Hematologists with Vanderbilt-Ingram Cancer Center have published strategies for implementing outpatient treatment programs for bispecific antibodies, an immunotherapy that can cause adverse reactions.

The recommendations, published recently in JCO Oncology Practice, detail a comprehensive overview of the potential risks, treatment options for dealing with reactions, prophylactic protocols to prevent them from occurring, and the roles of an interdisciplinary care team within an outpatient program. The team at Vanderbilt-Ingram has expertise in outpatient care models for immunotherapy treatment because Vanderbilt-Ingram was among the first in the nation to establish outpatient protocols for another personalized immunotherapy, CAR-T.

Bispecific antibodies (BsAb) utilize engineered antibodies, molecular spikes, which bind to both cancer cells and immune cells, activating a patient’s T cells to attack hematologic malignancies. With CAR-T (chimeric antigen receptor T-cell therapy), T cells are harvested from a patient, then reengineered to recognize and destroy cancer cells before being infused back into the patient’s body. Both therapies can elicit strong immune responses with complications that pose risks, including cytokine release syndrome, a potentially life-threatening reaction that can damage healthy tissues and organs.

For this reason, the BsAb and CAR-T therapies typically require inpatient monitoring, which can be an economic and logistical burden for both patients and hospitals.

“Bispecific antibodies are a major advance in the field of cancer immunotherapy,” said the article’s corresponding author, Bhagirathbhai Dholaria, MBBS, associate professor of Medicine. “This class of drugs is available off the shelf, which makes them ideal for utilization in the community settings. In this article, we have provided a comprehensive framework to establish an outpatient bispecific antibodies program, especially for community practices, which do not have an already established CAR-T program. Our strategy has the potential to greatly reduce the logistical and financial burden during step-up dosing of bispecific antibodies while maintaining safety of the patients.”

The protocols suggested are for seven BsAb therapies that have been approved by the Food and Drug Administration for non-Hodgkin lymphoma and multiple myeloma. They address potential complications, including cytokine release syndrome, infections, cytopenia, tumor flare reactions, and immune effector cell-mediated neurotoxicity syndrome.

The authors noted that while outpatient programs for CAR-T were established before bispecific antibodies, CAR-T poses higher risks for adverse reactions. Their recommendations prioritize early recognition and intervention for these complications, particularly in the first cycle of treatment with BsAb when most cytokine release syndrome events are likely to occur.

The paper provides an infrastructure and workflow guide for how clinicians can work with patients to implement monitoring and address care needs. They also stress the importance of educating both patients and family/friend caregivers about proper protocols for remote monitoring.

The article’s additional authors are Kian Rahbari, MD, and Raul del Toro Mijares, MD, Kathryn Kennedy, RN, Leslie Mader, RN, Salyka Sengsayadeth, MD, Reena Jayani-Kosarzycki, MD, James Jerkins, MD, Andrew Jallouk, MD, Tae Kon Kim, MD, Shakthi Bhaskar, MD, Vivek Patel, MD, Brittney Baer, RN, Sarah Moseley, RN, David Morgan, MD, Bipin Savani, MD, Adetola Kassim, MD, Muhamed Baljevic, MD, and Olalekan Oluwole, MD.

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About 1 in 5 patients with cancer who undergo genetic testing are incidentally found to have mutations in their blood called clonal hematopoiesis of indeterminate potential (CHIP). A study from Vanderbilt Health researchers reveals that it puts them at increased risk for heart disease following cancer treatment.

The findings, published Jan. 8 in JAMA Oncology, support the potential benefits of screening patients for CHIP before they undergo cancer treatment so they can be more closely monitored for heart complications. CHIP is a condition, not a disease, characterized by age-related variants in blood stem cells, and it is typically asymptomatic.

The researchers were able to determine which patients had CHIP by using Vanderbilt Health’s biorepository, BioVU, to link electronic health records with whole-genome sequencing data. They compared the cardiovascular health outcomes of the patients with CHIP to outcomes of patients without the condition. All the patients had been diagnosed with solid tumors, and none had heart failure, ischemic heart disease or arrhythmia before undergoing cancer treatment.

Over a 10-year period following treatment, patients with CHIP had a significantly higher incidence of heart failure (20.3% versus 14.5%) and ischemic cardiovascular disease (25.3% versus 18.5%). The effect was amplified in patients who received more intensive chemotherapy.

“We frequently find CHIP in patients with cancer, but previously we did not consider this to be an important result for their care. We now know that these patients are at higher risk of heart disease and would likely benefit from including cardiologists in their care team,” said the study’s corresponding author, Alexander Bick, MD, PhD, associate professor of Medicine, holder of the Edward Claiborne Stahlman Chair, and director of the Division of Genetic Medicine and Clinical Pharmacology.

The patients received chemotherapy, radiotherapy, immunotherapy, or a combination of the treatments. Cardiovascular disease is the leading cause of noncancer deaths among cancer survivors.

The researchers analyzed data from 8,004 patients, and 549 of them were identified with CHIP. To their knowledge, the study is the largest to date evaluating the association between CHIP and cardiovascular disease in patients with solid tumors who underwent cancer treatment. Most patients with CHIP were male (54% versus 45%) and had hypertension (78% versus 69%) compared to patients without the condition.

The clinical implications of the study are that there may be value in testing patients for CHIP prior to cancer treatment to stratify risk and tailor monitoring for cardiovascular diseases and offering early cardio-oncology consultations as well as consideration of cardioprotective strategies.  

The researchers received support from the National Institutes of Health (grants DP5OD029586 and T32GM007347). The sequencing of 250,000 individuals who have donated samples to BioVU has been funded by the Alliance for Genomic Discovery.

The study’s first authors are Derek Shyr, PhD, and Yash Pershad. The study was jointly supervised by Bick and Leo Luo, MD, assistant professor of Radiation Oncology at Vanderbilt Health.

Other Vanderbilt Health authors on the study are Ashwin Kishtagari, MD, Robert Corty, MD, PhD, Eric Shinohara, MD, MSCI, Ben Ho Park, MD, PhD, and Brett Heimlich, MD, PhD.

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A multi-institutional research team that included genomic scientists from Vanderbilt Health has identified a potential target for blood cancer prevention and treatment.

Their report, published Jan. 1 in the journal Science, could lead to new treatments for blood cancers, which kill an estimated 23,540 people in the United States every year.

The research team, led by scientists from Boston Children’s Hospital, Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and Memorial Sloan Kettering Cancer Center, found that the protein Musashi-2 (MSI2) is essential for the function of blood-forming stem cells.

High levels of MSI2 can support the unchecked growth of abnormal stem cells, a precancerous condition known as clonal hematopoiesis of indeterminate potential, or CHIP.

The researchers used a genome-wide association study (GWAS) meta-analysis to identify a haplotype, or inherited grouping of genomic variants, which reduces MSI2 expression, thereby protecting against CHIP.

To validate these findings in humans, Alexander Bick, MD, PhD, Yash Pershad, and colleagues leveraged Vanderbilt Health’s DNA biobank, BioVU, the world’s largest repository of genetic material linked to de-identified electronic health records based at a single academic center.

By analyzing a unique longitudinal cohort of 3,000 patients with genetic sequencing performed approximately six years apart, the Vanderbilt Health team tested whether a variant which reduced the expression of MSI2 protected against the expansion of precancerous mutations.

Patients who carried the protective variant had precancerous clones that grew significantly more slowly than those without the variant. In many of these patients, the abnormal cells were transient; that is, they disappeared entirely over the study period rather than expanding into cancer.

“Most genetic studies only provide information from a snapshot in time, but the longitudinal samples in BioVU allowed us to study the mutations over six years,” noted Pershad, an MD/PhD student in the Bick lab, who with Bick is among the paper’s co-authors.

“We could clearly see that in people with the protective variant, precancerous clones behaved fundamentally differently than we expected — they shrunk or disappeared rather than expanding and becoming cancer,” Pershad said.

While CHIP results from somatic (acquired) blood stem cell mutations, this protection against it is inherited. This human genetic evidence suggests a potential way to prevent blood cancer by targeting MSI2 through small molecule inhibition or genome editing.

“More broadly,” the researchers concluded, “we provide an example of how resilience to cancer can arise through inherited genetic variation, motivating the search for other natural pathways that could be leveraged to prevent or treat malignancy.”

Bick, the Edward Claiborne Stahlman Professor, associate professor of Medicine, and director of the Division of Genetic Medicine and Clinical Pharmacology at Vanderbilt Health, is internationally known for his research on the genetics of blood disorders.

His research is supported in part by National Institutes of Health grants DP5OD029586, R01AG088657 and R01AG083736, a Burroughs Wellcome Fund Career Award, a Pew-Stewart Scholar for Cancer Research award, and a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research.

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Vanderbilt Health’s Lucy Spalluto, MD, MPH, professor of Radiology and Radiological Sciences, and Jennifer Lewis, MD, assistant professor of Medicine in the Division of Hematology and Oncology, have received a grant from AstraZeneca to understand and improve veteran access to mobile lung cancer screening.

The study, “REACHing veterans at high risk for lung cancer outside the guidelines and through mobile screening,” will receive approximately $1 million in total grant funding over a four-year period. As explained by Spalluto and Lewis, lung cancer is the leading cause of cancer death in the United States, with incidence higher in veterans compared to the civilian population.

“Improving access to lung cancer screening for a broader population, including those who live in rural areas, through mobile services can increase the early detection of lung cancer and improve lung cancer outcomes,” Spalluto says. “The REACH study explores the impact of mobile lung cancer screening in the Veterans Health Administration. An important component of the REACH study is understanding veterans’ perspectives of mobile screening.”

Screening for lung cancer with low-dose CT scans is an effective strategy to detect lung cancer early and improve mortality. However, this screening is widely underutilized, including in the Veterans Health Administration. Veterans living in rural areas are less likely to be screened for lung cancer, and individuals living in rural areas have higher mortality from lung cancer compared to those who live in nonrural areas.

In response to the low screening and high mortality rates, the VA’s Midsouth Veterans Integrated Service Network has partnered with the VA Lung Precision Oncology Program to offer mobile lung cancer screening to better reach veterans who reside in rural areas. Spalluto and Lewis have been awarded the REACH grant through AstraZeneca to understand the reach of mobile lung cancer screening among veterans within and outside current screening eligibility criteria, as well as veterans’ experiences with mobile lung cancer screening.

This work is particularly pertinent to veterans who may have been exposed to war-related chemical, waste and other similar smoke inhalation.

“Exposures that veterans have had because of their military service, such as Agent Orange and burn pits, may place them at high risk for lung cancer,” Lewis explains. “This study will help us understand how many veterans are eligible for lung cancer screening not only based on age and smoking history, but also other important risk factors, such as family history, personal history of cancer, diagnosis of COPD and military environmental exposures. These data will be critical for VA leadership.”

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Anna Means, PhD, whose 25 years of research at Vanderbilt Health advanced the understanding of early pancreatic cancer, died Nov. 28 at her sister’s home in Pelham, Alabama, following a 2023 diagnosis of brain cancer. She was 63.

A longtime collaborator of the late R. Daniel Beauchamp, MD, former chair of the Section of Surgical Sciences, in 2024 Dr. Means moved to the Department of Plastic Surgery where, as research professor of Plastic Surgery and Cell & Developmental Biology, she helped oversee development of a tissue engineering laboratory.

“Dr. Anna Means was my close friend, collaborator and colleague for over 30 years,” said Maureen Gannon, PhD, professor of Medicine in the Division of Diabetes, Endocrinology and Metabolism.

In addition to her research, Dr. Means mentored dozens of undergraduate, graduate and postdoctoral students, research staff and faculty. She was also a highly knowledgeable bird watcher, talented gardener and outdoor enthusiast. “She inspired us all with her grace and positivity and love of life,” Gannon said. “I will miss her terribly.”

An outstanding independent scientist and valued colleague, Dr. Means “was exacting and thorough in her scientific efforts and had an exceptional sense of integrity,” said Seth Karp, MD, H. William Scott Jr. Professor of Surgery and chair of the Section of Surgical Sciences. “She was highly respected across our campus and in the scientific community for her honesty, compassion and intelligence.”

A native of Ohio, Dr. Means earned her doctorate in Cell and Molecular Biology from the University of Wisconsin-Madison in 1991 and did postdoctoral work at Cornell University Medical College and Vanderbilt University before joining the Vanderbilt faculty in the Department of Surgery in 2000.

For 10 years until Dr. Beauchamp’s death in 2022, she was a close collaborator, serving as senior scientist in his lab, overseeing the work of research staff, and contributing as co-investigator and co-author to research that yielded important insights into the development of colorectal cancer.

In collaboration with other Vanderbilt faculty including Gannon and Christopher Wright, DPhil, professor of Cell & Developmental Biology, Dr. Means also led a highly productive research effort in pancreatic cancer and development of the pancreas.

She was founder and organizer of the Vanderbilt Pancreatic Cancer Researchers group, which convened a monthly research conference for basic and clinical investigators studying pancreatic cancer, and she organized the Beta Cell Interest Group, which held weekly seminars on studies related to pancreas development and function.

In 2009 Dr. Means received a Vanderbilt-Ingram Cancer Center Impact Award for her contributions to cancer research.

“At her core, Dr. Means was kindhearted, compassionate and deeply committed academically,” Karp said. “She demonstrated tireless dedication and achieved significant contributions to oncologic research as well as to the critical research and education missions of Vanderbilt. She made everyone around her better for having known, admired and worked with her.”

Dr. Means is survived by her mother, Joan Means, brothers, Christopher (Kim), Peter (Liz), and Patrick (Pam), and sisters, Michele Dragga (Chuck) and Kirsten Means.

Pending the arrangement of a memorial service in Nashville at a later date, donations in Dr. Means’ name may be made to the National Audubon Society, Friends of Radnor Lake, and Proverbs 12:10 Animal Rescue.

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Interim results from an ongoin​​g Phase 1 clinical trial for an off-the-shelf CAR-T therapy indicate that no dose-limiting toxicities or severe cytokine release syndrome instances occurred in an early and limited cohort of patients. 

The results were reported in Nature Communications on Nov. 24. Vanderbilt-Ingram Cancer Center accrued the most patients nationwide for the clinical trial for P-BCMA-ALLO1 – a chimeric antigen receptor T cell therapy (CAR-T) derived from healthy donors’ white blood cells. Currently, all CAR-T therapies approved by the U.S. Food and Drug Administration are autologous or made individually from each patient’s own reengineered T cells. An off-the-shelf or allogenic therapy derived from healthy donors would expedite the manufacture of this immunotherapy and make it readily available to patients, allowing them to start treatment sooner and expanding access to those patients not healthy enough for their own T cells to be reengineered. 

T​​he results reported in the Nature Communications study include​ data​ from 11 patients who received enhanced lymphodepletion, which is short-course chemotherapy to reduce the number of lymphocytes and create a favorable environment for the CAR-T therapy. Clinical analyses of patient responses and additional enrollment continue in the ongoing phase 1 trial. 

“P-BCM-ALLO1 differs from other CAR T-cell products due to the non-viral vector gene editing technology used during manufacturing. This approach allows P-BCMA-ALLO1 to retain T-cell memory phenotype compared with an activated T-cell phenotype common with CAR-T products using a viral-vector,” said Bhagirathbhai Dholaria, MBBS, associate professor of Medicine at Vanderbilt University Medical Center, who is leading the clinical trial at VUMC and is one of the study’s lead authors. 

P-BCMA-ALLO1 has exhibited characteristics that are crucial for CAR-T therapy because it is typically a one-and-done treatment. The study’s authors noted that the therapy had an optimal potency profile characterized by a strong memory phenotype and significant proliferative capacity. They stated that it “functions as a prodrug, conferring multipotency to rapid expansion and control of the tumor.” 

The interim results do not include enough data to make determinations about clinical efficacy of P-BCMA-ALLO1 because of the limited number of participant responses analyzed at this point, but Dholaria has observed positive results in individual patients. 

​​​​​“I have observed remarkable response rates in heavily pre-treated multiple myeloma with minimal cytokine release syndrome or neurological side effects,” he said. “In this study, I have also treated patients who have previously failed autologous CAR-T therapies or bi-specific antibodies. The ongoing study will help determine optimal cell dose and conditioning regimen for P-BCMA ALLO1.” 

The clinical trial for P-BCMA-ALLO1 is continuing to recruit participants. For more information about the clinical trial at Vanderbilt-Ingram Cancer Center, call 800-811-8480 or 615-936-5847 or email cip@vumc.org. 

“These are exciting times for our patients,” said Olalekan Oluwole, MBBS, MPH, associate professor of Medicine, who leads the cellular therapy research program at Vanderbilt-Ingram. “P-BCMA-ALLO1 CAR-T was engineered for the safety of patients. Furthermore, being an off-the-shelf CAR-T product meant we could get it to our patients almost immediately.” 

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Researchers from Vanderbilt-Ingram Cancer Center will present findings from clinical trials, laboratory discoveries and innovations in caring for patients with hematologic cancers and other blood diseases at ASH 2025 in Orlando, Florida, Dec. 6-9. 

ASH 2025 is the American Society of Hematology Annual Meeting and Exposition. Established in 1958, ASH is the world’s largest professional organization for clinicians and scientists who study blood diseases.  

Three of the presentations from Vanderbilt-Ingram researchers will focus on chimeric antigen receptor T-cell (CAR-T) therapies, a form of immunotherapy that involves treating cancer with white blood cells that have been reengineered to attack cancer cells. Vanderbilt-Ingram is an international leader in advancing the efficacy of and expanding access to CAR-T therapies.

Olalekan Oluwole, MBBS, MPH, associate professor of Medicine, who leads the cellular therapy research program at Vanderbilt-Ingram, will present data on health care resource utilizations of the therapies in U.S. patients treated at newly authorized treatment centers. He will also provide an overview of outcomes for inpatient and outpatient CAR-T treatment. Grace Mercadante, MD, will present data on the impact of clonal hematopoiesis on CAR-T therapy. 

Michael DeBaun, MD, MPH, the J.C. Peterson, MD, Professor of Pediatrics and founder and director of the Vanderbilt-Meharry Sickle Cell Disease Center of Excellence, will speak at a special session focusing on ASH’s sickle cell disease initiative. He will present findings from “Sickle Cell Trait Does Not Cause ‘Sickle Cell Crisis’ Leading to Exertion Related Death: A Systematic Review.” 

Other topics researchers will address include acute myeloid leukemia, myelodysplastic syndrome, drug resistance, potential adverse reactions and risk comparisons of treatments, pediatric blood disorders, multiple myeloma, bispecific antibody treatment, and graft-versus-host disease. 

A complete list of presentations from Vanderbilt researchers follows: 

Sally Momoh, MD – Sex-related differences in silent cerebral infarction burden among adults with sickle cell disease 

Jamila Mammadova, MD – Behind the blood-brain barrier: Contemporary screening practice patterns and trends of central nervous system involvement in acute myeloid leukemia treated with intensive regimens and hypomethylating agent/venetoclax 

Alyssa Jarabek – Impact of innate immune memory on myelodysplastic syndrome progression by TET2-driven inflammation 

Raymond Zhang – VISTA contributes to disease progression in high-risk myelodysplastic syndrome 

Mattew Villaume, MD, PhD – EB2023 primes mitochondria for BCL2 dependence and induces pyroptotic cell death via AMPK signaling and the unfolding protein response 

Grace Mercadante, MD – The impact of clonal hematopoiesis on CAR-T cell therapy outcomes: a single-center analysis 

Ghadeer Dawwas, PhD, MSc, MBA – Risk of serious bleeding with concomitant use of apixaban or rivaroxaban with amiodarone compared to flecainide or sotalol in patients with atrial fibrillation  

Olalekan Oluwole, MBBS, MPH – Real-world health care utilization following CAR-T cell therapy in U.S. patients treated in newly authorized treatment centers 

Erin Christensen, MS, DO – A case series of pediatric patients with congenital thrombotic thrombocytopenia purpura treated with recombinant ADAMTS13 

Andrew Jallouk, MD, PhD – Real-world outcomes of mosunetuzumab use in indolent and aggressive lymphomas  

Bhagirathbhai Dholaria, MBBS – Characterization of a population with newly diagnosed standard risk multiple myeloma by 2025 ims/IMWG definition with exceptional long-term outcomes after fixed duration therapy 

Y. Emily Chu – The acute myeloid leukemia microenvironment is defined by ineffective immune surveillance despite the presence of activated, clonally-expanded CD8 T cells with preserved effector function 

Michael DeBaun, MD, MPH – Findings from “Sickle cell trait does not cause ‘sickle cell crisis’ leading to exertion related death: a systematic review ”

Mattew Villaume, MD, PhD – F1 subunit-specific ATP synthase inhibition disrupts AML mitochondrial metabolism distinctly from other electron transport chain inhibitors 

Lauren Klein, MD, – Early weight gain predicts nutritional recovery in children with sickle cell anemia and severe acute malnutrition in Nigeria 

Olalekan Oluwole, MBBS, MPH – U.S. cost consequence and time toxicity model for advanced therapies in the treatment for relapsed/refractory third-line or later diffuse large B-cell lymphoma: a comparison of axicabtagene ciloleucel with bispecific antibodies 

Olalekan Oluwole, MBBS, MPH – Outcomes of inpatient and outpatient CAR-T in newly authorized treatment centers in the United States 

Elizabeth Pollard, MD – Leukapheresis for acute leukemia with hyperleukocytosis: line complications, resource utilization, and early mortality outcomes 

Carrie Kitko, MD – Long-term treatment duration and safety of axatilimab among patients with chronic graft-versus-host disease in AGAVE-201 

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While most women over age 50 schedule mammograms for breast cancer, only a minority who are also eligible for low-dose CT scans for lung cancer undergo those potentially lifesaving screenings. A new study shows that targeted outreach can close the gap.

The study results, published Dec. 1 in the Journal of the American College of Radiology, showed that the improvement in lung cancer screenings exceeded the target enrollment set by the researchers. The study also demonstrated that two different types of outreach initiatives were effective in increasing uptake. Called CALM, an acronym for Coordinate A Lung screening with Mammography, the study was funded by the American Cancer Society.

At one academic medical center, a research team from pulmonary medicine determined eligibility by manual review of smoking history in electronic health records and then contacted patients directly to inform them of eligibility. The team also conducted surveys at mammography locations about smoking history. They had a target enrollment of 200 new patients for lung cancer screening and exceeded it by enrolling 214 patients.

At the other academic center, researchers from radiology identified patients eligible for lung screenings one month prior to their mammography appointments through a review of electronic health records. The patients were offered the opportunity to have both cancer screenings on the same day at the same location. They also exceeded their target enrollment of 322 patients by enrolling 445 patients.

“For years, we have recognized that many women screened for breast cancer are in fact dying from lung cancer. This study allowed us the opportunity to inform women and their referring providers of lung screening eligibility and to facilitate lung screening exams.  We are incredibly grateful for the American Cancer Society and for the National Lung Cancer Roundtable as they supported this multicenter initiative.  We plan to continue these efforts at VUMC and with institutions across the country to save more lives,” said Kim Sandler, MD, professor of Radiology and Radiological Sciences at Vanderbilt University Medical Center, director of the Vanderbilt Lung Screening Program, and the study’s corresponding author and co-principal investigator.

A previous study revealed that 58% of women who were eligible for lung cancer screening had reported having a mammogram within two years compared to only 7.9% who underwent lung cancer screening. Overall, participation in lung cancer screening by both men and women is low, with less than 20% of those eligible for low-dose CT scans receiving the screenings.

“It has been more than 10 years since annual screening for lung cancer was recommended, and screening rates still are disappointingly low. There are many reasons for these low rates, but mostly identifying eligible individuals is challenging in the primary care setting, and there is evidence showing a surprising lack of awareness about lung cancer screening among eligible individuals. The CALM model demonstrates we can successfully recruit eligible women through mammography screening. Perhaps we also will be able to enlist them to encourage eligible family members to have a conversation about lung cancer screening with their health care providers. There is enormous potential here, and the ACS is thrilled with the outcome of this study,” said Robert Smith, PhD, senior vice president and director of the American Cancer Society Center for Early Cancer Detection and the study’s other co-principal investigator.

The researchers hypothesized that mammography screening could be a “teachable moment” for women who are also eligible for lung cancer screening. The study period was from November 2019 to December 2021, but data from 2020 was excluded because of the disruptions in health care screenings due to the onset of the COVID-19 pandemic. Initially, women were considered eligible for lung cancer screening from ages 55 to 80 with a 30 pack-year history of smoking; guidelines expanded in 2021, and women were eligible beginning at age 50 with a 20 pack-year history. One pack year is equal to smoking an average of 20 cigarettes, or one pack, every day for a year. A person who has smoked half a pack per day for 30 years has a 15 pack-year history.

Other VUMC authors on the study are Caroline Godfrey, MD, MPH, Valerie Welty, PhD, Stephen Deppen, PhD, MA, Alexis Paulson, MS, Shanna Joyner, Hannah Marmor, MD, MPH, Grace Wallace, CCRC, Lauren Hatcher, MD, MBA, Landon Fike, MD, and Arulita Gupta, MD.

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Researchers at Vanderbilt University Medical Center and the University of Calgary have established an analytical framework that integrates genomic, proteomic and electronic health record data to identify cancer risk proteins and therapeutics for cancer prevention.

Their study, reported Dec. 2 in the American Journal of Human Genetics, identifies previously unreported protein biomarkers and candidate drug targets across six major cancer types and highlights approved drugs with potential cancer preventive effects.

To date, genome-wide association studies (GWAS) have identified several hundred genetic variants associated with increased risk for breast, colorectal and prostate cancer, and several dozen risk variants for other cancers, including lung, pancreatic and ovarian cancer.

“Previous research, including our work, has identified hundreds of putative cancer susceptibility genes that could be regulated by these risk variants; however, most dysregulated gene expression has not been thoroughly investigated at the protein level,” said Xingyi Guo, PhD, associated professor of Medicine in the Division of Epidemiology at VUMC.

Guo is a co-senior author of the current study with Zhijun Yin, PhD, MS, associate professor of Biomedical Informatics at VUMC, and Quan Long, PhD, associate professor of Biochemistry and Molecular Biology at the University of Calgary.

“To deepen the understanding of causal mechanisms and enhance drug discovery efforts, it is imperative to explore data from transcriptomic to proteomic studies,” Yin said.

In the current study, the investigators integrated large GWAS data for breast, colorectal, lung, ovarian, pancreatic and prostate cancers and population-scale proteomics data from over 75,000 participants (combined from the Atherosclerosis Risk in Communities study, deCODE genetics, and UK Biobank Pharma Proteomics Project) to identify risk proteins associated with each cancer.

They identified 365 proteins associated with cancer risk, and through further analysis narrowed the list to 101 proteins, including 74 not reported in previous studies. Using a variety of pharmaceutical databases, the researchers comprehensively annotated the risk proteins as therapeutic targets of approved drugs or drugs in clinical testing. The idea, they said, is to find drugs that can potentially be repurposed for cancer prevention.

“Traditional drug discovery faces challenges of escalating costs, lengthy timelines, and high failure rates. Drug repurposing is a promising strategy to identify new applications for existing drugs with well-documented characteristics,” Guo said.

Among the 101 risk proteins, the researchers identified 36 druggable proteins potentially targeted by 404 drugs already approved or in clinical trials. Nineteen of the druggable proteins were targeted by drugs approved or in trials to treat cancer. The researchers compared drug effects using data from more than 3.5 million electronic health records (EHRs) from VUMC. They demonstrated in simulated trials with EHR data that several approved drugs, for example the diuretic medication acetazolamide, were associated with reduced colorectal cancer risk.

“Our findings offer additional insights into therapeutic drugs targeting risk proteins for cancer prevention and intervention. It is essential to evaluate the effects of the reported candidate drugs through both in vitro and in vivo assays in future research,” Yin said.

Co-first authors of the AJHG paper are Qing Li,PhD; Qingyuan Song; and Zhishan Chen, PhD. The research was supported by the National Institutes of Health (grants R37CA227130, R01CA269589, R01CA297582).

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Vanderbilt University Medical Center is one of two facilities in Tennessee recognized by Becker’s Hospital Review as “hospitals and health systems with great oncology programs” for 2025. 

“Vanderbilt-Ingram Cancer Center, part of Vanderbilt University Medical Center, is the only NCI-designated comprehensive cancer center in Tennessee that provides care for both adults and children,” Becker’s Hospital Review noted. “Recognized by U.S. News & World Report as a top-performing cancer hospital, Vanderbilt-Ingram serves more than 49,000 distinct patients and manages over 250,000 outpatient visits annually. With a team of more than 200 cancer specialists and over 300 physician-scientists, the center leads in precision medicine and translational research, supported by more than $150 million in total research funding, including $69 million in competitive NCI grants.

“Vanderbilt-Ingram offers access to more than 350 clinical trials and is the developer of MyCancerGenome.org, a globally recognized resource for genetically informed cancer care. As a member of the National Comprehensive Cancer Network, Vanderbilt-Ingram helps shape national standards in cancer prevention, treatment and survivorship care.” 

The other Tennessee hospital that made the list is Memphis-based St. Jude Children’s Research Hospital. 

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