Tag: Yale Cancer Center/Smilow Cancer Hospital

Patients Less Likely to Experience Death at Academic and High-Volume Hospitals When Treated with Immunotherapy for Metastatic Cancers

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Newswise — A new study led by Yale Cancer Center researchers at Yale School of Medicine revealed a significant increase in patients starting immunotherapy within one month of death. Using a national clinical database, the researchers focused on patients with metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). They were treated with immune checkpoint inhibitors from the point of FDA approval, through to 2019. The melanoma cohort began treatment in 2012 and the RCC and NSCLC cohorts in 2016.

The findings were published in JAMA Oncology on January 4.

“Immunotherapy has revolutionized the field of oncology over the last decade,” said Sajid Khan, MD, senior author of the study and section chief of Hepato-Pancreato-Biliary (HPB) and Mixed Tumors at Yale School of Medicine. “Because survival is substantially improved for many patients treated with these drugs, it’s application has increased across the United States. In our study, we focused on immunotherapy initiation at the end of a patient’s life with cancer metastasis.”

Because the therapy is relatively new, the study aimed to “offer insights into national prescribing patterns and serve as a harbinger of shifts in the clinical approach to patients with advanced cancer.”

The study included 20,415 stage IV melanoma patients, 197,331 stage IV NSCLC patients, and 24,625 stage IV RCC patients. Researchers considered each patient’s age, sex, race, and ethnicity as well as the location of metastases and the medical facility where treatment was given.

“We were interested in gauging how frequently immunotherapy is initiated within the last 30 days of life,” said Khan, a member of Yale Cancer Center and the co-director of Team Science at Yale Center for Clinical Investigation. “Our study found that the initiation of immunotherapy in the last month of a patient’s life has significantly increased in the last 10 years, accounting for one in 14 immunotherapy treatments overall.”

For patients with metastatic melanoma, the increase was from 0.8% to 4.3%, for NSCLC 0.9% to 3.2%, and for RCC 0.5% to 2.6%. In 2019, these end-of-life-initiated (EOL-I) treatments represented 7.3% of all immunotherapy treatments, indicating a growing application of EOL-I immunotherapy.

Where patients were treated with immunotherapy mattered. “There were improved survival outcomes when the therapy was administered at academic and high-volume facilities,” said Khan. While patients treated at non-academic or low-volume hospitals had higher odds of receiving EOL-I immunotherapy, patients were less likely to experience death at academic and high-volume hospitals when given immunotherapy for metastatic cancers.

“Another noteworthy finding was that the outcome for patients receiving immunotherapy towards the end of their life was different depending on the burden of metastasis. Patients with more than three sites of distant metastases are more likely to die within one month of immunotherapy initiation than those with only distant lymph node metastasis.”

The researchers note that immunotherapy provides a strong overall survival benefit and can salvage patients with metastasis, even those in high-risk sub-groups. The study findings highlight the need for further investigation into the implications of EOL-I immunotherapy with the hope of refining treatment guidelines for the benefit of patients facing metastatic cancer.

Daniel Kerekes from Yale School of Medicine and Yale Department of Surgery was the study’s first author. Alexander Frey, Elizabeth Prsic, Thuy Tran, James Clune, Mario Sznol, Harriet Kluger, Howard Forman, Robert Becher, and Kelly Olino were Yale co-authors.

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January 4, 2024
AI more accurately identifies patients with advanced lung cancer that respond to immunotherapy and helps doctors select treatments

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Newswise — Treatment planning for lung cancer can often be complex due to variations in assessing immune biomarkers. In a new study, Yale Cancer Center researchers at Yale School of Medicine used artificial intelligence (AI) tools and digital pathology to improve the accuracy of this process.

Researchers compared AI-powered digital scoring with traditional manual scoring of the PD-L1 immune biomarker to determine if a new immunotherapy treatment, atezolizumab, could benefit patients with advanced non-small cell lung cancer. PD–L1 expression is considered the best biomarker to predict responsiveness to immune-checkpoint inhibitors.

Roy S. Herbst, lead study author and deputy director of Yale Cancer Center, will present the new findings at the World Conference on Lung Cancer in Singapore on Sept. 11.

“Our study suggests that artificial intelligence has the ability to improve the identification of PD-L1 positive patients by providing a predictive accuracy that was better than manual scoring,” said Herbst, who is also the assistant dean of translational research at Yale School of Medicine. “The research underscores the potential of digital pathology and AI tools in enhancing PD-L1 scoring accuracy for both clinical practice and clinical trials.”

To conduct this study, researchers used data from the phase III trial IMpower 110, which tested the effectiveness of atezolizumab compared to chemotherapy as a first-line treatment for advanced non-small cell lung cancer (NSCLC). Using both manual and AI-powered tumor cell scoring, researchers found that the AI model was able to identify more patients as PD-L1 positive compared to the conventional manual scoring.

The study also demonstrated that both manual and digital scoring methods were equally adept at predicting patient outcomes, including overall survival and progression-free survival. The AI model also helped conclude that among patients with squamous histology (a specific subtype of NSCLC), the presence of PD-L1+ lymphocytes correlated with improved progression-free survival when treatment included atezolizumab.

“The insights gained with AI and digital scoring could make diagnosing and choosing the right treatment easier,” said Herbst. “Our data shows that this AI technology can help refine strategies for treating advanced non-small cell lung cancer.”

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September 8, 2023
New immunotherapy treatment brings hope to patients with advanced non-small cell lung cancer

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Newswise — Although immunotherapies have shown promise in treating non-small cell lung cancer (NSCLC), many patients still do not respond well, and those who do may eventually develop resistance. In a new study, Yale Cancer Center researchers at Yale School of Medicine tested a new immunotherapy, NC318, in combination with the targeted immunotherapy, pembrolizumab (KEYTRUDA). The study’s findings suggest that NC318, both alone and in combination with pembrolizumab, improved response rates and clinical outcomes for some patients with NSCLC.

The researchers will present their findings at the IASLC 2023 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer in Singapore on Sept. 12. The research team partnered with the developer of NC318, NextCure, on this phase II trial.

“Our goal is to offer patients with non-small cell lung cancer more effective options, especially when other treatments may fall short,” said the study’s senior author Roy S. Herbst, deputy director of Yale Cancer Center and assistant dean of translational research at Yale School of Medicine. “The fact that NC318, in combination with pembrolizumab, is well-tolerated in patients who had previously been treated with immune checkpoint inhibitors is encouraging. It provides another treatment for patients in need of therapeutic options for advanced lung cancer.”

In the trial, researchers administered NC318 either alone or in combination with pembrolizumab to patients with advanced NSCLC that had progressed after receiving checkpoint inhibitor therapy. Among the 11 patients who received NC318 alone, one patient had a partial response, two had stable disease (tumor size did not grow or shrink), and eight patients had progressive disease (at least a 20% growth in tumor size).

Among the 18 patients who received the NC318-pembrolizumab combination treatment, three patients had a partial response (one after initial pseudo-progression), six patients had stable disease, and nine patients had progressive disease. Two of the patients with stable disease had ongoing stability at 21.6 months and 7.6 months, respectively.

Some patients experienced treatment-related adverse events, but researchers say the overall tolerability was good, similar to standard immunotherapy.

“Although the data is promising, these are preliminary findings and further research is ongoing with a focus on optimizing treatment dose and schedule, and evaluating predictive biomarkers,” said the study’s first author Scott Gettinger, chief of thoracic medical oncology at Yale Cancer Center and Smilow Cancer Hospital.

Gettinger and Herbst were joined by Yale co-authors Sarah Goldberg, Anne Chiang, Frederick Wilson, So Yeon Kim, Elin Rowan, Heather Gerrish, Emily Duffield, Marianne Davies, Vanna Dest, Roliya Jackson, Jennifer Pope, Wei Cheng, David Rimm, and Lei Chen.

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September 8, 2023
Yale Cancer Center expert available to discuss nationwide drug shortages and impact for patients with cancer

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Thousands of patients across the U.S. are facing delays in getting treatments for cancer, with shortages for critical cancer drugs in the United States at near record levels. Daniel Petrylak, MD, an expert in cancers of the urinary system at Yale Cancer Center, is available for interviews to explain the impact on patients with cancer and what’s being done to alleviate the drug crisis. As professor of medicine and urology at Yale School of Medicine, Dr. Petrylak is a pioneer in the research and development of new drugs and treatments to fight bladder and testicular cancers, which have been most affected by the drug shortages.

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June 27, 2023
Promising Phase III Results Give Hope to People Living with Myelodysplastic Syndromes

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Newswise — Amer Zeidan, MBBS, medical director of the hematology early therapeutics research program at Yale Cancer Center and associate professor of medicine (hematology) at Yale School of Medicine, will reveal new data at the American Society of Clinical Oncology (ASCO) annual meeting from a phase III study evaluating the efficacy of imetelstat in red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndrome (LR-MDS) patients. Myelodysplastic syndromes(MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The study results demonstrate significant and clinically meaningful efficacy, representing a potential breakthrough in the treatment of anemic LR-MDS.

Imetelstat, a telomerase inhibitor, was evaluated in patients who were heavily RBC transfusion-dependent LR-MDS and who were refractory or ineligible for erythropoiesis-stimulating agents (ESAs), but did not receive lenalidomide or hypomethylating agents (other drugs used to treat MDS). The phase III study, known as IMerge, enrolled a total of 178 patients. The findings from the study provide critical evidence supporting imetelstat’s efficacy and safety profile. These results are expected to have a substantial impact on future treatment strategies for patients diagnosed with LR-MDS.

Dr. Zeidan, first and presenting author of the research at ASCO, answered questions on the study and its significance for patients living with MDS:

Q: What is the significance of this study?

A: “This is a very important study. Imetelstat is a first-in-class agent. It’s a first-in-class telomerase inhibitor, and this is the first time we have a phase III study of a drug in this class. We already completed the phase II study that was single arm that looked at a similar population of patients with lower risk MDS (myelodysplastic syndromes) who are heavily transfusion dependent, and the transfusion independence rate with the drug was around 40%. Transfusions in MDS are associated with increased risk of complications, increased risk of death, not to mention healthcare utilization and costs. So, trying to reduce transfusions and ideally make patients transfusion independent is a very important goal of treatment in patients with lower risk MDS.

So the excellent activity of imetelstat in the phase II part of the study was taken to a phase III trial and what we have found in this study is what we actually expected based on the phase II trial: the transfusion dependence rate was much better with imetelstat compared to placebo, it was around 40% for an eight-week duration of transfusion dependence, the primary endpoint of the study, compared to 15% with a placebo; and most importantly, it was also durable. The median duration of transfusion independence for those who responded was more than 50 weeks. So clearly, a very positive study, very consistent with the phase II data. I think this drug could become an important option for patients.”

Q: What are the key findings from the data? What will you highlight at ASCO?

A: “During the ASCO presentation, we’ll discuss in detail, the efficacy of the drug in terms of transfusion independence, hematologic improvement, durability of response, but also looking within subgroups for patients based on the genetic profile. We will also discuss early signs of disease modification that we are seeing through reduction of variable allele frequency of important mutations that contribute to the pathogenesis of MDS. We’ll also discuss the side effect profile and how the interruption of therapy has led to, I think, a manageable and reversible side-effect profile, mostly in the setting of liver enzyme abnormalities and cytopenias (a medical condition where there are a low number of red blood cells).”

Q: Are there other treatment options for this niche group of patients affected by this cancer?

A: “Yes, so myelodysplastic syndromes have been renamed neoplasms by the World Health Organization, the most recent classification to emphasize that it’s a cancer. Many people think of MDS as an anemia or a pre-leukemia or a syndrome, but they are actually cancers. However, they differ in their severity. Patients in general are grouped into two big groups, lower risk and higher risk. In lower risk patients, those patients can live for years, but they have a lot of complications related to the low blood counts. That could be anemia, thrombocytopenia, or neutropenia, or a combination of these, but the most common use cytopenia is anemia. Anemia often is associated with reduced quality of life. The patient often needs regular transfusions. It’s also associated with significant complications and high risk of death, as well as issues related to needing to go to the clinic frequently, healthcare utilization costs. Correction of anemia is very important. Historically, the only treatment we had was erythropoiesis stimulating agents for patients with lower risk MDS. In recent years, other drugs have been approved like lenalidomide, as well as hypomethylating agents and luspatercept. However, the response to these drugs is limited, and at some point, the patient will progress and will need additional treatment. I think imetelstat potentially could fill a very important gap there because those patients are generally not going to be cured without a bone marrow transplant, which is not something that’s commonly done in MDS patients where the average age is in the early 70s. The goal is to try to improve quality of life in those lower risk MDS patients and make them transfusion independent as much as possible and that’s generally achieved by sequential therapy. So you go from one agent to the next, while trying to maintain quality of life keeping the patient out of the hospital and minimizing complications of the treatment itself.”

Q: What is next in terms of research. What would you like done in future studies?

A: “This is a very important question. I think the next step is going to be focusing more on how to increase the overall durability of response as well as increased the rate of response. And I think that’s going to be done by combining drugs. We have several active drugs now. So, figuring out how to combine them, and probably trying to treat patients earlier in their disease course will be important, so they don’t even get to the point of becoming transfusion dependent. Several of those studies I think are going to happen over the next few years. And of course, there are other drugs that are being studied in phase I and phase II trials. Some of those hopefully will also lead to benefit to patients so that if we cannot cure the disease, we can for most patients at least improve their quality of life, make transfusions as least as possible, and also make sure they are out of the hospital and having a good quality of life.”

Q: What does the presentation at ASCO mean to you?

A: “It’s one of the most gratifying moments for a clinical investigator when we hear a trial we worked on is positive. The reason why we do clinical trials is to help our patients. So have a positive trial and especially with an agent that you have worked on for years, and you have been very involved in the trial for a long time, not only in accruing patients, but also in the design and the conduct and oversight of the study and to have a trial being positive, especially for a randomized phase III trial, is a very good feeling, and the day when you hear that the results are positive is a day that you tend to remember for a very long time because what you have worked on did not only help your own patients, but hopefully if the drug gets approved, it’s going to help many patients that you have not directly interacted with, which is I think is the most important mission of any clinical research. We are the face of the trial as clinical investigators, but we have a huge team here at Yale. A lot of coordinators, clinical research nurses, regulatory staff, and our nurse practitioners – all of them have been very important to the conduct of the trial here at Yale. This was a global study that happened in many countries, many centers, and it’s a coordinated effort. So we are presenting the data on behalf of everybody and hoping that the regulatory review will be successful, and we have another option for our patients.”

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June 1, 2023
Connecticut Magazine’s 2023 “Top Doctors” issue recognizes 82 Smilow Cancer Hospital and Yale Cancer Center physicians

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Newswise — Each year, Connecticut Magazine recognizes some of the state’s best physicians, who provide exceptional care for patients, with its annual “Top Doctors” issue. This year’s list includes 82 physicians from Smilow Cancer Hospital and Yale Cancer Center, the only National Cancer Institute-designated comprehensive cancer center in the state.

“It is wonderful for many of us to be included on the 2023 list of top cancer doctors in Connecticut,” said Eric Winer, MD, director of Yale Cancer Center and physician-in-chief of Smilow. “This is a top honor, and we are grateful for the recognition and the support.”

The magazine partnered with Castle Connolly, a leading national health care research firm, to compile the annual list of the state’s top physicians. Castle Connolly’s extensive survey identified more than 1,600 Connecticut physicians, all nominated by their peers and vetted to meet the criteria to earn the designation of “Top Doctors.” In other words, these are the cancer experts who other doctors recommend. The complete “Top Doctors” list appears in the May 2023 issue of Connecticut Magazine.

Congratulations to this year’s “Top Doctors” affiliated with Smilow Cancer Hospital and Yale Cancer Center:

Top Doctors

Nita Ahuja — Surgery

Michael Alperovich — Surgery

Harry Aslanian — Gastroenterology

Masoud Azodi — Gynecologic Oncology

Joachim Baehring — Neurology

Elizabeth Berger — Breast Surgical Oncology

Jean Bolognia — Dermatology

Robert Bona — Hematology & Oncology

D. Barry Boyd — Medical Oncology

James Clune — Surgery

Michael Cohenuram — Thoracic Oncology

John Colberg — Urology

Frank Detterbeck — Thoracic Surgery

Kevin Du — Therapeutic Radiology

Andrew Duffy — Surgery

Beverly Drucker — Medical Oncology

Richard Edelson — Dermatology

Neal Fischbach — Medical Oncology

Francine Foss — Medical Oncology-Hematology-Oncology

Gary Frielaender —Pathology-Musculoskeletal Oncology

Scott Gettinger — Thoracic Oncology-Medical Oncology

Michael Girardi — Dermatology

Earl Glusac — Pathology-Dermatology

Rachel Greenup — Breast Surgical Oncology

Roy Herbst — Medical Oncology-Thoracic Oncology

Susan Higgins — Therapeutic Radiology-Breast Cancer Radiotherapy

Silvio Inzucchi —Endocrinology-Diabetes Medicine & Management

Gary Israel — Radiology-Biomedical Imaging

Dhanpat Jain — Pathology-Internal Medicine (Digestive Diseases)

Priya Jamidar — Gastroenterology-Hepatology

Michele Johnson — Radiology-Biomedical Imaging

Kimberly Johung — Therapeutic Radiology

Benjamin Judson — Surgery

Jennifer Kapo — Internal Medicine-Hospice & Palliative Care

Patrick Kenney — Urology

Sajid Khan — Surgical Oncology-Gastrointestinal Surgery

Sanjay Kulkarni — Surgery

Pamela Kunz — Medical Oncology

Jill Lacy — Medical Oncology

Johanna LaSala — Medical Oncology-Hematology & Oncology

Stephen Lattanzi — Medical Oncology

Alfred Lee — Hematology

Merlin Lee (M.Sung Lee) — Hematology-Oncology

David Lefell — Dermatology

Jonathan Leventhal — Dermatology

Walter Longo — Surgery

Maryam Lustberg — Breast Oncology

David Madoff — Radiology-Biomedical Imaging

Asher Marks — Pediatric Hematology & Oncology

Kelsey Martin — Hematology & Oncology

Bruce McGibbon —Therapeutic Radiology

Saral Mehra — Surgery

Ehud Mendel — Neurosurgery

Jon Morrow — Pathology

David Mulligan — Surgery

Justin Persico — Medical Oncology

Daniel Petrylak — Medical Oncology-Urology

Jeffrey Pollak — Radiology-Biomedical Imaging

Jennifer Possick — Thoracic Oncology

Lajos Pusztai — Medical Oncology, Breast Oncology

Elena Ratner — Gynecologic Oncology

Vikram Reddy — Colon and Rectal Surgery

David Rimm — Pathology-Medical Oncology

Kenneth Roberts — Therapeutic Radiology-Medical Oncology

Alessandro Santin — Gynecologic Oncology

Ronald Salem — Surgery

Niketa Shah — Hematology & Oncology

Sangini Sheth — Gynecologic Oncology

Dinish Singh — Urology

Kathleen Suozzi — Dermatology

Gordon Sze — Radiology-Biomedical Imaging

Mario Sznol — Medical Oncology

Lynn Tanoue — Pulmonology & Sleep Medicine

Kelsey Martin Thompson — Hematology

Hugh Taylor — Gynecologic Oncology

Juan Vasquez — Pediatric Hematology-Oncology

Jeffrey Weinreb — Radiology-Biomedical Imaging

Lynn Wilson — Therapeutic Radiology

Eric Winer — Medical Oncology

David Witt — Medical Oncology

George Yavorek — Colorectal Surgery

Nwanmegha Young — Clinical Surgery

*Alex Choi in the Palliative Care Program at Smilow Cancer Hospital was also named a 2023 Castle Connolly Rising Star

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May 1, 2023
Raising Awareness About Colorectal Cancer

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Newswise — With the arrival of March, Colorectal Cancer Awareness Month, faculty and staff in the Department of Internal Medicine’s Section of Digestive Diseases are redoubling their efforts to spread the word about the importance of screening, especially in younger individuals and those with a family history of the disease.

Colorectal cancer is the second most common cause of cancer death in the United States. Still, many people are unaware of the role screening plays in reducing their risk of developing the disease.

“Caught early, this cancer has an excellent prognosis, and screening has been shown to decrease incidence and mortality,” said Xavier Llor, MD, PhD, professor of medicine (digestive diseases), Yale School of Medicine; medical director of the Cancer Screening and Prevention Program and Colorectal Cancer Prevention Program at Smilow Cancer Hospital and Yale Cancer Center.

Despite the continued overall decline of colorectal cancer, recent statistics are worrisome, Llor said. According to the latest report from the American Cancer Society, the proportion of cases among those younger than 55 has increased and the progress against colorectal cancer as a whole has slowed.

Llor recommends that health care providers start the discussion with patients by age 40, to increase the chances that they will get screened by 45. Individuals with a parent, sibling, or child who had colorectal cancer should start screening earlier, at age 40, he said.

“It takes time and repeated reminders for many people to finally have a colorectal cancer screening done,” he said. “If we promote awareness together, with the help of general practitioners, we can make a difference.”

Since forming one of the nation’s first sections of hepatology and then gastroenterology over 50 years ago, Yale’s Section of Digestive Diseases has had an enduring impact on research and clinical care in gastrointestinal and liver disorders. To learn more about their work, visit Digestive Diseases.

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March 10, 2023
New Class of Drugs Could Prevent Resistant COVID-19 Variants

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Newswise — The constant evolution of new COVID-19 variants makes it critical for clinicians to have multiple therapies in their arsenal for treating drug-resistant infections. Researchers have now discovered that a new class of oral drugs that acts directly on human cells can inhibit a diverse range of pathogenic SARS-CoV-2 strains.

In their newly published study, the team found a novel mechanism through which the gene that expresses angiotensin converting enzyme-2 (ACE-2)—the cellular receptor to which SARS-CoV-2 binds so that it can enter and infect the cell—is turned on. They also found that a class of oral drugs currently in human clinical trials can block this pathway and potentially be a therapeutic for all SARS-CoV-2 variants, as well as any newly emerging SARS-like viruses. The team published its findings in Nature Genetics on March 8.

Targeting these master regulatory complexes complements existing approaches and fills a need for a new drug class that can be exploited to help combat drug resistance and infection. -Craig Wilen, MD, PhD

“Because of drug-resistant variants, we’re down to only one drug, Paxlovid, as far as our oral options,” says Craig Wilen, MD, PhD, associate professor of laboratory medicine and of immunobiology, and a member of Yale Cancer Center. “Targeting these master regulatory complexes complements existing approaches and fills a need for a new drug class that can be exploited to help combat drug resistance and infection.” Wilen and Cigall Kadoch, PhD, of Dana-Farber Cancer Institute, are co-senior authors of the study. The co-first authors are Jin Wei, PhD, postdoctoral scholar in the Wilen Lab, and Ajinkya Patil, MS, graduate student in the Kadoch Lab and the Program in Virology at Harvard Medical School.

Researchers Identify Potential Anti-Viral Targets

In a previous study published in 2021, Wilen’s team at Yale performed genetic screening to identify host factors that are essential for SARS-CoV-2 infection. One of the key players was the mammalian switch/sucrose non-fermentable (mSWI/SNF, also called BAF) chromatin remodeling complex, a group of over a dozen very conserved proteins that allow certain genes to turn on.

“At that point, I’d never heard of it in the setting of virus infection, and we couldn’t understand why it was important for coronaviruses,” says Wilen. Thus, the group teamed up with experts on this complex, the Kadoch Lab at the Dana-Farber Cancer Institute and Harvard Medical School to find out how the protein complex acts to make cells susceptible to infection and if newly emerging drugs against these complexes could stunt viral infection.

At the time they embarked on their collaborative work, the U.S. Food and Drug Administration had authorized six monoclonal antibody treatments for emergency use, yet none of these treatments work against the newest Omicron variants. This leaves clinicians with remdesivir, which can only be administered through an IV, limiting its use; molnupiravir, an oral drug that works similarly to remdesivir but only has 30 percent efficacy; and Paxlovid, an oral antiviral that works through inhibiting the viral protease. Paxlovid, Wilen says, is the mainstay of current treatment.

“It’s a great drug that works well, but there has been some emerging drug resistance to it,” he says. “And currently, that is the only drug in our toolbox that we can give as an oral form.” The dwindling of effective treatments further highlights the critical need for a new class of drugs to add to the toolbox, and ideally, ones that are less susceptible to quick-acting resistance mechanisms.

Blocking mSWI/SNF Protects Cells Against SARS-CoV-2

First, the team discovered that disrupting mSWI/SNF complexes prevented viral entry into human cells. Because mSWI/SNF is known to regulate genes turning on and off, they then hypothesized that it might also play a role in activating the ACE-2 receptor. Next, they uncovered its mechanism: mSWI/SNF binds to another protein called HNF1A, a transcription factor, which directs it to the gene that encodes ACE-2. Upon disrupting mSWI/SNF complexes, the cell could no longer make ACE-2 and became resistant to infection by any virus that uses that receptor. This includes many coronaviruses.

Small molecule inhibitors that target mSWI/SNF have already been developed by Kadoch-founded Foghorn Therapeutics and are in phase I clinical trials as a therapeutic for several cancers. Wilen and Kadoch found that this class of drugs was effective against multiple variants of SARS-CoV-2—including a remdesivir-resistant strain isolated from a Yale patient—without any adverse effects on the cell. “This is proof of principle that this can be a really important first- or second-line tool to combat drug resistance,” says Wilen.

“Further, this speaks to the wide, multi-disease potential for pharmacologic modulation of chromatin remodeling complexes,” says Kadoch. “These molecular machines sit at the top of the pyramid in governing gene expression programs that go awry in many different human diseases—we are just at the tip of the iceberg in identifying and exploring their utility”.

Wilen believes the drugs in these clinical trials can potentially be repurposed to inhibit both current and future coronaviruses. Furthermore, Wilen and Kadoch hope the work can provide insight into why certain people and specific cell types may be more susceptible to coronavirus than others. “Future work is needed to look at the underlying biology of why some people are asymptomatic while others experience severe infection and death,” Wilen says.

COVID-19 will not be the last severe viral outbreak. Wilen’s lab studies coronaviruses circulating in wild bats, which he believes pose the highest risk for infecting humans and causing the next pandemic. Many of these viruses use ACE-2 as a receptor, which means that this new study may hold the key to slowing or stopping the next outbreak. “We’re going to have another pandemic, whether it’s in a few years or a decade. And we’re underprepared for it,” he says. “The best way to prepare is to have as many vaccines and drugs as possible ready to go so that we can combat the outbreak early with maximum effectiveness.”

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March 10, 2023