role in cancer and other diseases, two cancer clinical trials to date using microRNAs showed little response and significant toxicity. A team of investigators at Brigham and Women’s Hospital and Harvard Medical School has begun looking at these molecules in an entirely new way. Rather than modulating just one, they grouped together multiple microRNAs that naturally occur in the brain by encoding them in a small, artificial gene, and co-opted cancer cells’ molecular machinery to overproduce these groups of molecules to weaken the cells. Their approach has shown promising results in preclinical models, increasing survival in a murine model of glioblastoma by five-fold when combined with chemotherapy. The team’s results are published in Nature Communications.
“I like to think of it as hitchhiking. Cancer cells have a built-in system to produce and recognize microRNAs and we’re getting them to ‘pick up’ our sequence—which encodes multiple microRNAs—and start making more copies of them. The cellular machinery is running, and our sequence is along for the ride,” said corresponding author Pierpaolo Peruzzi, MD, PhD, an attending clinical neurosurgeon in the Department of Neurosurgery, as well as a principal investigator in the Harvey Cushing Neuro-Oncology Laboratories at the Brigham.
Peruzzi and colleagues, including lead author Vivek Bhaskaran, PhD, a postdoctoral fellow in the Department of Neurosurgery, set out to find groups of microRNAs responsible for regulating complex pathways. Using bioinformatic analysis, the team focused on a group of three microRNAs—miR-124, miR-128 and miR-137—which work as a team in properly developing neurons but are lost during the formation of brain cancer. The team found that several of these microRNAs’ targets included proteins involved in glioblastoma recurrence and resistance to conventional therapies.
The research team tested its findings using multiple cancer cell lines, including glioblastoma as well as non-glioblastoma cell lines. In addition, investigators tested the effectiveness of modulating all three microRNAs at once in a mouse model of intracranial tumors. The team reported a significant survival benefit. Without treatment, the mouse model survived 12 days post-tumor implantation, and chemotherapy extended this to a median of 18 days. But when chemotherapy and the multi-microRNA treatment were combined, survival was extended to a median of 48.5 days.
“These results are very encouraging and may provide a realistic treatment option,” said Bhaskaran.
Peruzzi notes that the multi-microRNA strategy weakens tumor cells but does not directly kill them. “While it seems a bit counterintuitive, this is actually an advantage, since by remaining alive, although severely impaired, cancer cells continue to produce microRNAs which eventually flood the entire tumor.” Indeed, the authors showed that these artificial microRNAs spread through the tumor through tiny vesicles and leave it more vulnerable to chemotherapy.
“We’re coaxing the tumor to produce its own poison, and then we hit it for good with chemotherapy or radiation,” said Peruzzi. “And we’re optimistic that in a relatively short time we can advance this approach to the clinic. A further refined and even more potent version of this concept is already in the pipeline.”
There are currently clinical trials underway at the Brigham leveraging viral vectors and gene-therapy approaches for treating glioblastoma (both primary and recurrent). Peruzzi and colleagues are working to further refine their microRNA approach with the goal of using viral vectors to deliver these microRNAs to tumors in brain cancer patients.
Funding for this work was provided by the Neurosurgery Research Career Development Program and the National Institute of Neurological Disorders and Stroke (grants K12NS80223 and K08NS101091).
Paper cited: Bhaskaran, V et al. “The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma” Nature Communications DOI: /10.1038/s41467-019-08390-z
New Therapeutic Targets for Kidney Fibrosis Emerge
Study identifies key factor leading to cell cycle arrest and a cellular structure that is key for kidney fibrosis progression
Chronic kidney disease is a global health concern, affecting about 10 percent of the world’s population—and increasing in prevalence. A final, common pathway in chronic kidney disease is fibrosis. Just as fibrosis—or the formation of fibrous connective tissue—can cause devastating effects in the lung, liver, heart and elsewhere, fibrosis of the kidneys can ultimately lead to end-stage kidney failure. In recent years, investigators have found that after acute kidney injury, the kidneys often fail to completely repair themselves, and kidney cells may get stuck during the cell cycle in a state in which they release profibrotic factors. A new study, published in Science Translational Medicine, builds upon these findings, identifying key factors involved in this cell cycle arrest and illuminating their consequences. Based on these discoveries, the research team, led by investigators at Brigham and Women’s Hospital, also identifies a novel intracellular structure and new therapeutic targets for kidney fibrosis.
“As a disease mechanism, fibrosis may account for more deaths than any other,” said corresponding author Joseph Bonventre, MD, PhD, chief of the Division of Renal Medicine at the Brigham and a faculty member of the Harvard Stem Cell Institute. “Our lab has been studying acute and chronic kidney injury and fibrosis for many years. We’re now focused on the transition from acute to chronic kidney disease and what leads to fibrosis in the kidneys.”
Bonventre and colleagues studied the transition from acute to chronic kidney disease in mice, using extracted epithelial cells and conducting unbiased gene expression analyses. They found that during kidney fibrosis progression, a critical compartment formed within kidney cells. The presence of the target of rapamycin-autophagy spatial coupling compartment (TASCC) increased the amount of secreted factors that promote fibrosis (TASCCs also form during liver fibrosis). In addition, the team identified a key role for cyclin G1 (CG1), a protein involved in regulation of cell cycle arrest, to also induce the formation of TASCCs. Blocking the formation of TASCCs reduced the severity of kidney fibrotic disease progression in preclinical models.
The team also studied a group of patients with chronic kidney disease that had developed progressive fibrotic lesions. They found that the kidney tissue from these patients, compared to controls, had more kidney cells arrested in the G2/M phase of the cell cycle and that these cells contained TASCCs. TASCC-containing cells were also found in patients with acute kidney injury.
The authors conclude: “We have identified a mechanism of fibrosis progression involving the induction of CG1-promoted TASCC formation, which facilitates profibrotic factor secretion in cells in the G2-M phase of the cell cycle. This pathway may represent a new promising therapeutic target.”
Former Bonventre laboratory members, Guillaume Canaud, MD, PhD, currently a faculty member at INSERM Necker-Enfants Malades Hospital in Paris, Craig Brooks PhD (Vanderbilt U), Seiji Kishi MD, PhD (Kawasaki Med Sch) and other authors played important roles in the work described.
Funding for this work was provided by National Institutes of Health (R37DK039773, R01DKD072381, K01DK099473 and P30 DK114809), Safra Foundation, Philippe Foundation Inc., Bettencourt Schueller Foundation, Société Française de Néphrologie, Emmanuel Boussard Foundation (London, UK), Day Solvay Foundation (Paris, France), Assistance Publique- Hôpitaux de Paris, University Paris Descartes, Research Fellowship from Sumitomo Life Welfare and Culture Foundation, Japan and Grant in Aid for Scientific Research. Bonventre is a co-inventor on KIM-1 patents assigned to Partners Healthcare. He is an advisor for Boehringer Ingelheim, BioMarin, Takeda, and Lilly and receives grant support from Boehringer Ingelheim unrelated to this work. He holds equity in Goldfinch Bio, Theravance, Sentien, and Rubius.
Paper cited: Canaud, G et al. “Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair” Science Translational Medicine DOI: 10.1126/scitranslmed.eaav4754
Study Sheds Light on Why Checkpoint Blockade Therapy Succeeds or Fails
Researchers uncover novel immune cell populations that respond to immunotherapy treatment as well as key molecular factor required for therapy to succeed
There have been many success stories for checkpoint blockade therapies both in preclinical models and in patients with cancer. But many questions remain about exactly how such immunotherapies elicit their response and what determines when and where checkpoint blockade therapy succeeds or fails at reinvigorating the immune system to eradicate cancer. A new study led by investigators from Brigham and Women’s Hospital in collaboration with colleagues at the Broad Institute examines the effects of checkpoint blockade therapies on different populations of T cells, a key class of immune cells in tumors. The team’s surprising results point to a population of T cells that have been overlooked in the past and led to the identification of a molecular factor that may be predictive of response to treatment. The investigators’ findings are published in Immunity.
“Our study takes advantage of the observation that there is great diversity in the T cells within tumors. When we looked at the effect of therapies on different cell populations, we were surprised and puzzled to find that even T cells that don’t express checkpoint inhibitors showed significant changes at the genetic level,” said co-corresponding author Ana Anderson, PhD, a scientist at the Brigham. “These are cells that have largely been ignored before. Our study broadens the focus of what checkpoint blockade therapy may be doing and how it mediates its effects.”
Anderson and colleagues leveraged modern technology to explore the effect of therapy on T cells across different cancers, capitalizing on computational methodologies and single-cell RNA-seq, a technique for measuring the output of thousands of genes from individual cells in a given population. The researchers took an iterative approach, allowing the data to point them toward interesting leads and then performing further testing in preclinical models of cancer.
This approach led them to Tcf7, a transcription factor that is required for the maintenance and function of an immune cell population that is capable of memory. Through their experimental models, the team found that this factor was required for immune-based therapies to succeed.
Anderson notes that, to date, the field has been largely focused on fully matured, end-stage T cells that are equipped with checkpoint receptors such as PD1 or CTL4. In the early stages of activation, T cells don’t yet express these receptors, and yet, these nascent cells still show a response to the therapy.
“We need to understand these early-stage T cells to shed light on how checkpoint blockade therapy works,” said Anderson. “Our study helps define an important immune cell population that responds to checkpoint blockade immunotherapy across different cancers and points to a critical factor in this therapy’s success. With further study, we may be able to define biomarkers to predict a patient’s response to therapy and identify which cells are most important to target with immunotherapy approaches.”
Funding for this work was provided by grants from the National Institutes of Health (R01NS045937, P01AI073748, R01CA187975), the American Cancer Society (RSG-11-057-01-LIB) and by the Klarman Cell Observatory at the Broad Institute and HHMI. Anderson is a member of the SAB for Potenza Therapeutics and Tizona Therapeutics, which have interests in cancer immunotherapy. Co-author Vijay Kuchroo has an ownership interest and is a member of the SAB for Potenza Therapeutics and Tizona Therapeutics. Co-author Aviv Regev is a SAB member for Thermo Fisher and Syros Pharmaceuticals and Driver Group. A provisional patent application was filed including work in this manuscript.
Paper cited: Kurtulus, S et al. “Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1‾CD8+ Tumor-Infiltrating T Cells” Immunity DOI: 10.1016/j.immuni.2018.11.014