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Cancer has an obesity-related risk factor, and it depends on sex and cancer type

Source: Cell Press
Date: 6/12/2023
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Obesity has been previously linked to an increased risk of cancer, but most studies have not differentiated the risks between male and female patients. A new study published June 12 in the journal Cancer Cell takes a closer look at this connection. The investigators report that both overall fat accumulation and fat distribution in different parts of the body confer different cancer risks depending on sex. Additionally, the risks vary across cancer types, like colorectal, esophageal, and liver cancer.

“Doctors and scientists are aware that obesity increases cancer risk, but this connection is less well known to members of the public,” says first author Mathias Rask-Andersen, a researcher at Uppsala University in Sweden. “These observations are important for risk assessment and to gain a deeper understanding of adiposity-related disease risks.”

“An important aspect of obesity-associated disease risk is the distribution of fat in different compartments of the body,” says senior author Åsa Johansson, also of Uppsala University. “Fat stored in the abdomen is considered more pathogenic compared to subcutaneous fat. In addition, the amount of fat stored in different compartments, as well as the rates of most cancers, is known to differ between females and males. These facts motivated a careful sex-stratified analysis of adiposity-related cancer risk.”

The investigators used data from the UK Biobank, a cross-sectional cohort of 500,000 U.K. residents aged between 37 and 73 who were recruited between 2006 and 2010 and then followed for a mean time of 13.4 years. Among the data collected from participants in the database were details about the distribution of fat in their bodies and whether they developed cancer.

The researchers used Cox proportional hazards modeling to identify the associations between the levels and distribution of fat in the participants’ bodies at the time of the initial assessment and their later rates of cancer. The team found that all cancer types except brain, cervical, and testicular cancers are associated with at least one obesity-related trait.

In female patients, the strongest links between overall fat accumulation and cancer were in gallbladder cancer, endometrial cancer, and esophageal adenocarcinoma. In males, the strongest links between overall fat accumulation and cancer were in breast cancer, hepatocellular carcinoma, and renal cell carcinoma. In terms of fat accumulation and distribution, there were differential effects between sexes on colorectal, esophageal, and liver cancer. For instance, a larger proportion of fat stored in the abdomen was associated with esophageal squamous cell carcinoma in females, but not in males. Additionally, body fat accumulation was associated with a high risk for hepatocellular carcinoma in males, an effect that was not present in females.

“We were surprised to see that there appeared to be a difference in the effect of obesity on cancer risk, not only between males and females, but also between post- and pre-menopausal females,” Johansson says. “Most remarkable, obesity is only a risk factor for breast cancer after menopause, probably due to the change in estrogen production in association with menopause.”

The investigators note limitations to this study, especially that it was limited largely to British White participants, which make up almost 95% of the UK Biobank. They explain that their findings may differ from or may not be applicable to other ethnicities. They also say that because participants were older, the results are likely not directly transferable to younger populations.

They plan to do additional studies to help develop a complete understanding of the molecular mechanisms underlying these findings. Future work will also focus on genetic and environmental risk factors for cancer, which are not static but differ across a person’s lifespan. This includes taking a closer look at the variation in the effects of obesity before and after menopause.

“Given the rapidly increasing rates of obesity globally, obesity is now the fastest-growing risk factor for overall cancer risk,” Rask-Andersen says. “Measures to prevent and reduce the occurrence of obesity and being overweight are therefore highly motivated. However, it is important to consider that reducing weight does not eliminate the risk of cancer. There are still many individual risk factors that play a much larger impact on specific types of cancer, such as smoking for lung cancer and exposure to sun for skin cancer.”

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Antihistamine drugs may improve outcomes for cancer patients receiving immunotherapy

Source: Cell Press
Date: 11/24/2021
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Since the first checkpoint inhibitor drugs were developed for the treatment of cancer about a decade ago, investigators have focused on ways to make them more effective. A study appearing November 24 in the journal Cancer Cell reports that the over-the-counter second-generation antihistamines appear to improve outcomes for cancer patients treated with anti-PD-1/PD-L1 therapies for a number of different types of cancer.

“We believe our findings could have implications for clinical practice if validated in prospective clinical studies,” says senior author Dihua Yu, a professor and chair ad interim of the Department of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center. “For example, our study suggests that before immunotherapy treatment, testing patients’ plasma histamine level could help doctors decide whether patients may benefit from antihistamine treatment.”

The discovery was made after the investigators decided to look at the influence of 40 common medications on the efficacy of checkpoint inhibitors. These included over-the-counter drugs such as antacids and anti-inflammatories and prescription drugs such as antibiotics and steroids. When the researchers reviewed the patients’ electronic health records, they found that taking H1-antihistamines by patients receiving immunotherapy was significantly associated with improved overall survival.

Second-generation H1-antihistamines include cetirizine (Zyrtec), loratadine (Claritin), and, more recently, fexofenadine (Allegra). These drugs, which block metabolites called histamines released by immune cells, are widely used in cancer patients not only to relieve allergy symptoms but to prevent nausea and vomiting. However, the role of histamines has not previously been connected directly to cancer outcomes.

Meanwhile, the researchers noticed that some patients with “hot tumors”—those with high infiltration of cytotoxic T cells—who normally would be expected to respond well to immunotherapy still had very poor survival. To get an insight on what made these tumors different, they performed global gene expression analysis on patient samples.

“We found that histamine receptor 1 (HRH1) was identified as one of the top hits that show strong association with poor clinical outcome in hot tumors,” says co-first author Yi Xiao, an instructor of the Department of Molecular and Cellular Oncology and a member of Yu’s lab at MD Anderson.

Since H1-antihistamines specifically block histamine binding to HRH1, they connected the above findings back to the lab in mice. Their experiments revealed that cancer-secreted and allergic reaction-released histamines, as well as HRH1 high expression in macrophages, suppressed cytotoxic T cell activation and conferred resistance to immunotherapy, whereas antihistamines partially rescued all the phenotypes.

They also measured pretreatment plasma histamine levels in patients who were treated by anti-PD-1 immunotherapy. Corroborating their findings in mice, high histamine levels in patients were significantly correlated with worse responses to anti-PD-1 immunotherapy compared to patients with low levels of plasma histamine levels.

“We were surprised to find that almost all the cancer cells we tested have significantly increased secretion of histamines compared to normal cells,” Xiao says. “We know that allergy responses release a lot of histamines but didn’t expect such a stunning suppressive effect on antitumor immunity.”

One limitation of the research is that it focused solely on the function of macrophage-expressed HRH1 but not HRH1 in other immune and non-immune cell types. The researchers say it’s also possible that histamines may have a broader impact on the phenotype and activity of macrophages. That’s something they may explore in the future. 

They also note that it’s critical to choose the right antihistamines for cancer patients. This research indicated that only second-generation H1-antihistamines, which target HRH1 specifically, but not first-generation, non-selective H1-antihistamines led to improved outcomes.

“Tens of millions of people experience allergies every year. But how allergies impact cancer development and therapeutic response has not been well studied,” Yu says. “Our study just uncovered a tip of the iceberg, and we will continue to explore the relationship between the two diseases.”

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Study confirms safety and effectiveness of COVID-19 vaccination in people with cancer

Source: Cell Press
Date: 6/10/2021
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Since the early days of the COVID-19 pandemic, there were questions about how people in active cancer treatment would fare if they became infected with SARS-CoV-2. The worries were due, in large part, to the effects that cancer and its treatments can have on the immune system. Now that COVID-19 vaccines are widely available, concerns have shifted to the safety and effectiveness of vaccination in this potentially vulnerable population. A study published June 5 in the journal Cancer Cell aims to allay those fears.

In a review of 200 patients with a wide spectrum of cancer diagnoses, researchers at Montefiore Health System and Albert Einstein College of Medicine in the Bronx, NY, found that after full vaccination, 94% of patients overall demonstrated seroconversion, which was determined by the presence of antibodies to the SARS-CoV-2 spike protein. Response rates were very high among patients with solid tumors and were lower in people with certain blood cancers, but even the majority of those patients mounted an immune response.

“Studies from early in the pandemic found that cancer patients who get COVID-19 have higher rates of morbidity and mortality compared to the general population,” says senior co-author Amit Verma, director of the Division of Hemato-Oncology at Montefiore and professor of medicine and of developmental and molecular biology at Einstein, and associate director, translational science, Albert Einstein Cancer Center. “We really need efforts to protect these vulnerable patients from infection. This study should help people feel reassured that these vaccines work very well, even in those receiving chemotherapy or immunotherapy.”

“This study confirms that there is no need for patients to wait for vaccination until they finish their chemotherapy or immunotherapy,” says senior co-author Balazs Halmos (@DrSteveMartin), director of the Multidisciplinary Thoracic Oncology Program at Montefiore, professor of medicine at Albert Einstein College of Medicine, and a member of the Albert Einstein Cancer Center (AECC). “The side effects from vaccination seen in these populations were not substantially worse than in other groups. Not a single patient had to go to the emergency room or be admitted to the hospital because of side effects from the vaccines.”

This study was the largest of its kind to look at seroconversion rates in cancer patients who have been fully vaccinated. Previous studies have looked at much smaller populations or have analyzed antibody levels after only the first dose of two-dose vaccines.

In serum tests to look for IgG levels after vaccination, the researchers found that among patients with solid tumors, 98% showed seroconversion. Among patients with hematologic cancers, the rate of seroconversion was 85%.

Patients receiving some treatments fared worse than others. Those receiving therapies for blood cancers that work by killing B cells (such as rituximab or CAR T therapies) had seroconversion rates of 70%. For those who had recently had bone marrow or stem cell transplants, the rate was 74%. But those rates were still much higher than expected, the researchers say.

“Although those receiving treatments that affect B cells didn’t do as well, patients with blood cancers that affect the myeloid cells rather than the lymphoid cells had a pretty good response with regard to seropositivity,” says first author Astha Thakkar (@asthakkar15) a Montefiore hematologic oncology fellow. “This includes people with acute myeloid leukemia and myelodysplastic syndrome.”

The researchers say that one reason their data are so significant is that they include patients who had a broad range of cancers and who were undergoing a number of different treatments. “The patients themselves were also diverse and were representative of the patients we treat in the Bronx,” Halmos says. “About one-third were Black and 40% were Hispanic.”

“Vaccination among these populations have been lower, even though these groups were hardest hit by the pandemic,” Verma concludes. “It’s important to stress how well these patient populations did with the vaccines.”

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Clinic Screens High-Risk Patients to Reduce Incidence of Anal Cancer

Source: Brigham and Women's Hospital
Date: 5/30/2023
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Screening guidelines for cervical cancer have been recognized for decades. But for other cancers linked to human papillomavirus (HPV), including anal cancer, cancer screening guidelines are not well-developed.

Since 2020, a unique Brigham and Women’s Hospital clinic has offered high-resolution anoscopy (HRA) to screen for anal dysplasia in people at increased risk of anal cancer due to HPV infection, HIV status, and other factors. The clinic aims to reduce the incidence of anal cancer in high-risk populations.

“The value of treating anal dysplasia to prevent anal cancer for the highest-risk patient population has now been established and is still being studied for lower-risk groups,” says colorectal surgeon James Yoo, MD, one of the two founders of the HRA clinic. “The field is still evolving, and more data are needed to determine the best practices. But this is clearly an area where we can make an impact in cancer prevention, especially for patients at higher risk.”

“As an infectious disease doctor, I’m obviously interested in the different diseases and complications that affect HIV patients,” says Jennifer A. Johnson, MD, a clinician-educator and the clinic’s other co-founder. “We know that people with HIV are one of the highest-risk groups for the development of anal dysplasia and anal cancer, making this an important population to focus on.”

A Collaborative Approach to Patient Care

Results from the phase 3 Anal Cancer–HSIL Outcomes Research (ANCHOR) trial, published in The New England Journal of Medicine in June 2022, demonstrated for the first time that treatment for anal high-grade squamous intraepithelial lesions reduced the progression to anal cancer when compared with active monitoring. Drs. Yoo and Johnson note that this study’s findings help illustrate the value of the Brigham’s HRA clinic.

“HRA requires special equipment that’s not commonly available as well as special training to learn how to perform the procedure and to know what to look for,” Dr. Yoo says. “In terms of what our clinic can offer, it’s relatively special.”

In addition to Drs. Yoo and Johnson, colorectal surgeon Ronald Bleday, MD, also participates in the clinic.

The clinic’s collaborative approach produces significant benefits for patients. Follow-up care may consist of a range of actions depending on what is found during the HRA exam. These include annual anal Pap smears, HRA exams offered on an annual or semiannual basis, ablation of dysplastic lesions, and more extensive surgical procedures.

HRA Offered as Simple Office Procedure

When a patient is referred to the clinic, they can have their HRA exam performed on their first visit. This makes scheduling less burdensome.

“The HRA procedure is very similar to a cervical colposcopy,” Dr. Johnson notes. “It requires no anesthesia beyond sometimes a local anesthetic. It is minimally invasive, doesn’t require any specific preparation on the patient’s part, and doesn’t affect their activities for the rest of the day.”

Beyond those with HIV, patients taking immune-suppressing drugs to treat autoimmune diseases may also be at increased risk of developing lesions caused by HPV. The leaders of the HRA clinic provide consultations to physicians both inside and outside the Brigham to help them identify which patients may benefit from enrollment in the clinic’s programs. The clinic also provides opportunities to counsel patients on topics like HPV vaccination.

“These visits provide a good opportunity to make sure we’re paying attention to any concerns the patients have about minimizing their cancer risks,” Dr. Johnson says.

“We have a pipeline of patients who come to us because their providers are aware of the need to screen for anal dysplasia,” Dr. Yoo adds. “One of our continuing roles is to educate other doctors about which patients they should send to us for evaluation.”

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Making Headway in Targeting Glioblastoma Multiforme

Source: Brigham and Women's Hospital
Date: 6/14/2022
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The past two decades have seen considerable progress in developing targeted therapies for cancer. Many of these drugs are successful in treating both primary tumors and metastases. Additionally, when patients develop resistance to certain therapies, often other targeted treatments and new options are available.

Unfortunately, advances in precision oncology for glioblastoma multiforme (GBM) have lagged behind many other cancers. A multicenter, philanthropically funded effort now aims to address that deficit. Break Through Cancer is a foundation that brings together several elite cancer research centers to accelerate research through collaboration, conduct clinical trials, and ultimately develop cures for the deadliest cancers. One of those cancers is GBM.

Along with colleagues at the Dana-Farber Cancer Institute (DFCI), as well as investigators at the MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Johns Hopkins Medicine, and Massachusetts Institute of Technology, a team from Brigham and Women’s Hospital has been assembled to work on these efforts.

Conducting Serial Biopsies of the Brain

One reason for the disparity in available targeted therapies for GBM is the difficulty in obtaining regular biopsies of these tumors due to their location in the brain. Biopsies are a crucial part of targeted therapy.

“For decades we have run multiple trials for GBM, and none of them have been very successful,” says Nathalie Y. R. Agar, PhD, founding director of the Surgical Molecular Imaging Laboratory in the Brigham’s Department of Neurosurgery. “What many of us in the field have realized is that the main difference in treating other cancers is that, as part of clinical trials, patients undergo biopsies to assess the response of the tumor to the therapeutic agent under investigation.”

“Patients routinely receive multiple biopsies throughout the course of treatment for other cancers or other diseases to see whether drug X or drug Y actually is doing what it’s supposed to do,” adds E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery. “But we’ve never done that for GBM. This is what we’re proposing to do.”

Treatment With a Modified Oncolytic Virus

Because of the logistical and ethical issues surrounding the repeated collection of biopsies that require drilling into the skull, this research is being conducted in conjunction with a clinical trial that also requires direct access to the brain—delivery of an oncolytic virus that aims to destroy GBM tumors.

This treatment, in which a modified herpes simplex virus 1 is injected directly into the tumor, has already been tested in a phase 1 clinical trial at the Brigham and DFCI that enrolled 50 patients between 2017 and 2022. The treatment appeared to be safe and provided benefit to some patients.

The new research, an extension of the earlier trial, will enroll 12 more patients (three at each of the four Break Through Cancer-funded clinical institutions) to receive up to six doses over a four-month period. At the same time the patients receive the treatment, a biopsy of their tumor will be collected to assess how the cancer is responding.

“This treatment requires only conscious sedation and is guided by a GPS-like robotic system,” Dr. Chiocca says. “It’s very well tolerated, and most patients go home the next day.”

The hope is that by regularly collecting tumor tissue, researchers will be able to learn more about the mechanisms that underlie the cancer’s response to treatment, potentially leading to more personalized approaches as well as new, more effective therapies.

Looking at Combination Treatments

Eventually, the investigators plan to conduct additional trials in which other agents that require intratumoral injection are used. This next phase is likely to include a biologic agent that triggers the immune system to fight cancer.

Dr. Agar noted that this research has a strong translational science component, including the development of new model systems that will help investigators select new drugs or combinations of drugs that may also be effective.

“This work has been possible not only because of Break Through Cancer, but thanks to strong leadership at both the Brigham and DFCI,” she says. “We hope that it eventually will revolutionize the way that GBM is treated.”

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Researchers Probe Links Between Colorectal Cancer, Bariatric Surgery

Source: Brigham and Women's Hospital
Date: 4/26/2022
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The microbiota, the collective term for all the microorganisms living in the body, has been called the “forgotten organ” for its broad influence across many bodily systems. But in recent years, increased research focused on the microbiota—and the gut microbiota in particular—has meant that it’s not quite so forgotten anymore.

Investigators at Brigham and Women’s Hospital are undertaking a new project to look at the link between the microbiota and colorectal cancer. By harnessing unique partnerships among members of the Laboratory for Surgical and Metabolic Research, which includes many physician-scientists from the Division of General and Gastrointestinal Surgery, researchers hope to learn more about this connection. This includes taking a closer look at how bariatric surgery changes the microbiome along with the impact this connection may have on the development of colorectal cancer.

“We know that obesity and bariatric surgery are both on the rise,” says James Yoo, MD, a member of the Section of Colon and Rectal Surgery at the Brigham, who is co-leading the new research initiative. “In addition, colorectal cancer is one of the most common cancers in the world. The first step of this research is to try to understand some of the mechanisms that may connect the two.”

Looking at Complicated Connections

The aim of bariatric surgery is to alleviate obesity, a known risk factor for colorectal cancer and other cancers. “But although there is a lot of evidence in the literature that bariatric surgery and weight loss reduce the risk for more types of cancer, findings from studies looking at this connection for colorectal cancer, in particular, have been mixed,” says surgeon Eric G. Sheu, MD, PhD, who is the other co-leader of the research initiative. “Some studies have suggested that bariatric surgery may actually increase the risk of colorectal cancer.”

To get at the heart of this mystery, the team has turned to mouse models of bariatric surgery that had previously been established in the lab. Obese mice are treated with a gastric sleeve procedure similar to the one used in humans. Their feces are collected before and after the procedure and their microbiota are analyzed. (The same can be done in humans.)

“There are some specific types of changes in the microbiota we’ve observed that are consistent after bariatric surgery in both mice and patients,” Dr. Sheu says. “We’re working to understand which groups of organisms may mediate these changes on the microbe side and exactly what the changes are on the host side.”

Once these connections are made, one outcome of this research may be using certain strains or microbial signatures as a biomarker to determine which patients might need to be monitored more closely for the development of colorectal cancer after their bariatric surgery. According to Dr. Sheu, he and his colleagues are not able to narrow the connection down to particular strains. Rather, they are focused on trying to understand the mechanisms that may be involved.

Collaboration Enables Unique Studies

Collaboration is important not only for this research but for the work of the Laboratory for Surgical and Metabolic Research more broadly. The lab has several active areas of investigation involving animal models of surgery and translational studies of patients and patient samples.

In his other work, Dr. Yoo examines the molecular mechanisms in colorectal cancer signal transduction, which includes studying colitis-associated cancers. Dr. Sheu’s other research focuses on understanding the role of immunometabolism and the microbiome in type 2 diabetes resolution after bariatric surgery.

“The members of our lab are very collaborative, which allows for a lot of cross-specialty interactions,” Dr. Yoo says. “There’s a lot of research firepower at the Brigham, and being able to access all these resources and bring together people with seemingly different specialties allows us to address these complicated problems that would be difficult to tackle elsewhere.”

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Role of Neurons in the Tumor Microenvironment that Drive Cancer Growth

Source: Brigham and Women's Hospital
Date: 4/5/2022
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Cancer researchers increasingly are recognizing the role that different cell types within the tumor microenvironment play in advancing disease growth. In recent years, research discoveries in angiogenesis and immunotherapy have led to the approval of drugs that slow the growth and spread of cancer by targeting cells within the tumor microenvironment, validating this approach. Yet the role of neurons and the nervous system has remained largely unexplored.

Humsa Venkatesh, PhD, a cancer biologist in the Department of Neurology at Brigham and Women’s Hospital, is studying the neural regulation of cancer and how nerve cells found within the tumor microenvironment drive malignant growth. Her research has implications for primary brain tumors such as gliomas as well as for other types of cancers both in and outside of the brain.

“My work lays the foundation for a new field focused on the neurobiology of cancers,” Dr. Venkatesh says. “We’ve found that the nervous system plays a fundamental role in tumor growth and that this dependency on neural input is a huge vulnerability for a number of cancers.”

How Brain Cancer Hijacks Normal Growth Mechanisms

Dr. Venkatesh began this area of inquiry as a postdoctoral fellow at Stanford, with a focus on pediatric high-grade gliomas. She hypothesized that since neurons are a large component of the brain tumor microenvironment and neural activity plays such a strong role in development, the cancer cells may similarly rely upon activity for progression.

Using techniques such as optogenetics and single-cell sequencing, she and her colleagues showed that interactions between neurons and glioma cells include activity-dependent secretion of mitogens and, perhaps more importantly, electrochemical communication that occurs via direct neuron-to-glioma synapses.

“It is interesting because cancer cells seem to hijack normal mechanisms of neural signaling,” Dr. Venkatesh says. “Our findings make it clear that these tumor cells physically and functionally integrate into the brain’s normal, healthy neural circuits.”

The work, published in Nature, utilized preclinical models of glioma to further demonstrate that blocking this electrochemical signaling either with drugs or by inducing genetic changes slowed tumor growth.

“This electrical aspect of cancer biology has been completely underappreciated, and it gives us a new strategy to attack these tumors therapeutically,” Dr. Venkatesh says.

This research led to the development of clinical trials of repurposed neuromodulatory drugs for the treatment of some forms of primary brain cancer.

Shifting Focus to Brain Metastasis

Since joining the Brigham, Dr. Venkatesh’s work has expanded to study the role that neurons within the tumor microenvironment play in the progression of metastatic brain cancers.

“We know that a lot of cancers tend to be innervated, including prostate, lung and pancreatic cancers,” she says. “This got me thinking about whether these non-glial derived cancers also respond to neuronal cues.”

Although many cancers have the ability to spread to the brain, they are different from brain cancers in that they do not originate in glial cells. “But what is fascinating is that these metastatic cells upregulate similar neuronal gene expression profiles,” Dr. Venkatesh says.

Currently, Dr. Venkatesh’s research is largely focused on small cell lung cancer. Her team is looking at how these cancer cells have the ability to use signals from neurons in the tumor microenvironment and leverage them to communicate with neighboring cells. This integration and communication appear to be essential for the growth and spread of tumors.

“We know there may be different mechanisms and different neural populations involved,” she says. “But what’s become quite clear is that neuronal communication is a critical component of the tumor microenvironment for a large number of different cancers.”

Uniting Disciplines to Study Cancer Neuroscience

Dr. Venkatesh explains that she came to the Brigham to help grow a new program in cancer neuroscience. She’s looking forward to collaborating with other investigators at the Brigham as well as with colleagues at Massachusetts General Hospital, Harvard Medical School and MIT.

“We’re at a critical juncture where there have been so many advances in technology as well as in interdisciplinary science,” she says. “Neuroscientists, molecular biologists, cancer biologists and others have all worked together to advance this interesting and exciting new field.”

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Study Reveals How Cancer Cells Hijack Mitochondria From Immune Cells

Source: Brigham and Women's Hospital
Date: 1/25/2022
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By taking the brakes off the immune system and allowing it to attack cancer cells, checkpoint inhibitors have spurred significant advances in the treatment of many people with cancer over the past decade. But for patients who do not respond to these drugs — still the majority of people with cancer — alternative interventions are needed.

A team of investigators from Brigham and Women’s Hospital and MIT is using the power of nanotechnology to develop an entirely new approach for boosting the immune response to cancer. Through the use of field-emission scanning electron microscopy (FESEM), they have learned that cancer cells actually steal mitochondria from T cells — an action that both strengthens the cancer cells and weakens the immune response.

“Nanotechnology is helping us to better understand important basic biological functions,” says Shiladitya Sengupta, MS, PhD, co-director of the Brigham’s Center for Engineered Therapeutics and the study’s senior author. “If we could develop a drug to inhibit this hijacking of mitochondria, it could make immune checkpoint therapy much more effective. That’s what we’re now trying to do.”

Dr. Sengupta and team’s latest study was published in November in Nature Biotechnology.

Observing the Transfer of Mitochondria

To study the interactions between cancer cells and immune cells, Dr. Sengupta’s team co-cultured breast cancer cells with different types of immune cells, including T cells. When they looked at the cells using FESEM, they saw that tube-like filaments were connecting the two types of cells. “The cancer cell sends out these nanotubes, which are almost like tentacles,” he says.

When researchers zoomed in further, they noticed there were small particles along the length of these filaments. Suspecting the particles were mitochondria, they labeled these organelles with a fluorescent green dye that bonds to mitochondrial proteins. They then were able to observe the mitochondria being pulled out of the T cells, traveling the length of the nanotubes and being incorporated into the cancer cells.

Further analysis of the metabolic functions of both the immune cells and the cancer cells confirmed that the shift in mitochondria from one cell to the other was affecting cell function.

Look for Drug Strategies to Protect Immune Response

Next, the researchers tested whether they could intervene and prevent the cancer cells from hijacking mitochondria. In mouse models of breast cancer, they injected a drug that blocks the formation of these filaments. When they combined this agent with immune checkpoint inhibitors, they saw a significant reduction in tumor growth in the mice.

Dr. Sengupta’s team is now working with other investigators to develop next-generation filament-inhibiting agents that are more drug-like and potentially could be developed for evaluation in clinical trials.

“The implication of this work is that if we can prevent the mitochondrial hijacking from happening, essentially preventing the T cell’s batteries from being stolen by the cancer cells, then the immune cell retains the energy to attack the cancer cell,” he explains.

Dr. Sengupta expects this approach could be successful for a number of different solid tumors. “We’ve observed this behavior in lung cancer, breast cancer, melanoma and many other tumor types,” he says. “We believe this could be part of a broad strategy for making immunotherapy more effective.”

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STUDYING NEW APPROACHES FOR IMMUNOTHERAPY IN RENAL CANCER

Source: Brigham and Women's Hospital
Date: 2/3/2021
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Immunotherapy with checkpoint inhibitor drugs is an emerging treatment for renal cell carcinoma. Now investigators from Brigham and Women’s Hospital have reported the results from lab research looking at a potential new way to boost the immune system’s ability to fight cancer.

The approach, which uses a small molecule to target the protease inhibitor SerpinB9, not only affects tumor cells themselves but also cells in the microenvironment, including immunosuppressive cells. Results from this work were published recently in Cell.

“Not much is known about this protein and its role in tumor immunity, so more work needs to be done,” said Reza Abdi, MD, of the Brigham’s Division of Renal Medicine and the paper’s senior author. “But based on our early work, we thought that targeting SerpinB9 would introduce a potentially more multifaceted approach than current checkpoint inhibitor drugs.”

Targeting a Molecule That Protects Cells From Attack

SerpinB9 is an inhibitor of granzyme B, a protease that induces apoptosis. Granzyme B is commonly found in two types of immune cells, natural killer cells and cytotoxic T cells, and they use it to attack tumor cells. The role of SerpinB9 is to prevent granzyme B from attacking the immune cells themselves.

“It appears, however, that tumor cells put out their own SerpinB9 to fight against immune cells,” Dr. Abdi said. “That makes this protease inhibitor a potential target for anticancer therapy.”

In the paper, the investigators report that when they used a small molecule to block SerpinB9, it slowed the growth of tumor cells, indicating this molecule is important for tumor growth. The research was done in cell cultures and in mouse models of several types of cancer, including renal cancer. Additionally, targeted SerpinB9 appeared to affect both the tumor stromal cells and immunosuppressive cells in the tumor.

Looking for Synergistic Effects and Future Applications

Dr. Abdi said that one focus of his current work is optimizing the molecules that could be used to target SerpinB9. Additional research is needed on the binding and kinetics as well as on potential toxicities. He explained that because SerpinB9 can be blocked with a small molecule rather than an antibody, this type of drug may prove less costly to develop.

“Checkpoint inhibitors can have frequent and sometimes lethal toxicities,” he noted. “This should prompt us to look for other approaches and compare them head to head for both efficacy and toxicity.”

Dr. Abdi also plans to study in more depth whether adding a SerpinB9-targeting drug to treatment with an immune checkpoint inhibitor could have a synergistic effect. “Immune checkpoint drugs don’t work very well on ‘cold’ tumors that lack immune infiltration,” he said. “Because SerpinB9 is also found in the tumor microenvironment, blocking it may make these drugs work better.”

In addition to its potential applications for renal cancer, this drug could prove effective in other solid tumors as well. The paper also studied it in models of melanoma, breast cancer and lung cancer. “This is an exciting field, and the ability to target a different mechanism of action in cancer opens up new opportunities for treatment,” Dr. Abdi concluded.

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CLINIC SCREENS HIGH-RISK PATIENTS TO REDUCE INCIDENCE OF ANAL CANCER

Source: Brigham And Women's - On a Mission
Date: 5/30/2023
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Screening guidelines for cervical cancer have been recognized for decades. But for other cancers linked to human papillomavirus (HPV), including anal cancer, cancer screening guidelines are not well-developed.

Since 2020, a unique Brigham and Women’s Hospital clinic has offered high-resolution anoscopy (HRA) to screen for anal dysplasia in people at increased risk of anal cancer due to HPV infection, HIV status, and other factors. The clinic aims to reduce the incidence of anal cancer in high-risk populations.

“The value of treating anal dysplasia to prevent anal cancer for the highest-risk patient population has now been established and is still being studied for lower-risk groups,” says colorectal surgeon James Yoo, MD, one of the two founders of the HRA clinic. “The field is still evolving, and more data are needed to determine the best practices. But this is clearly an area where we can make an impact in cancer prevention, especially for patients at higher risk.”

“As an infectious disease doctor, I’m obviously interested in the different diseases and complications that affect HIV patients,” says Jennifer A. Johnson, MD, a clinician-educator and the clinic’s other co-founder. “We know that people with HIV are one of the highest-risk groups for the development of anal dysplasia and anal cancer, making this an important population to focus on.”

A Collaborative Approach to Patient Care

Results from the phase 3 Anal Cancer–HSIL Outcomes Research (ANCHOR) trial, published in The New England Journal of Medicine in June 2022, demonstrated for the first time that treatment for anal high-grade squamous intraepithelial lesions reduced the progression to anal cancer when compared with active monitoring. Drs. Yoo and Johnson note that this study’s findings help illustrate the value of the Brigham’s HRA clinic.

“HRA requires special equipment that’s not commonly available as well as special training to learn how to perform the procedure and to know what to look for,” Dr. Yoo says. “In terms of what our clinic can offer, it’s relatively special.”

In addition to Drs. Yoo and Johnson, colorectal surgeon Ronald Bleday, MD, also participates in the clinic.

The clinic’s collaborative approach produces significant benefits for patients. Follow-up care may consist of a range of actions depending on what is found during the HRA exam. These include annual anal Pap smears, HRA exams offered on an annual or semiannual basis, ablation of dysplastic lesions, and more extensive surgical procedures.

HRA Offered as Simple Office Procedure

When a patient is referred to the clinic, they can have their HRA exam performed on their first visit. This makes scheduling less burdensome.

“The HRA procedure is very similar to a cervical colposcopy,” Dr. Johnson notes. “It requires no anesthesia beyond sometimes a local anesthetic. It is minimally invasive, doesn’t require any specific preparation on the patient’s part, and doesn’t affect their activities for the rest of the day.”

Beyond those with HIV, patients taking immune-suppressing drugs to treat autoimmune diseases may also be at increased risk of developing lesions caused by HPV. The leaders of the HRA clinic provide consultations to physicians both inside and outside the Brigham to help them identify which patients may benefit from enrollment in the clinic’s programs. The clinic also provides opportunities to counsel patients on topics like HPV vaccination.

“These visits provide a good opportunity to make sure we’re paying attention to any concerns the patients have about minimizing their cancer risks,” Dr. Johnson says.

“We have a pipeline of patients who come to us because their providers are aware of the need to screen for anal dysplasia,” Dr. Yoo adds. “One of our continuing roles is to educate other doctors about which patients they should send to us for evaluation.”