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.

The post Guide published for outpatient cancer treatment with bispecific antibodies appeared first on VUMC News.

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.

The post Patients with clonal hematopoiesis have increased heart disease risk following cancer treatment  appeared first on VUMC News.

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.

The post Study identifies potential target for blood cancer treatment, prevention appeared first on VUMC News.

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.”

The post Lucy Spalluto and Jennifer Lewis awarded $1 million lung cancer screening grant appeared first on VUMC News.

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.” 

The post Interim data reported for multiple myeloma off-the-shelf CAR-T therapy   appeared first on VUMC News.

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 

The post Vanderbilt-Ingram researchers present cancer advancements at ASH 2025  appeared first on VUMC News.

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).

The post Large-scale integration of genomics, proteomics and clinical records identifies cancer risk proteins and potential therapeutics appeared first on VUMC News.

Vanderbilt University Medical Center offers access to new resources that help relatives connect and join forces to protect their families from inherited diseases. 

VUMC is one of the first cancer centers to partner with the ConnectMyVariant program, which offers resources for families with hereditary cancer risk. The resources make genetic medicine approachable, can help people discover distant relatives they didn’t know before, and can assist families in talking across dinner tables about a potentially sensitive topic. It’s akin to an ancestry game that allows people to amplify the family benefits of cancer prevention, and the person who starts it can be a superhero. 

To launch a connection search, someone with a specific gene variant signs up to meet others who share that variant. When people have the same gene variant, there is more than 90% chance they are related, even if it is several generations back. This begins the process of sharing stories with others who are likely to be relatives, discovering new connections with unknown relatives, and encouraging family members to get tested. The program is designed around the perspective and experience of lay people — not clinicians. It is an innovative approach to encourage genetic testing, and it’s needed, said Tuya Pal, MD, professor of Medicine in the Division of Genetic Medicine and Clinical Pharmacology at VUMC. 

“Family communication, which is the basis of what we call cascade testing, is hugely important,” said Pal, who is also Ingram Professor of Cancer Research and an associate director at Vanderbilt-Ingram Cancer Center. “BRCA genes were identified 30 years ago, but we’ve found maybe 20% of adults who are at risk for cancer. There’s a lot of adults walking around with a BRCA mutation. They could get ongoing prevention, but they don’t know it. This is a challenging nut to crack, but it is of huge public health relevance. If we can get to these people, we can save lots of lives.” 

BRCA1 and BRCA2 gene variants, which increase risk for breast, ovarian, pancreatic and prostate cancer, have received the most media attention. However, in recent years, several other gene mutations have been discovered that can also put people at risk for cancer. Pal stressed that people should seek genetic testing from reputable and accredited laboratories, which are different from many direct-to-consumer testing companies that offer testing for “recreational genetics.” While direct-to-consumer labs offer ancestry testing, sometimes they also delve into other genes; however, the quality of the data they provide is not always accurate for disease risk. For this reason, it is important to get tested through providers knowledgeable about genetic testing options, such as the Vanderbilt Hereditary Cancer Clinic. Insurance typically covers the cost for those at high risk, such as those with a personal history of specific cancers (and diagnosed at certain ages), family history of specific cancers, and those who already have a relative found to have a gene mutation. The tests, which can be done with either blood or saliva samples, cost about $250 for self-paying patients.  

Pal likens a gene mutation to a spelling mistake. 

“When we’re talking about an inherited predisposition, you can think of each gene as a big book, and a mutation is like a ‘spelling mistake’ in that book — leading to the gene not working quite right and thereby raising risk of certain cancers,” she said. “If you’ve got the same spelling mistake between two people, they are somehow related. People sometimes have trouble sharing broadly with family members, so this tool can make this experience of family communication and testing more enjoyable. You can connect with people you don’t know that are related from maybe eight generations ago.” 

ConnectMyVariant, which is operated as a nonprofit organization, was developed by Brian Shirts, MD, PhD, associate professor of Pathology, Microbiology and Immunology and of Biomedical Informatics, who was recruited to VUMC in December 2024. He is the service medical director of the Molecular Genetics Laboratories. 

“Scientific modeling has shown that if we could reach out to second and third cousins effectively of people with known variants, we could identify everyone who has a hereditary cancer risk,” said Shirts, who is also President of ConnectMyVariant’s Board of Directors. 

However, he stressed that ConnectMyVariant is not a research program or a direct clinical resource.  

“It’s an educational program,” Shirts said, noting that people should schedule a visit with a genetic counselor affiliated with a medical provider if they discover they have relatives with mutations that put them at increased risk for cancer.  

ConnectMyVariant offers educational resources for adult-onset hereditary diseases for which there are established preventive actions people can take. It is not intended for use by people younger than 18, so it does not offer resources for autosomal recessive pediatric diseases.  

“The way I like to think about what we offer is ‘If I talk to my relatives, are they going to be able to do something?’ If the answer is yes, and they can get genetic testing and do something that will improve their health, then that’s included,” Shirts said. 

The ConnectMyVariant program also offers participants access to resources for ancestry research, such as professional assistance from the Center for Family History and Genealogy at Brigham Young University.  

For individuals with inherited cancer predisposition, Vanderbilt-Ingram has the Inherited Cancer Registry (ICARE), which Pal founded in 2010. It has grown into one of the largest registries for inherited cancers, with almost 8,000 participants enrolled to date. Through the registry, the latest care and research updates are shared with participants by newsletter, email and links to presentations, and it is a way for people to be part of the larger research mission. 

Pal serves as vice chair of the National Comprehensive Cancer Network Genetics/Familial Guidelines Committee for Breast, Ovarian and Pancreatic Cancer. She leads a team of certified genetic counselors at the Vanderbilt Hereditary Cancer Clinic.

The post New resources help people take action to prevent inherited diseases appeared first on VUMC News.

A multidisciplinary team led by investigators at Vanderbilt University Medical Center has received a $4.2 million grant from the National Cancer Institute (NCI) to probe the genetics of colorectal adenomas — polyps that can develop into colon cancer — and to identify drug candidates that could reduce adenoma recurrence. 

Colorectal cancer is the second most common cause of cancer-related death in the United States, according to the NCI, part of the National Institutes of Health. Removing precancerous polyps during colonoscopy procedures significantly reduces the burden of colorectal cancer, but about 30% of patients who have a colorectal adenoma removed will develop recurrent adenomas. 

“Patients who have recurrent adenomas are at higher risk for developing cancer,” said Xingyi Guo, PhD, associate professor of Medicine in the Division of Epidemiology and lead principal investigator for the project. “We will integrate cutting-edge genomic research with real-world patient data from electronic health records, with the goal of translating genetic discoveries into actionable strategies to prevent colorectal cancer.” 

Zhijun Yin, PhD, MS, associate professor of Biomedical Informatics, is co-principal investigator for the four-year project. 

The team previously conducted genome-wide association studies (GWAS) of about 8,000 colorectal adenoma cases from European American and African American participants included in BioVU, VUMC’s de-identified DNA biobank and linked electronic health records. Using a large-scale analysis of electronic health records and pathology reports, the investigators also established the Vanderbilt Colonoscopy Cohort of colorectal adenoma cases after polyp removal, which includes 76,664 cases. 

With the new funding support, the team will extend its efforts to establish the largest-ever genetic study of colorectal adenoma, drawing on BioVU, the Mass General Brigham Biobank, and the NIH All of Us Research Program to include over 25,000 cases in European Americans and 6,500 cases in African Americans, with thousands of recurrences. African Americans are about 20% more likely to have colorectal cancer and about 40% more likely to die from it compared to other racial groups, according to the American Cancer Society. 

“Our approach will allow us to examine racial differences in adenoma recurrence and colorectal cancer risk,” Guo said. 

In addition to GWAS, the team will conduct transcriptome-wide, methylome-wide, and proteome-wide association studies to identify genes and proteins associated with colorectal adenomas and their recurrence. The investigators will integrate findings from these “omics” studies with electronic health record data from the Vanderbilt Colonoscopy Cohort and the Mass General Brigham Colonoscopy Cohort and use machine learning frameworks to identify candidate drugs that could prevent colorectal adenoma recurrence. They will test the most promising drug candidates in colorectal adenoma and cancer cells, patient-derived organoids, and animal models. 

“This project is an innovative integration of multiomics analyses with electronic health record-based real-world clinical evidence,” Yin said. “We anticipate that our findings will inform personalized colorectal polyp surveillance, guide therapeutic prevention strategies, and ultimately reduce the burden of colorectal cancer nationwide.” 

Guo holds a secondary appointment in the Department of Biomedical Informatics at VUMC, and Yin holds secondary appointments in the Department of Computer Science and the Department of Electrical and Computer Engineering at Vanderbilt University. Guo and Yin have both received NCI R37 MERIT Awards, which provide long-term grant support to outstanding investigators. 

Other collaborators for the new NCI grant (R01CA297582) include VUMC Department of Medicine investigators Wei Zheng, MD, PhD, MPH, Qiuyin Cai, MD, PhD, and Wanqing Wen, MD, MPH, Division of Epidemiology; Bhuminder Singh, PhD, Division of Gastroenterology, Hepatology and Nutrition; and Kristen Ciombor, MD, MSCI, Division of Hematology and Oncology; and Harvard T.H. Chan School of Public Health investigator Mingyang Song, ScD, Departments of Epidemiology and Nutrition.

The post New NCI-funded project targets polyp recurrence to prevent colon cancer appeared first on VUMC News.

Researchers from Vanderbilt University Medical Center have demonstrated in a precision-based clinical trial that a magnesium supplement increases gut bacteria in humans that have been shown to synthesize vitamin D and inhibit colorectal cancer carcinogenesis.

However, the effect was observed primarily in females — an outcome that the researchers surmised may be attributable to the role that estrogen plays in shifting magnesium from circulation into cellular uptake.

Intestinal microbiome data and colonoscopy results were analyzed from participants who were randomized by whether they had the TRPM7 genotype, which plays a crucial role in regulating magnesium and calcium uptake.

Previously, the investigators showed in the same randomized trial that magnesium enhances the synthesis of vitamin D and increases the blood levels of vitamin D. The findings from the current study suggest that magnesium also increases the gut synthesis of vitamin D, which does not go to the blood and takes effect locally.

These results from the Personalized Prevention of Colorectal Cancer Trial were published Sept. 12 inThe American Journal of Clinical Nutrition. 

“Our previous study showed magnesium supplementation increased blood levels of vitamin D when vitamin D levels were low,” said Qi Dai, MD, PhD, professor of Medicine. “The current study reveals that magnesium supplementation also increases the gut microbes which have been shown to synthesize vitamin D in the gut without sunlight and locally inhibit colorectal cancer development.”

The participants were divided into two arms, one that received the magnesium supplement and another that received a placebo. Their gut microbiome was analyzed from stools, rectal swabs and rectal tissues. Among participants with adequate TRPM7 function, the magnesium supplement increased Carnobacterium maltaromaticumand Faecalibacterium prausnitzii, which were previously found to work synergistically to increase vitamin D and decrease colorectal carcinogenesis. Among those with inadequate TRPM7function, the magnesium supplement reduced the abundance of F. prausnitziiin rectal mucosa.

Among 236 participants who all had a history of colorectal polyps, 124 underwent colonoscopies after completing the trial with a 3.5-year median follow-up time. A higher abundance of F. prausnitzii in rectal mucosa was associated with an almost threefold increase in developing additional polyps.

The findings suggest that magnesium supplementation treatment may decrease colorectal cancer risk in individuals with inadequate TRPM7function. All together, these findings provide new insights into the interplays between nutrition and gut microbiome contributing to colorectal carcinogenesis and establish the foundation for a precision-based strategy for prevention of colorectal cancer in high-risk populations.

The researchers received support from the National Cancer Institute (R01 DK110166, R01 CA149633 and R03 CA 189455) and the Vanderbilt-Ingram Cancer Center Endowment Fund. Dai and Martha Shrubsole, PhD, Ingram Professor of Cancer Research and research professor of Medicine, are principal investigators of the grant that funded the microbiome research from the National Institute of Diabetes and Digestive and Kidney Diseases (DK110116).

Other major Vanderbilt authors on the study include Elizabeth Sun, Xiangzhu Zhu, MD, MPH, Reid Ness, MD, MPH, Harvey Murff, MD, MPH, and Lei Fan, MD, PhD. The first author, Elizabeth Sun, a medical student at Vanderbilt University School of Medicine, was elected for an Early Investigator Travel Award, a young investigator lightning talk, and an in-person poster presentation at the Precision Nutrition Forum and PREDIMED Omics Symposium 2025 held by Harvard University.

The post Study shows magnesium inhibits colorectal cancer carcinogenesis by increasing vitamin D-synthesizing bacteria   appeared first on VUMC News.