Breast cancer study surmounts key technological hurdle, offers intriguing insights into breast cancer biology
In the last several years, scientists across the world have identified hundreds of genetic variations associated with cancer risk. Thanks in part to advances in genomic technologies, uncovering these “risk alleles” is no longer an insurmountable scientific obstacle. But uncovering their functions — specifically, what genes they influence and how they work on a biological level to increase or decrease a person’s risk of developing cancer — remains a significant challenge.
Aditi Hazra, PhD, MPH, a genetic epidemiologist in the Division of Preventive Medicine, and her colleagues have been working over the last several years to address this challenge, with a particular focus on breast cancer. This work, part of the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) consortium in the Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative launched in 2010, overcomes a significant technical leap that now opens up an untold number of tumor samples for research.
Prior to Hazra’s study, tumors preserved using standard clinical methods — known as FFPE, for formalin-fixed paraffin-embedded tissue — were essentially off-limits because they could not be analyzed using cutting-edge, genome-wide techniques for probing gene activity. These techniques seek to measure, in a comprehensive and quantitative manner, the activities of the roughly 20,000 genes in the human genome. But these methods came with an important technical caveat: they only worked on tissues preserved by rapid freezing — not by FFPE. That essentially ruled out the significant fraction of tumors that have been collected by pathologists over the last several years, even so-called archival tissue that has been stored for decades.
“We faced many obstacles, but I knew this was the right step to answer the question we wanted to ask, so I persisted,” said Hazra. “Eventually, we came across the Affymetrix Human Transcriptome Array platform that was optimized for formalin-fixed paraffin-embedded tissue, so it is this technological innovation — together with our own perseverance — that now enables work on these types of tissues.”
Hazra was able to unearth some intriguing biological findings about breast cancer. She and her colleagues studied 70 genetic variants linked to the disease — the majority of which are poorly understood and reside in the no-man’s-land equivalent of the human genome, the so-called non-coding regions. Simply put, these variants are not directly tied to known genes, leaving big questions about their functions. Hazra found a surprisingly large number of long-distance regulatory associations, meaning that these genetic variants impact genes that are not nearby, but instead lie in far-flung regions of the genome, even on different chromosomes.
Now, Hazra is expanding her research to gain a more complete view of the biology of breast cancer and examine samples from patients with more diverse, multi-ethnic backgrounds.
A candidate for the Fulbright Specialist Program in Global Health, she emphasizes that her research has a global aim. “Not only is our own scientific team drawn from multiple different countries, but my own work is focused on improving the health of understudied populations locally and globally.”
Paper cited: Quiroz-Zárate A et al. “Expression Quantitative Trait loci (QTL) in Tumor Adjacent Normal Breast Tissue and Breast Tumor Tissue.” PLOS One DOI: 10.1371/journal.pone.0170181
Deep study of key immune cell type could spur new approaches to autoimmune diseases
There are two opposing sides to the immune system: one that drives inflammation and another that restrains it. Different cell types help carry out these distinct activities, including a subset of T-cells known as Tr1 cells (for type 1 regulatory T-cells), which help tamp down the immune response. While there is great interest in these cells and their therapeutic potential — particularly for helping to ameliorate autoimmune diseases — surprisingly little is known about their biology. In fact, the dearth of knowledge about Tr1 cells is so significant that scientists struggle to definitively distinguish them from other types of immune cells due to a lack of robust molecular markers.
To shed light on the biology of Tr1 cells, Katarzyna Karwacz, PhD, of the Evergrande Center for Immunologic Diseases at BWH, and her colleagues combined several large-scale methods to systematically characterize the events that unfold at the level of the genome during the earliest stages of the cells’ differentiation. The researchers’ analyses turned up two essential regulators, IRF1 and BATF, which function as a special type of transcription factor, known as a pioneering factor.
These pioneering factors help prepare the ground, so to speak, within the genome. They ensure that the molecular packaging that encases the genome — called chromatin — is opened up in the right places. In turn, this ensures that subsequent waves of molecular regulators can gain access to the appropriate genes, either to switch them on or off. Such precise coordination is required for the normal development of Tr1 cells, as well as countless other cell types.
Together, the researchers’ findings offer an important glimpse into the biology of Tr1 cells and help set the stage for future studies.
“One of the big outstanding questions is whether the differentiation of these cells is controlled by a ‘master regulator,’ as is the case for other T helper cell lineages,” said Karwacz, who conducted the work together with senior author Vijay Kuchroo, PhD, DVM, of the Evergrande Center for Immunologic Diseases and other collaborators. “That will be another important piece in the puzzle of Tr1 biology.”
Paper cited: Karwacz K et al. “Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation.” Nature Immunology DOI: 10.1038/ni.3683
Phase 3 clinical trial tests IV therapies for severe cases of influenza
Every year, the health care community equips itself to fight a familiar foe: the influenza virus. Patients are urged to fend off infection at the start by receiving a seasonal flu vaccine. Despite this push, there remains a striking paradox: Although the microbe kills some 25,000 – 50,000 patients annually in the U.S., there are alarmingly few treatments that can help heal those who do succumb to the virus — particularly those who develop severe cases and require hospitalization.
“The swine-flu pandemic of 2009 was really a wake-up call,” said Francisco Marty, MD, an infectious disease physician at BWH. “It changed how we think about the flu and its urgency.”
Marty and his colleagues recognized a need for potent antiviral therapies, particularly ones that can be delivered intravenously to hospitalized patients with the flu, who can develop severe complications such as hemorrhagic pneumonia and shock. These patients often cannot take drugs made for oral or inhaled administration — like the majority of drugs approved to treat influenza. While the antiviral drug peramivir is available for intravenous use in influenza, it is only approved for mild cases in non-hospitalized patients.
That need motivated the team to conduct a phase 3 clinical trial, funded by GlaxoSmithKline, to evaluate three distinct treatment regimens: two daily doses of the intravenous antiviral drug zanamavir, at either 300 mg or 600 mg, compared with the current standard-of-care, 75 mg of the FDA-approved oral antiviral drug oseltamivir (brand name Tamiflu), twice a day.
Designed as a randomized, double-blind study, the trial ran from January 2011 to February 2015 and enrolled 626 patients worldwide. The researchers’ analyzed how long it took patients to respond to the different treatments, reflected both in improved vital signs and discharge from the hospital. Marty says studies such as his can be complicated by a number of factors, not least of which is the degree of illness among study participants.
Still, the trial’s results hewed to researchers’ expectations. For patients who can take medications orally or intravenously, both drugs performed similarly. Although the trial findings are not considered statistically significant, it appears that intravenous zanamavir can lead to more rapid improvement in severely ill patients, particularly those in the Medical Intensive Care Unit (MICU) or on assisted ventilation. Both zanamavir doses seemed to perform similarly, though there were hints that the higher dose (600 mg) may be associated with slightly faster response times and a decreased likelihood of drug resistance.
Marty stresses that these latter zanamavir findings lack the statistical power needed to substantiate the claim that the drug works better than oseltamavir. Nevertheless, as he and his colleagues write in their recent paper: “Our data suggest that intravenous zanamivir could be a potentially valuable intravenous treatment option for patients admitted to hospital with severe influenza infection.”
Paper cited: Marty FM et al. “Intravenous zanamivir or oral oseltamivir for hospitalized patients with influenza: an international, randomized, double-blind, double-dummy, phase 3 trial.” Lancet Respiratory Medicine DOI: 10.1016/S2213-2600(16)30435-0