Updated on Mar 7, 2023 | Featured, Research
More than 50 years after the United States formally declared war on cancer, what is the prognosis for innovative cancer research and care?
Two Mount Sinai leaders in cancer care and research, Ramon Parsons, MD, PhD, Director of The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and Cardinale Smith, MD, PhD, Vice President, Cancer Clinical Services for the Mount Sinai Health System, offered their perspectives as part of a recent 92nd Street Y online event. You can watch the video here.
The two agreed on this overarching message: Tremendous progress has been made in unraveling the complex biology of cancer and targeting its many forms with advanced new medicines, particularly immunotherapies. But looming just as large are the challenges that remain in areas like overcoming resistance to these medicines, early detection of cancer through screening, and ensuring the equitable distribution of cancer care to diverse and disadvantaged populations.
Ramon Parsons, MD, PhD
“After 50 years we have a much more sophisticated understanding of how genes are altered in the cancer cell and how cancer cells reprogram the tumor microenvironment,” said Dr. Parsons, the Ward-Coleman Chair in Cancer Research. “And that has pushed the envelope in terms of our knowledge of the biology of cancer and, just as importantly, how we treat it. We’re seeing better outcomes for more and more of our patients and believe cancer rates will continue to come down because of treatments we didn’t have in the past, and more informed prevention.”
Dr. Smith, who is also Chief Medical Officer for the Tisch Cancer Hospital and a Professor of Medicine (Hematology and Medical Oncology), described the dramatic changes in cancer care and treatment, particularly in her specialized field of lung cancer.
“When I finished my fellowship training 12 years ago we had just two drugs for lung cancer, and now there are so many more,” she said. “Patients I treated as a fellow are still alive today thanks to clinical trials for new investigative drugs they were able to enroll in.”
Immunotherapies have carved out many of the greatest gains, while also raising some obstacles for the research community. Immunotherapy refers to treatments that use a person’s own immune system to fight cancer.
“The next frontier is determining which patients are going to have a long-term response to immunotherapy, and how do we overcome the resistance we so often see with these therapies,” said Dr. Parsons. “That’s the biology we still need to figure out, and to that end some of the research we’re most excited about is aimed at helping us better understand the switches in the immune system and how they can be regulated therapeutically.”
Two other areas of research where Dr. Parsons sees great promise are tumor suppressors, which are genes that regulate a cell during cell division, and liquid biopsies, which can detect through a simple blood test at the doctor’s office circulating tumor cells and tumor DNA.
With a strong background in tumor suppressors, he sees great advantage in being able to develop gene therapy or other innovative approaches to restore tumor suppressors, a natural part of the body’s defense mechanism that becomes altered or mutated in almost every type of cancer.
Liquid biopsies, still in early-stage development, could be another significant development. “This idea of being able to catch cancers before they are recognizable is going to ultimately move the needle in improving patient survival,” he said.
Cardinale Smith, MD, PhD
For Dr. Smith, early detection includes more aggressive screening by the health care providers.
“Uptake of lung cancer screening has been slow,” she said. “A lot of the work we’ve been doing at Mount Sinai is connecting with the community to understand what their needs are and how they prefer to partner with us. As a result, we’ve increased mammographies for women to detect breast cancer, and improved colorectal cancer screening for both men and women. Now we need to make the same kind of progress with lung cancer screening.”
She noted that as part of its outreach, Mount Sinai in April 2022 launched the Mount Sinai Robert F. Smith Mobile Prostate Cancer Screening Unit after noticing a high mortality rate for the disease in certain neighborhoods of New York City with a high Black male population. The purchase was funded by a $3.8 million donation from philanthropist Robert F. Smith. This successful effort between the Institute and the Department of Urology has been collecting blood samples to measure PSA levels and referring individuals for follow-up care when a problem is detected.
The nation’s war on cancer formally began with the National Cancer Act of 1971, which established the National Cancer Institute. As for the future of cancer care, Dr. Smith foresees patient care navigation and a palliative care workforce as movements with transformative potential.
Navigators with the ability to compassionately guide people through the often challenging cancer screening and treatment process would be an extremely beneficial allocation of resources, she maintains. So would development of specialized palliative care teams that could provide training and skills to oncologists and other clinicians, including nurses and advanced practice providers.
“We know that palliative care when combined with standard oncologic care can improve patients’ quality of life and mood by decreasing depression,” she said. “It also decreases unnecessary utilization of acute care, such as emergency room visits, hospitalizations, and readmission. Most importantly, it aligns cancer care with the goals and values of the patients, which all of us as clinicians need to hold as sacred in the years ahead.”
Updated on Aug 31, 2022 | Featured, Research, School
Jenneifer Chan, PhD, and Ian Maze, PhD
Jennifer Chan, PhD, whose work is vastly expanding knowledge about pregnancy, brain health, and stress, is the recipient of the 2022 Robin Chemers Neustein Postdoctoral Fellowship Award, established in 2010 to encourage and support female research scientists at the Icahn School of Medicine at Mount Sinai.
Recipients are senior postdoctoral scientists who intend to complete their training within two years, have demonstrated high-impact accomplishments in biomedical sciences, and exhibit the potential for an independent scientific career. Dr. Chan is the 23rd recipient of the award, created through a generous gift from Robin Chemers Neustein, JD, MBA, a former member of Mount Sinai’s Boards of Trustees.
Dr. Chan works in the laboratory of neurobiologist Ian S. Maze, PhD, in the Nash Family Department of Neuroscience. Dr. Maze, who was appointed as a Howard Hughes Medical Institute (HHMI) Investigator in 2021, is a Professor of Neuroscience, and Pharmacological Sciences, and the founding director of the Center for Neural Epigenome Engineering at Icahn Mount Sinai, the nation’s first center devoted exclusively to neuroepigenomic engineering.
Dr. Maze’s lab is focused on delineating the molecular and biochemical mechanisms of neuroepigenetic plasticity—changes in the underlying biochemical mechanisms that control whether genes are turned on or off within a given cell-type in the brain. This plasticity is important for allowing brain cells to appropriately respond to changing environments, which is critical for proper neurodevelopment—and which can cause disease when there is inappropriate tuning of gene expression.
Jennifer Chan, PhD
For example, aberrations in these processes can produce devastating neurological and psychiatric disorders, such as epilepsy, Parkinson’s disease, Alzheimer’s disease, substance use disorders, and major depressive disorders. These aberrations can occur during brain development or throughout life due to such factors as environmental toxins, physical trauma, chronic stress, and exposure to drugs of abuse.
The Maze lab—through the integration of technologically innovative and sophisticated new methodologies in chemical biology, proteomics, protein biochemistry/engineering, and structural biology—is advancing the understanding of these processes and working toward the development of targeted neurotherapeutics to treat these conditions.
“Using the most advanced epigenomic, metabolomic, and gene editing approaches in my lab, Dr. Chan is revolutionizing our understanding as to how environmental stimuli, both adaptive and maladaptive, impact epigenetic regulation of gene expression in the maternal brain to alter neural circuitry and behavior,” says Dr. Maze. “Delineating the mechanisms through which the experience of pregnancy imparts long-lasting changes in molecular and physiological properties of the brain promises to greatly aid in our understanding of how such a profound lifetime experience—shared by so many—contributes to brain health. Dr. Chan is an exceptionally talented and innovative young scientist, and I am absolutely thrilled by such prestigious recognition of her paradigm-shifting work.”
Dr. Chan joined the lab in 2018. Her research interests focus on understanding how biological systems outside the nervous system interact with stress to impact the brain during windows of neuroplasticity—times of active brain organization that are particularly susceptible to environmental and physiological challenges. Specifically, her work examines periods of early brain development and female reproductive experiences in rodents, including the long-term impact of pregnancy and postpartum experiences on the brain, and how stress disrupts normal organizational processes during these important windows.
“The experience of being pregnant dramatically changes both the body and brain,” says Dr. Chan. “While studies in patient populations and animal models have shown that these changes can persist long after giving birth, we still don’t understand the molecular mechanisms that control these processes.”
In particular, Dr. Chan investigates the contribution of epigenetic mechanisms underlying these experiences by combining molecular, biochemical, genome editing, and behavioral approaches in her postdoctoral research.
“The fundamental understanding of what reproductive experience does to the brain long-term has not been well studied,” says Dr. Chan. “My work shows that stress during these periods has a significant effect on the maternal rodent brain. I hope that through my research we can learn more about how pregnancy and postpartum experiences contribute to brain health and also emphasize that overall we need to do a better job of reducing stress during these critical windows—such as encouraging parental leave and making sure people have the financial, social, and health-related resources needed to support themselves.”
Says Dr. Chan: “I am incredibly honored to be the recipient of this year’s Robin Chemers Neustein Postdoctoral Fellowship Award. The direction for this research project was sparked by personal interest, and I am extremely encouraged by Dr. Maze’s support and that the selection committee also believes in these important questions.”
Updated on Aug 12, 2022 | Inside Mount Sinai Psychiatry, Psychiatry, Research
Schahram Akbarian, MD, PhD, is a recipient of the prestigious NIH Director’s Pioneer Award (DP1), a five-year award that supports creative scientists who are pursuing pioneering approaches to major scientific challenges.
Most clinical studies benefit from taking repeated measurements over weeks, months, years. Researchers studying epigenetic disease processes in the brain don’t have that luxury. “You harvest the brain, and you only get one time point,” says Schahram Akbarian, MD, PhD, Professor of Psychiatry and Neuroscience and Chief of the Division of Psychiatric Epigenomics at the Icahn School of Medicine at Mount Sinai. “In this field, most studies are cross-sectional.”
Now, Dr. Akbarian is developing a novel method — longitudinal epigenetic profiling — that allows him to study epigenetic changes in the brain over time. The innovative idea has earned him the National Institutes of Health (NIH) Director’s Pioneer Award (DP1), a five-year award that supports creative scientists who are pursuing pioneering approaches to major scientific challenges. The project, Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant, will use the new technique to explore dynamic changes in HIV-infected cells in the brain.
“In the last 10 or 15 years, research on the epigenetics of disease has taken off, thanks to modern sequencing technologies that allow us to study genome organization in a relatively cost-efficient way,” Dr. Akbarian says. “There’s a big need for more research on HIV in the brain, and I hope to morph this new idea into something specific and exciting for HIV research.”
HIV and the Brain
At the Akbarian Laboratory of Epigenetic Regulation of the Human Brain, much of the research has focused on psychiatric diseases such as schizophrenia and depression. Several years ago, Dr. Akbarian began to extend his research to HIV, in part because so many critical questions about the virus’ impact on the brain remain unanswered. More than 38 million people worldwide are living with HIV, and 1.5 million were newly infected in 2021, according to the World Health Organization. Some 75 percent of them have received antiretroviral therapy — yet for many, brain-related symptoms remain.
HIV can infect the microglia, the innate immune cells of the central nervous system, and can also cause inflammation. People with HIV can experience a range of symptoms, including headaches, forgetfulness, mood disorders, and behavioral changes. “People are still having neurological symptoms from HIV infection, even if they take antiretroviral drugs. The question is, why? What’s causing damage in the brain?” Dr. Akbarian says.
He hopes that his longitudinal epigenetic profiling method will begin to answer that question. The technique involves differentiating pluripotent human stem cells into microglia, then introducing those microglia into the brains of mice. Using epigenomic tagging of single chromatin fibers, he and his colleagues can explore dynamic changes of epigenomic dysregulation of the cells over time. “We can switch it on and off, then months later, isolate the immune cells and see how genome organization looked four months ago,” he says. “It’s a bit like a telescope that allows astronomers to look back in time in the universe. This “telescope” allows us to look back in time in the cell.”
In this study, he is focusing on HIV-infected cells that have also been exposed to opioids and stimulants. Drug abuse is a major risk factor for HIV, because drug use increases risky behaviors that can make a person more susceptible to infection. “A brain that’s exposed to drugs of abuse and to HIV is probably more unhealthy than brains from a person with HIV but no history of drug use,” Dr. Akbarian says. “We want to see if exposure to drugs of abuse makes the brains more vulnerable to infection with HIV, or to the neurological defects that HIV can trigger.”
A third goal of the project, he says, is to contribute to efforts to rid the body of HIV for good. HIV inserts itself into the genome, an ingenious trick that allows it to hide from the immune system and makes it devilishly complicated to treat. “The big question is, does HIV do this in the brain, and if so, how can we flush it out?” Dr. Akbarian says. “If we can rid the body of HIV in every cell, people can stop taking antiretroviral medication”— and effectively be cured of HIV.
Advancing Psychiatric Epigenetics Through Collaboration
The project is in its early stages, but if this longitudinal method proves effective, Dr. Akbarian hopes it could lead to new innovations for studying other diseases of the brain. Many psychiatric conditions, such as schizophrenia and depression, emerge in young adulthood. However, many researchers suspect the disease process begins much earlier, possibly even prenatally. “There’s lots of indirect evidence, but we can’t look back in time. If we study the brain of a person with schizophrenia, we have no idea what happened in their brain earlier in life,” he says. Someday, this novel longitudinal technique may uncover some important clues.
First, though, he’s applying the method to the intertwined problems of HIV and drug use. Though Dr. Akbarian’s name is on the Pioneer Award supporting the study, it’s a project he says he could not have done without support from his colleagues at Mount Sinai. “I’m a newcomer to the field of HIV. I wouldn’t be able to do this without the exceptionally collaborative atmosphere among my colleagues at Mount Sinai, including Benjamin Chen, MD, PhD, Talia Swartz, MD, PhD, and Susan Morgello, MD, who are doing experimental HIV research and were willing to help me learn,” he says. “It’s ironic that this award is in my name, because the success of this project depends so much on teamwork with these HIV researchers, as well as stem cell scientists including Samuele Marro, PhD.”
The collaborative culture at Mount Sinai makes this kind of innovation possible, he adds. “Mount Sinai has precisely the right mixture of top-notch basic neuroscience, top-notch clinical neuroscience, and a very active hospital setting,” he says. “Together they give very fertile soil to do productive research in the fields of neurology and psychiatry.”
