Early clinical research by Vanderbilt Health and Cumberland Pharmaceuticals Inc. suggests that an investigational drug originally developed to treat cardiovascular disease may reduce the risk of metastasis — or spread — of breast, lung and other solid tumors.

The pilot clinical trial of 29 patients with solid tumors at high risk of early metastatic recurrence confirmed that ifetroban, a thromboxane A2 receptor antagonist, was safe and well tolerated, and supported further development of the drug to prevent cancer metastasis.

While not statistically powered for efficacy, the randomized, double-blind, and placebo-controlled Phase 2a clinical trial also compared the percentage of patients who experienced a distant metastatic recurrence 12 months after completion of the study.

Seventeen percent of participants who received ifetroban experienced a distant metastatic recurrence, compared to 50% of those who received an inactive placebo. No deaths due to distant metastatic disease occurred among those who received ifetroban, while three deaths occurred in the placebo group.

“We are encouraged that ifetroban demonstrated a favorable safety profile in this patient population and the potential efficacy trends are promising, supporting further clinical development,” said Cumberland Pharmaceuticals Chief Executive Officer A.J. Kazimi.

Cumberland Pharmaceuticals is a Nashville-based specialty pharmaceutical company focused on developing new products for rare diseases.

“A therapeutic intervention aimed at metastasis prevention for cancer patients with high risk of recurrence that is given during the period of ‘watchful waiting’ could be groundbreaking if proven beneficial in larger scale investigations,” said Ben Ho Park, MD, PhD, the Benjamin F. Byrd Jr. Professor of Oncology, professor of Medicine, and director of Vanderbilt-Ingram Cancer Center.

The study is a project of Vanderbilt Health’s Drug Repurposing program, which was established in 2016 under the Vanderbilt Institute for Clinical and Translational Research (VICTR).

The program uses human genetic data from BioVU, Vanderbilt Health’s DNA biobank, which is linked to de-identified electronic health records, to find new indications for drugs that are already approved or have passed Phase 1 and Phase 2 clinical safety studies. For example, the drug repurposing team has found that adding guanfacine, a drug used to treat high blood pressure, to routine trigeminal nerve block injections can enhance pain relief in patients with trigeminal neuralgia, intense, sudden facial pain.

Earlier this year, they reported that EG501, an investigational drug developed by Evergreen Therapeutics Inc. which targets a receptor in the brain involved in learning and memory, improved cognitive function in patients with lupus, an auto-immune disease.

For the past 20 years, Vanderbilt Health researchers have been studying ifetroban for its potential to treat conditions ranging from fibrotic lung disease to heart failure in patients with Duchene muscular dystrophy.

The thromboxane A2 receptor plays a variety of roles in different cell types throughout the body, including the activation and aggregation of platelets, a type of blood cell involved in clotting. In turn, malignant cells that escape cancer treatment can stick to platelets and “ride” to distant parts of the body.

A phenome-wide association study (PheWAS) of BioVU’s genetic and health records database conducted by Vanderbilt Health investigators linked a variant in the receptor gene to an increased risk of metastatic disease across multiple primary cancers.

Preclinical studies demonstrated that ifetroban reduced metastasis in several animal models without affecting tumor growth.

By blocking platelet activation and aggregation through its action on the thromboxane A2 receptor, ifetroban is thought to limit the ability of tumor cells to migrate across blood vessel walls, invade other organs, and evade detection by the immune system.

After completing cancer therapy, patients at high risk of recurrence who were enrolled in the clinical trial received daily oral doses of ifetroban or placebo for 12 months, then were followed for another 12 months.

Kazimi praised the contributions of the Vanderbilt Health research team, which he said, “have been essential to this advance in oncology patient care.”

Results of this study will be used to guide the design of larger human trials verifying efficacy and further demonstrating safety.

“We look forward to pursuing those pivotal studies as we relentlessly look for treatments to benefit patients living with cancer,” Park said.

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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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