A Snapshot of Science at Mass General: A New Approach to Targeted Cancer Treatments, Identifying Genes that Help Protect the Gut and Much More!

We wanted to share some recent Massachusetts General Hospital research that has been published in high impact, top-tier journals. This is just a small snapshot of the incredible research that takes place at Mass General each day — there’s lots more to find on the Mass General website!


Cognitive Decline, Tau and β-Amyloid in Healthy Older Adults
(Summary submitted by Rachel Buckley, PhD, and Rebecca Amariglio, PhD, both of the Martinos Center for Biomedical Imaging)

We published findings from the Harvard Aging Brain Study (Department of Neurology, Massachusetts General Hospital) investigating the link between subjective memory complaints (when a patient reports a worsening of their thinking abilities, including memory) and Alzheimer’s disease pathology in individuals who are otherwise cognitively normal. We found that increasing memory complaints were linked with greater amounts of tau in the brain, a naturally occurring protein that is associated with neuron loss in Alzheimer’s disease. We posit that memory complaints are a very early marker of disease, as they relate to tau build up before clinical tests can detect memory impairment.

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global β-Amyloid Burden
Buckley RF, Hanseeuw B, Schultz AP, Vannini P, Aghjayan SL, Properzi MJ, [et al.] Amariglio RE
Published in JAMA Neurology on October 2, 2017


New Approach to Targeted Cancer Treatment 
(Summary submitted by Conor L. Evans, PhD, of the Wellman Center for Photomedicine)

We have created a promising new light-activated, cancer-targeting therapeutic. Cancer drugs often cannot reach every cell in a tumor, leaving behind cells that can become resistant to treatment. At the same time, these drugs can cause unwanted systemic problems, such as weight and hair loss, elsewhere in the patient’s body. Our therapeutic was built to diffuse throughout tumors, target cancer cells, and kill these cells only when activated by light to avoid unwanted and burdensome side effects. We hope that this approach could one day find use in the fight against treatment-resistant cancers, like breast and lung.

An Integrin-Targeted, Highly Diffusive Construct for Photodynamic Therapy
Klein OJ, Yuan H, Nowell NH, Kaittanis C, Josephson L, Evans CL
Published in Scientific Reports on October 17, 2017


Identifying Genes that Help Protect the Gut 
(Summary submitted by Javier Elbio Irazoqui, PhD, formerly of the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease)

The intestinal epithelium is a single layer of cells that protects the gut from environmental insult. Defects in this layer are linked to many diseases, including inflammatory bowel disease. Despite its critical importance, very little is known about the genes in the epithelium involved in this function. We found that transcription factor TFEB, a master regulator of lysosomal gene expression, provides a protective effect, and this function is mediated by expression of apolipoprotein A1, the major constituent of HDL, aka “good” cholesterol. Our findings suggest that enhancement of TFEB activity in the intestinal epithelium could be a therapeutic approach to enhance Apolipoprotein A1 expression for the treatment of inflammatory bowel disease.

Transcription Factor TFEB Cell-Autonomously Modulates Susceptibility to Intestinal Epithelial Cell Injury In Vivo
Murano T, Najibi M, Paulus GLC, Adiliaghdam F, Valencia-Guerrero A, Selig M, [et al.] Xavier RJ, Lassen KG, Irazoqui JE
Published in Scientific Reports on October 24, 2017


Patient Resistance to Immune Checkpoint Blockade Therapies
(Summary submitted by Nir Hacohen, PhD, of the Cancer Center)

Cancer therapy has been transformed in the last few years by immune-based therapies, called ‘checkpoint blockade’ therapies. An important question is why some people respond and others do not respond to this therapy. By analyzing the DNA of tumors from patients who developed resistance to checkpoint therapy, we found changes in the DNA of a key gene that is critical for tumors to be detected by the immune system. In this way, the tumor has learned how to hide from the immunotherapy. Knowing this will help us decide which patients would benefit from immune therapy. Finding ways to make these resistant tumors visible to the immune system is an important goal for the coming years.

Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation
Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, [et al.] Flaherty KT, Sullivan RJ, Hacohen N
Published in Nature Communications on October 26, 2017

Researchers Use Machine Learning to Improve Breast Cancer Screening Techniques

Imagine enduring a painful, expensive and scar-inducing surgery—only to find out afterwards that it wasn’t necessary.

This is the situation for many women with high-risk breast lesions—areas of tissue that appear suspicious on a mammogram and have abnormal but not cancerous cells when tested by needle biopsy. Following surgical removal, 90% of these lesions end up being benign.

A change in the standard of care could be on the horizon thanks to researchers at Massachusetts General Hospital and MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) who have found a more precise and less invasive way to separate harmful lesions from benign ones.

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From left: Manisha Bahl, director of the Massachusetts General Hospital Breast Imaging Fellowship Program; MIT Professor Regina Barzilay; and Constance Lehman, chief of the Breast Imaging Division at MGH’s Department of Radiology. Photo courtesy of MIT News

“The decision about whether or not to proceed to surgery is challenging, and the tendency is to aggressively treat these lesions [and remove them],” said Manisha Bahl, MD, Director of the Breast Imaging Fellowship Program at Mass General, in a recent interview.

Bahl, along with a team of researchers, have harnessed the power of artificial intelligence (AI) to develop a more accurate and less invasive screening method for high-risk lesions. When tested, the machine correctly diagnosed 97 percent of 335 high-risk breast lesions as malignant and reduced the number of benign surgeries by more than 30 percent compared to existing approaches. These results were recently published in Radiology.

The team developed an AI system that uses machine learning to distinguish between high-risk lesions that need to be surgically removed from those that should just be watched over time. They created this model by feeding it data on over 600 high-risk lesions, including information on the patient’s demographics and pathology reports, and then tasked it to identify patterns among the different data elements.

Through a process called deep learning, the machine uses the data to create an algorithm that can be used to predict which high-risk lesions should be surgically removed. This process differs from traditional software programming in that the researchers did not give the machine the formula for diagnosis, but rather let it analyze the data and identify patterns on its own.

“To our knowledge, this is the first study to apply machine learning to the task of distinguishing high-risk lesions that need surgery from those that don’t,” said collaborator Constance Lehman, MD, PhD, chief of the Breast Imaging Division at Mass General’s Department of Radiology, in a recent interview. “We believe this could support women to make more informed decisions about their treatment and that we could provide more targeted approaches to health care in general.”

Lehman says Mass General radiologists will begin incorporating the model into their clinical practice over the next year.

Weekend Links

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We’ve hand-picked a mix of Massachusetts General Hospital and other research-related news and stories for your weekend reading enjoyment:

Creative Minds: A New Way to Look at Cancer

Better Patient-Provider Communication Needed for Obesity Care

Eugenics 2.0: We’re at the Dawn of Choosing Embryos by Health, Height, and More

6 Speaking Tips for Scientists and Engineers (editor’s note: Melissa Marshall, featured in this article, recently spoke to Mass General clinicians about how to effectively present scientific work. We were so impressed by her talk that we wanted to introduce her to our readers) 

Looking for a great book for the young scientist in your life? The long list of 2018 AAAS/Subaru SB&F (Science Books and Films) Prize winners for Excellence in Science Books has been released. Prizes are awarded each year in the following categories:

  • Children’s Science Picture Books
  • Middle Grade Science Books
  • Young Adult Science Books
  • Hands on Science Books

See the full list here

 

Top photo: courtesy of Tim Lahan, MIT Technology Review

Liquid Biopsies Give Clues on When and Why Cancer Treatments Lose their Efficacy

With the advent of targeted cancer therapies and immunotherapy, and with new CAR-T therapies on the way, more cancer patients are living with their disease. However, many cancer patients find that their therapies have limitations and are faced with the potential of disease progression. Often, those who initially respond to a course of treatment eventually develop a resistance to these medications, forcing oncologists to switch therapeutic course.

Currently, one of the ways to know when a treatment stops working is by taking a biopsy of the tumor. These surgical procedures are invasive and costly, and because they can only be done sporadically, valuable treatment time can be lost. Additionally, some cancer patients may be too physically fragile for surgery.

Researchers have been looking for a safe, fast, less expensive and more accurate way to identify early signs of treatment resistance, while also searching for new insights into the genetic changes that occur within tumor cells to drive this resistance. This way, new therapy plans can be considered sooner, giving the patient a better chance for their best possible outcome.

A new diagnostic blood test known as a liquid biopsy has shown early promise in addressing these needs. Now researchers, including a team from the Mass General Cancer Center, are providing confirmatory data that may help to move liquid biopsies into clinical practice. These data were presented at the ESMO 19th World Congress on Gastrointestinal Cancer.

How do liquid biopsies work?

A liquid biopsy is a diagnostic test that detects circulating tumor DNA (ctDNA), which is genetic material released by dying tumor cells that flows through the bloodstream. These tests are less invasive than a tissue biopsy and therefore can be given with greater frequency.

Regularly monitoring ctDNA levels in a patient’s bloodstream can provide early notice when a treatment is no longer working. It could also offer a more complete picture of the genetic changes in tumor cells that are driving the resistance to treatment, which could guide new treatment courses.

Liquid biopsies and gastrointestinal cancer study

Mass General Cancer Center investigators followed nearly 40 patients with various forms of gastrointestinal cancers who had experienced initial success with targeted therapies, but then began to show signs of treatment resistance. Liquid biopsies were taken when the patients’ disease started to progress to analyze the levels and genetic profile of ctDNA in their bloodstream. Researchers identified one or more mutations or mechanisms that contributed to treatment resistance in 31 of the 40 patients. Fourteen of these patients had multiple mutations that contributed to resistance.

In patients who had both solid tissue biopsies and the liquid biopsies, the researchers found that in two-thirds of the cases, the liquid biopsies revealed the presence of more genetic mutations than tissue biopsies alone.

“Identifying what specific mutations are responsible for treatment resistance is very important in helping clinicians choosing what treatment path a patient should try next, whether it be another drug or perhaps radiation,” said study investigator Aparna Parikh, MD, from the Mass General Cancer Center.

“We have shown this approach is feasible across many different GI cancers,” she noted. “The next step is to study how best to use this new technology in daily practice. It’s important for clinicians to understand its utility as well as its limitations.”

Research Awards and Honors: September 2017

Massachusetts General Hospital’s talented and dedicated researchers are working to push the boundaries of science and medicine every day. In this series we highlight a few individuals who have recently received awards or honors for their achievements:

Aguirre

Aaron Aguirre, MD, PhD, of the Cardiology Division and the Center for Systems Biology, has received a 2017 Physician/Scientist Development Award for “Morphology and Dynamic Functions of Pericytes in the Heart.” Aguirre’s project will use state-of-the-art microscopy techniques to better understand the role of pericytes—unique cells that line the outer walls of the smallest blood vessels in the heart. Funding for the Physician/Scientist Development Awards is provided by the Executive Committee on Research along with the Center for Diversity and Inclusion.

“I am grateful for the research support provided by the MGH Physician Scientist Development Award. It will allow me to expand my current research into a new direction and to generate critical preliminary data necessary for future grant applications.”

 

Chung

David Chung, MD, PhD, attending neurointensivist in the Neurology Department, has been awarded the Timothy P. Susco Chair of Research and the Andrew David Heitman Foundation Chair of Research from The Brain Aneurysm Foundation for his work, “Impact of Spreading Depolarizations and Subarachnoid Hemorrhage on Brain Connectivity.” He is one of 14 awardees, given to those whose work is impacting a disease that affects one in 50 people in the United States, often leading to death or lifelong disability.

My immediate reaction to receiving this award was gratitude towards my mentors in the Department of Neurology at MGH: Cenk Ayata, Jonathan Rosand, Guy Rordorf, and Leigh Hochberg. Without their support, this work would not be possible. A major question in Neurocritical Care is how to prevent poor outcome after a ruptured brain aneurysm. Even when we successfully repair the aneurysm, many patients will develop a syndrome of progressive brain damage for unknown reasons. This award will enable us to examine unexplored causes of brain damage and poor outcome with the goal of improving quality of life in survivors of the disease.”

 

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Julie Levison, MD, MPhil, MPH, of the Division of General Internal Medicine, has received a CFAR ADELANTE Award from the National Institutes of Health, the Office of AIDS Research and the NIH-funded Centers for AIDS Research to support new  investigators working on HIV research in Latinos. Hispanic/Latino populations in the U.S. currently bear a disproportionate burden of the HIV/AIDS epidemic. The ADELANTE team is composed of Dr. Levison (principle investigator), Dr. Margarita Alegría, chief MGH Disparities Research Unit, and Carmen Rios, Respite Case Manager at the Barbara McGinnis House.

“The ADELANTE award is a special type of research award because it recognizes the value of community-academic collaborations in overcoming disparities in HIV outcomes in Latino populations. In this study, we will use qualitative research to solicit the needs and priorities of HIV-infected Latino migrants with substance use disorders or who report male-to-male sex and we will use that feedback to tailor and evaluate a community-based intervention we have developed for HIV-infected Latinos with inconsistent HIV primary care attendance.”

 

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Fatima Cody Stanford, MD, MPH, MPA, adult and pediatric obesity medicine physician of the MGH Weight Center, Department of Medicine-Gastroenterology and Department of Pediatrics-Endocrinology, has received a 2017 Physician-Scientist Development Award from the MGH Center for Diversity and Inclusion for “Exploring Referral Patterns and Shared Decision Making Regarding Weight Loss Surgery in Adolescents and Young Adults with Moderate to Severe Obesity.” Funding for the Physician/Scientist Development Awards is provided by the Executive Committee on Research in conjunction with the Center for Diversity and Inclusion. Stanford also has been selected to the inaugural class of Emory University Alumni Association’s “40 Under Forty,” a selected group of outstanding young alumni with impressive track records who are “go-to” leaders.

“I am delighted to be the recipient of the MGH Physician Scientist Development award in partnership with the MGH Center for Diversity and Inclusion and ECOR. I believe that we are just at the beginning of discerning issues associated with addressing obesity in the pediatric and adult populations. This award allows me to ascertain information about shared decision making in adolescents and young adults with moderate to severe obesity in which weight loss surgery might be utilized to help them achieve a healthy weight. To our knowledge, no one has investigated the use of shared decision making regarding weight loss surgery in young people. This awards allows us to do just that.”

 

Temel GreerJennifer Temel, MD, director of the Cancer Outcomes Research Program and Hostetter MGH Research Scholar, along with Joseph Greer, PhD, program director of the Center for Psychiatric Oncology & Behavioral Sciences, have received a research funding award from the Patient-Centered Outcomes Research Institute (PCORI) for their research “Comparative Effectiveness of Early Integrated Telehealth Versus In-Person Palliative Care for Patients with Advanced Lung Cancer.” The new awards were given to those whose work specifically focuses on community-based palliative care delivery. The goal of this project is to determine if telehealth is an effective, patient-centered, and accessible delivery modality for early palliative care.

“We are overjoyed to receive this research award from PCORI. By testing novel models of care using telemedicine, we hope to demonstrate that greater numbers of patients with advanced cancer and their families can access and benefit from essential palliative care services closer to the time of diagnosis.”

 

Whetstine.jpgJohnathan Whetstine, PhD, of the MGH Cancer Center and Tepper Family MGH Research Scholar, has received a Lung Cancer Discovery Award from the American Lung Association. This award supports investigators at any level of research experience focusing on novel treatments or a cure for lung cancer. His goal is to use studies about histone modifiers to provide insights into tumor heterogeneity and emerging drug resistance so that better molecular diagnostics, epigenetic therapeutic molecules, or use of novel therapeutic combinations can be achieved in cancer treatment.

“We are very excited to receive this award from the ALA.  This support allows my group to continue to expand our lung cancer research program in the area of tumor heterogeneity and drug resistance. Most importantly, these resources allow us the opportunity to explore novel regulatory pathways driving heterogeneity and copy gains of regions affiliated with resistant lung cancer, which provides insights into novel diagnostics and therapeutic opportunities in this hard-to-treat cancer.”

 

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Alik Widge, MD, PhD, director of the Translational NeuroEngineering Laboratory, Division of Neurotherapeutics, has received the 2017 One Mind/Janssen Rising Star Translational Research Award from the One Mind Institute and Janssen Research & Development, LLC. This award identifies and funds pivotal, innovative research on the causes of and cures for brain disorders. Toward boosting the recovery of patients with illnesses such as schizophrenia, major depression or obsessive-compulsive disorder, Widge proposes to identify precisely the brain circuits that govern the inflexibility of thinking common among patients with such illnesses, and to test whether neurostimulation of these circuits could improve mental flexibility.

“I was very excited about the Rising Star award, for two reasons. First, it brings much-needed seed funding to our lab for an unconventional but possibly high-yield project. We have found that electrical brain stimulation in humans can improve mental flexibility — the ability to “take the road less traveled by” and explore new behavior strategies. That ability is impaired in many mental illnesses. Our problem is that we don’t yet know how the electrical stimulation improves flexibility. The Rising Star award will let us set up animal experiments to identify the circuit basis of the effect, findings we could then translate back into humans. 

Second, this is a really important award in psychiatric research. It’s brought our lab’s other work into the spotlight, which will help those projects progress. I’m grateful both to the OneMind Institute for the award and to the MGH team that helped me get the preliminary data that made it possible.”

A Snapshot of Science: Detection of Alzheimer’s Disease, Development of Type 1 Diabetes, and Much More

We wanted to share some recent Mass General research that has been published in high impact, top-tier journals. This is just a small snapshot of the incredible research that takes place at Mass General each day — there’s lots more to find at massgeneral.org/research/news!

 

DETECTING AND TREATING STIFF TUMORS
Published in Nature Scientific Reports on August 14, 2017
(Summary submitted by Peter Caravan, PhD, of the Martinos Center for Biomedical Imaging)

In tumors, cancer cells are surrounded by a collection of proteins, enzymes, sugars, lipids, and minerals called the extracellular matrix (ECM). Many cancers have a fibrotic ECM, making the tumor stiff and preventing delivery of anti-cancer drugs. The presence of a fibrotic ECM is often associated with poor prognosis. We developed a new MRI method to detect tumor fibrosis non-invasively, and studied its effect in a mouse model of pancreatic cancer. The potential impact of this work is a new tool to stage the aggressiveness of tumors, guide treatment planning, and monitor the effectiveness of new tumor ECM altering treatments.

 

IMPACT OF BLOOD AND URINE FILTRATION IN LEAKY KIDNEY FILTERS
Published in Scientific Reports on August 16, 2017
(Summary submitted by Hua A. Jenny Lu, MD, PhD, of the Nephrology Division)

One major function of the kidney is filtering blood through an intricate “glomerular filter”. Disruption of any components of this highly sophisticated and dynamic filter’s structure leads to proteinuria (protein in the urine), a condition frequently seen in diabetic nephropathy and many other glomerular diseases. How blood filters though the glomerular filter and how proteinuria develops when the filter becomes leaky has not been well understood. This paper reports the application of a novel and powerful scanning microscopy technology, the Helium Ion microscopy (HIM) to identify previously unrecognized ultrastructural abnormalities of proteinuric glomerulopathy in animals. These newly discovered abnormalities provide important insight into the molecular and cellular mechanism underlying proteinuria kidney diseases.

 

OBSERVING THE DEVELOPMENT OF TYPE 1 DIABETES
Published in PNAS on August 24, 2017
(Summary submitted by Ralph Weissleder, MD, PhD, Director of the Center for Systems Biology)

Type 1 diabetes (T1D) is an autoimmune disease where insulin-producing cells are destroyed. Inflammation in islets of human patients has been hard to evaluate, given the challenging access to material. Now, our research team has discovered how the different cellular players interact. We created new reporter mice and new imaging agents where cells of interest (lymphocytes, macrophages, dendritic cells, beta cells) are fluorescent and can be observed by imaging. We were able to observe the intricate “dance” of different immune cells interacting with each other as diabetes develops. Throughout the process, Tregs (a unique type of T-lymphocyte) control the activation of many cell types. The “dynamic geography” of events uncovered here provide important clues to immunoregulation that underlies diabetes development.

 

NON-INVASIVE MEASUREMENT OF BRAIN ACTIVITY AND MEMORY ENCODING
Published in Scientific Reports on August 25, 2017
(Summary submitted by Meryem Yucel, PhD, of the Martinos Center for Biomedical Imaging)

Alzheimer’s disease (AD) is the most frequent cause of severe memory loss in the elderly. Early detection of AD is the key to preventing, slowing or stopping the disease. Near-infrared spectroscopy (NIRS) is a non-invasive neuroimaging technique capable of monitoring brain activation. Here, we investigated the utility of fNIRS in measuring the brain activity of healthy adults during memory encoding and retrieval under a face-name paired-associate learning task. Their study demonstrates that fNIRS can robustly measure memory encoding and retrieval-related brain activity. Future work will include similar measurements in populations with progressing memory deficits. Their approach, if successful, will introduce a non-invasive, inexpensive and easily accessible tool for identifying early stages of AD.

Research Awards and Honors: August 2017

Massachusetts General Hospital’s talented and dedicated researchers are working to push the boundaries of science and medicine every day. In this series we highlight a few individuals who have recently received awards or honors for their achievements:

Banister.jpg

Gaurdia Banister, RN, PhD, NEA-BC, FAAN, executive director of the MGH Institute for Patient Care and director of the Yvonne L. Munn Center for Nursing Research, has been named the inaugural incumbent of the Connell-Jones Endowed Chair in Nursing and Patient Care Research. The Department of Nursing and Patient Care celebrated the establishment of the chair June 26 at the Paul S. Russell Museum of Medical History and Innovation. The establishment of the chair is the second endowed chair in the Department of Nursing and Patient Care and will help advance the nursing profession and patient-and-family-centered-care through a diverse range of research programs. (Pictured from left: Britain Nicholson, MD, senior vice president for Development; Margot C. Connell, the donor; Banister; and Jeanette Ives Erickson, RN, DNP, NEA-BC, FAAN, chief nurse and senior vice president of Patient Care Services)

“It is impossible to put into words how honored and humbled I feel to have been chosen as the Connell- Jones Endowed Chair for Nursing and Patient Care Research. Advancing nursing knowledge and using that knowledge to deliver exemplary patient care is extremely important to me. One of my research interests is understanding and eliminating the barriers that compromise African American nurses and nursing students from achieving their full potential as clinicians and nurse leaders. Although minorities constitute 37 percent of the country’s population, minority nurses make up only 16.8 percent of the total nurse population. The disparity is even greater in leadership positions. Lack of access to health care providers who can deliver culturally and linguistically appropriate care can adversely contribute to existing health disparities. Improving the diversity of the nursing profession to meet the needs of patients and their families and eliminating these disparities are essential.”

GatchelJennifer Gatchel, MD, PhD, Mass General psychiatrist, has received the Outstanding Emerging Researcher Award from the BrightFocus Foundation. She presented her latest research during a June 8 reception and dinner event at the Andrew W. Mellon Auditorium in Washington, D.C.

“Improving the lives of older adult patients with depression, anxiety, and changes in memory and thinking is my central motivation as a Geriatric Psychiatrist and physician scientist. Towards this goal, my research at MGH focuses on better understanding the earliest mood and behavioral symptoms in older adults at risk for Alzheimer’s disease.  I am doing this by using a combination of clinical measures and novel brain imaging technology that enables visualization of disease-associated proteins in the brains of living older adults. The ultimate goal of my research is to translate this knowledge into ways to better prevent and treat Alzheimer’s disease and to promote healthy brain aging in vulnerable older adults.

I was thrilled and extremely honored to be recognized as the Outstanding Emerging Research Scientist by the Bright Focus Foundation in recognition of my work. This award has provided critical support to me as junior investigator.  It has helped make it possible for me to begin to develop an area of important research to benefit our aging population and their families—central to my mission as a Geriatric Psychiatrist.”

Hata.jpgAaron Hata, MD, PhD, of the Mass General Cancer Center, has received a 2017 Clinical Scientist Development Award from the Doris Duke Charitable Foundation. The awardees distinguish themselves by the rigor of their research endeavors and their commitment to future excellence as independent clinical researchers in the biomedical field. The award makes possible for recipients to dedicate 75 percent of their professional time to clinical research at a time when they are facing competing priorities as both researcher and clinical care provider.

“My research focuses on understanding how drug resistance develops in lung cancer patients whose tumors have mutations in the EGFR gene. Over the past decade, a number of new “EGFR-targeted” drugs have been developed that are able to initially shrink these tumors, however, they invariably stop working and relapse occurs. We are trying to understand how some cells are able to persist during treatment and ultimately grow back.

I am thrilled to receive a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. This award will enable us to generate a high-resolution understanding of how individual tumor cells evolve in patients over the course of treatment. Ultimately our goal is to develop new therapies that can target these surviving cells early before drug resistance is able to develop.”

LiangSteven H. Liang, PhD, of the Department of Radiology, has received the 2017 Early Career Award in Chemistry of Drug Abuse and Addiction from the National Institute on Drug Abuse. The award is to facilitate basic chemistry research applied to drug abuse and addiction.

“My scientific interests are radiochemistry, nuclear medicine and positron emission tomography (PET) imaging – a key and fast-growing ground for translational science and precision medicine in patient care. I have developed several novel radiolabeling technologies and PET imaging biomarkers to access important biological targets that were previously inaccessible.

As the recipient of 2017 Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM award) from NIH, my team will develop and translate new PET biomarkers for imaging an important biological enzyme, monoacylglycerol lipase (MAGL) in the endocannabinoid system. MAGL inhibition has recently emerged as a therapeutic strategy to treat drug addiction, substance-use disorders as well as neurodegenerative diseases including Alzheimer’s disease. I am thankful to the NIH for this support which will help us develop an imaging tool which we hope can be progressed for translational human imaging studies and used to investigate underlying mechanisms of MAGL-linked diseases.”

Pittet.jpgMikael Pittet, PhD, Samana Cay MGH Research Scholar, of the Center for Systems Biology, has received the inaugural MGH Principal Investigator Mentoring Award. This award is given to a principal investigator who has contributed to the success of PhD graduate students at Mass General.

Mikael Pittet’s laboratory at Center for Systems Biology studies the role of the immune system in cancer. Established in 2007, the Pittet laboratory has made several discoveries, which indicate new ways to successfully treat cancer with immunotherapy. Mikael also directs the Cancer Immunology Program at CSB and currently mentors three PhD students.

“I am greatly honored to be the recipient of this inaugural mentoring award. I am lucky to work with the most terrific students, and grateful about the fact that they nominated me. Thank you, team!”

SippoDorothy Sippo, MD, MPH, a Radiologist in Breast Imaging, has been awarded an Association of University Radiologists GE Radiology Research Academic Fellowship Award. The fellowships help radiologists by strengthening the research interest of radiologist-investigators by broadening their opportunities for continuing scholarship and by fostering original clinical and health services research in technology assessment, health and economic outcome methods and decision analysis.

“My project entitled, ‘Development and Assessment of an Automated Outcomes Feedback Application to Optimize Radiologist Performance Using Digital Tomosynthesis with Mammography,’ aims to automatically provide mammographers with feedback about the outcomes of their patients (whether or not breast cancer is ultimately diagnosed). The goal of this feedback is to enable continuous learning integrated into the patient care setting to aid mammographers in providing the highest quality care.

It is thanks to the strength and diversity of our research team, bringing together mentors and collaborators from the MGH Radiology Department, Harvard Medical and Public Health Schools that we have been able to formulate this informatics feedback intervention. It is being built into the electronic system breast imagers use for reporting. The GERRAF will support my study of radiologists using the feedback application for one year, with in-depth quantitative and qualitative analyses. My goal is for it to be an important stepping stone to future independent research funding.”

New Study Shows Lymph Nodes Aren’t Always to Blame for Cancer’s Progression

In a case of mistaken identity, researchers at Massachusetts General Hospital have found that lymph nodes are not always responsible for cancer’s deadly spread to other organs. These results buck many preconceived notions about lymph nodes’ role in cancer development and suggest a new pattern for the progression of certain types of cancer.

Doctors recognize that patients whose cancer spreads (metastasizes) from the original tumor to the surrounding lymph nodes have a worse prognosis than patients whose lymph nodes are cancer-free. This observation has traditionally been explained by a progression model of primary tumor to nearby lymph nodes to other organs. However, no conclusive evidence for this model has existed so far.

In a new study, researchers from the Edwin L. Steele Laboratories for Tumor Biology in the Mass General Department of Radiation Oncology investigated the “family tree” of metastases in colorectal cancer. Contrary to the prevailing belief that the spread begins in the lymph nodes, they found that the cancer could spread to both the lymph nodes and the organs simultaneously. In their report in the July 7 issue of Science, the researchers describe finding that, for the majority of colorectal cancer patients in the study, organ metastases (also called distant metastases) originated directly from the primary tumor, independent of any lymph node metastases.

Lymph node graphic 1

Lymph node graphic 2

“We now suspect that lymph node metastases simply indicate the presence of an aggressive primary tumor, rather than being directly responsible for the formation of distant metastases,” says lead and corresponding author Kamila Naxerova, PhD, Research Fellow at the Steele Labs.

The researchers analyzed more than 200 tissue samples of primary tumors, lymph node metastases and distant metastases from 17 patients with colorectal cancer. Samples from 35 percent of these patients followed the traditional progression model. In these samples, both lymph node and distant metastases came from the same cell type in the primary tumor, indicating that the cancer had spread from the primary tumor to the lymph nodes and then to other organs.

However, in 65 percent of patients, researchers found that cell types in lymph node and distant metastases were different and matched different cell types within the primary tumor, indicating independent origins for these metastasis types.

Their results suggest that although cancer progression can follow the traditional model described above, there is also a second distinct pattern of metastatic spread.

“These findings fill an important gap in our knowledge of metastatic disease evolution and have the potential to guide improvements in the clinical management of lymph node metastases,” says Naxerova.

The research team is now following up with a larger cohort of patients to confirm whether survival differences exist between patients with a traditional progression pattern vs the second progression pattern.

Rakesh K. Jain, PhD, Director of the Steele Labs, was senior author of this paper.

Could a Technique Echoing an Ancient Greek Military Strategy Point the Way to More Effective Cancer Treatments?

Trojan horse

According to Greek legend, the Trojan horse was a wooden structure built by Greek soldiers and presented to the Trojans as a gift after a long and fruitless siege of the city during the Trojan War. When the Trojans brought the gift horse within their city walls, the Greek soldiers who were hidden inside crept out under the cover of night and launched a deadly surprise attack. Historians continue to debate how much of the tale is based in fact and how much in myth.

At Massachusetts General Hospital, a real-life Trojan horse scenario that takes place on the nanoscale level could provide a way to sneak cancer drugs into fortified tumor cells so the drugs can attack from within.

Here are five things to know about a new study from the Mass General Center for Systems Biology:

    1. 1. Think of nanoparticles as the Trojan horses of cancer therapy. These tiny molecules (typically between 20 and 100 nanometers in size) are increasingly being used to transport drugs to a specific target in the body. The ability that researchers have to easily change the size and surface characteristics of the nanoparticles and control the time and location of the drug’s release makes them ideal for drug delivery systems.
    1. 2. Nanoparticles are small enough to carry the drugs (the Greek soldiers) through the body and can protect the encapsulated drug from toxic substances in the bloodstream that are used in infusion chemotherapy. However, in clinical practice, getting these nanoencapsulated drugs into patients’ tumors has been challenging—tumor blood vessels are difficult to break through, which limits the passage of any drugs from the bloodstream into tumor cells. Although it’s usually beneficial for blood vessels to maintain barrier function, their tough exteriors are a disadvantage in cancer therapies.
    1. 3. A 2015 study by Miles Miller, PhD, of the Center for Systems Biology, and his colleagues showed that tumor-associated macrophages — immune cells found around tumors that are in charge of engulfing pathogens, foreign materials and dead cells — can improve delivery of nanoparticle-based therapies to tumor cells. They also found that radiation therapy made it easier for substances to pass through tumor blood vessels. But exactly how these effects are produced and how they could be combined to enhance nanomedicine delivery was not known. Answering those questions was the goal of the current study.
    1. 4. Miller and his team found that macrophages can be prompted to act like Trojans, helping to bring the drugs inside the tumor, if the tumors are treated with radiation prior to administering the drugs. In the same way that a siege weakens the resistance of a city, the radiation weakens the blood vessels within the tumor. It also increases the number of macrophages attracted to tumor blood vessels which, in turn, pick up the drug-laden nanoparticles and bring them into the tumor. The sudden influx of macrophages into the weakened walls of the blood vessels causes many of the vessels to burst, thus flooding the tumor cells with the drug-laden nanoparticles and improving drug delivery by 600 percent.
    1. 5. “Finding that this combination of radiation and nanomedicine leads to synergistic tumor eradication in the laboratory provides motivation for clinical trials that combine tumor rewiring using radiation therapy with nanomedicine,” says Miller, who was lead author of the study. “Most of the treatments and nanomedicines employed in this study are FDA approved for cancer treatment, so this combination treatment strategy could be tested in clinical trials relatively quickly.”

     

    Radiation & Macrophages

  1. Ralph Weissleder, MD, PhD, Director of the MGH Center for Systems Biology is senior author of the Science Translational Medicine paper.

Mass General Researchers Investigate the ‘Big Eaters’ of the Immune System: #MacrophageMonday

macrophage
Macrophage in the body. Credit: Cell Press

Macrophages serve a vital function in the body’s immune system— these white blood cells are in charge of engulfing pathogens, foreign materials and dead cells.

Two new studies from Massachusetts General Hospital researchers have identified two unexpected roles that macrophages play in the body. In the heart, macrophages play a beneficial role, helping heart muscle cells maintain a steady heartbeat. When it comes to fighting cancer, however, macrophages appear to play a detrimental role by interfering with immunotherapy treatments.

Macrophages prove helpful in maintaining a steady heart beat

Researchers have known for decades that macrophages can be found in high numbers around inflamed or diseased hearts to help heal damaged tissue. However, macrophages’ function in healthy hearts has remained a mystery. A new study from Matthias Nahrendorf, MD, PhD, Director of the Mouse Imaging Program at the Center for Systems Biology at Mass General, suggests that macrophages help the heart function properly and keep its rhythm.

The research began when an MRI and an electrocardiogram of a mouse heart that was genetically engineered to lack macrophages revealed that it was beating too slowly. Comparative tests of a healthy mouse heart revealed that large quantities of macrophages could be found at the atrioventricular node, which passes electricity from the atria to the ventricles of the heart.

Cardio macrophage
Heart cells (red) and macrophages (green) in a human atrioventricular node.
Credit: Maarten Hulsmans & Matthias Nahrendorf

Nahrendorf and his team found that these congregated macrophages lend a helping hand by facilitating the conduction process — they prepare heart cells for continuous bursts of electricity by creating gap junctions to connect the cells to each other so the electrical current that regulates heartbeat can flow through smoothly.

This study is a giant step forward in understanding how the heart works and communicates with the body’s cells. Nahrendorf plans to continue investigating the relationship between macrophages and conduction in the heart to answer more unresolved questions.

When macrophages rebel

Another recent study from Mikael Pittet, PhD, of the Center for Systems Biology at Mass General, suggests that macrophages aren’t always the good guys.

Using advanced imaging techniques, Pittet and colleagues were able to see how macrophages can render cancer immunotherapy drugs inactive in the body within moments of the drugs being administered.

Cancer macrophage
A macrophage (red) removing immunotheraphy drugs (yellow) from a T-cell (blue).  
Credit: Center for Systems Biology, MGH

Immunotherapy drugs are designed to bind to T-cells in the body, another type of white blood cell that relies on chemical signals to identify and kill harmful cells in the body.

One way that tumor cells avoid detection and destruction by these T-cells is by adopting a chemical signal that tumor cells use to inhibit T cells from attacking them, essentially rendering themselves “invisible” to the immune system. Immunotherapy drugs are designed to override this process by binding to T cells at the receptors that typically receive this “all is well” signal, thus making the tumor cells vulnerable to attack.

However, as Pittet and his colleagues observed, when immunotherapy drugs were administered, macrophages would clear away the drugs from the T-cells within minutes of the treatment, essentially making the treatment ineffective. Pittet’s observation also explains why this type of promising immunotherapy hasn’t been proven widely successful (the treatment can work extremely well, but only in a minority of patients).

The good news is that Pittet also determined the chemical pathway that was driving this macrophage response, and identified potential strategies for blocking that pathway in mouse models. More research is needed to determine whether similar strategies improve the results of immune checkpoint blockade in human patients.