November 4, 2024 | A diagnostic test invented at the University of Arizona has demonstrated its potential to predict the likelihood of relapse or recurrence among patients with early-stage breast cancer and their response to antifibrotic therapy. The tool, known as MeCo Score, measures metastatic risk based on the acclimation of cancer cells to the mechanical stiffness of tissue (fibrosis) as computed from RNA sequencing data on tumor samples, reports Ghassan Mouneimne, Ph.D., an associate professor of cellular and molecular medicine at the University of Arizona College of Medicine – Tucson and of cancer biology in the Ginny L. Clements Breast Cancer Research Institute at the University of Arizona Cancer Center.
The Mouneimne lab has been studying the tumor microenvironment for a decade now and the basic research experiments done there determined the biomarker-based signature that generated the training dataset for refining a response-to-fibrosis algorithm. Among women with HER2-negative breast cancer flagged as high MeCo (mechanical conditioning) score patients, their response to the antifibrotic drug nintedanib dramatically improved event-free survival 10 years out, per a recently published study in Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-24-1518).
The long-term effect was the result of short-term treatment with nintedanib among patients in Spain who were enrolled in the first-ever study testing the antifibrotic drug in breast cancer. That trial was unsuccessful, but only because it lacked the diagnostic to detect the survival difference between the treated and untreated patient cohorts, Mouneimne says.
The next step for Mouneimne and his team is a pivotal clinical trial in support of hoped-for regulatory approval by the U.S. Food and Drug Administration (FDA), he adds, but this time enrolling early stage, high-risk hormone receptor positive (HR+) breast cancer patients receiving chemotherapy in the adjuvant setting, a portion of whom will also get the antifibrotic drug. That study will be led by oncologist Pavani Chalasani, M.D., of the George Washington Cancer Center in Washington, D.C.
To undertake this work, Mouneimne cofounded MeCo Diagnostics with one of his former students, Adam Watson, Ph.D., who serves as the company’s CEO. The MeCo Score is expected to come to market as a predictive biomarker of response to antifibrotic treatment in breast cancer, such as nintedanib.
Nintedanib is soon to go off patent and the development of generic formulations should help with the “financial toxicity” of treatment currently faced by many patients, says Mouneimne. Newer cancer therapies entering the market are at least 10 times more expensive than the old standards, with some costing up to $20,000 per month. Nintedanib will not only be much more affordable but is also very safe as it has been given to lung fibrosis patients for many years and is generally well tolerated.
The link between tissue stiffness and cancer prognosis, including its metastatic potential, has been studied for many years, Mouneimne says. But cancer cells respond differently to stiffness. “A lot of tumors are stiff but would not be very aggressive.”
Mouneimne’s background is in cell biology, but he has been doing more translational research since arriving at the University of Arizona in 2013—in particular, looking at how the protein network that cancer cells live in can help determine if, and how, they metastasize. Watson did his doctorate in the Mouneimne lab, and his research focused on developing MeCo Score for measuring the response to mechanical stiffness in the tissue.
The link between breast cancer progression to bone metastasis and fibrosis was first described in a 2021 study where the MeCo Score technique was utilized (Cell Reports, DOI: 10.1016/j.celrep.2021.109293). In the most recent study, mechanical conditioning was shown to function as a biomarker for progression of breast cancer and prediction of response to antifibrotic therapy.
Researchers in Spain—led by Miguel Quintela-Fandino, M.D., Ph.D., head of the clinical research program at the Spanish National Cancer Research Center—provided their bank of tissues collected from 130 patients at diagnosis, of which 76 passed quality control and were sequenced, says Mouneimne. The MeCo scores were computed from that data and clustered patients into either the high or low category. To get at their long-term response to antifibrotic therapy required the team’s clinical colleagues in Spain to follow up on all the patients in the original study at multiple hospitals throughout the country.
The focus was on HER2-negative breast cancer, a subtype with relatively few targeted therapies that includes many of the HR+ breast cancers as well as the triple negative breast cancers, Mouneimne says. The HR+ group accounts for 75% of all breast cancers.
His lab has been increasingly interested in HR+ breast cancers since they have proven, in recent investigations, to be highly mechanoresponsive and thus potentially reactive to fibrosis and susceptible to acquiring metastatic phenotypes, he explains.
Tech Launch Arizona, the technology transfer office at the University of Arizona, has been a key partner providing mentorship and guidance in the 2022 formation of MeCo Diagnostics, Mouneimne says. The startup company is being incubated by San Diego, California-based EvoNexus.
While the prognostic and predictive biomarkers for breast cancer are the company’s most advanced solutions, MeCo Diagnostics is also using a similar approach in developing molecular tools for measuring response to fibrosis in prostate and colorectal cancers, he says. Unlike how some genetics-based signatures are created, where the first step is establishing differences seen in patients with aggressive and non-aggressive disease, the development process here begins with preclinical experiments to come up with a biomarker signature to validate in people.
A unique, bioinformatics approach used both in vitro and clinical data to improve the MeCo Score, readying it for deployment in the upcoming prospective, multicenter clinical trial with HR+ breast cancer patients, says Mouneimne. The team is additionally working on the development of imaging-based approaches, which will be driven by artificial intelligence, to come up with histological signatures related to mechanical conditioning of diseased tissues.
Once the biomarker-based signatures of cancer are approved by the FDA, MeCo Diagnostics will partner with a lab certified to comply with the Clinical Laboratory Improvement Amendments (CLIA) to do the RNA sequencing required to compute the MeCo scores, he adds. All of this would happen at the point of diagnosis and the high scorers could be offered the option of receiving antifibrotic therapy prior to surgery to reduce their risk of metastasis 10 years down the road.
Breast cancer patients are the most important players in all this, emphasizes Mouneimne, who hopes to “empower patients on many levels.” This includes an understanding of the kind of therapies they might be offered, their effectiveness, and the out-of-pocket expense of those treatments.
A drug that is both safe and good would seemingly be the ideal combination, Mouneimne says, although the FDA and the Centers for Medicare & Medicaid Services do not prioritize cost considerations in regulatory decision-making.
MeCo Diagnostics, for its part, has been working with California-based patient advocacy groups to involve patients in the decision-making process early on—something the FDA has also been doing by soliciting patient input prior to approving new drugs, he notes. Therapies can be so expensive that it is a financial burden on everyone, including taxpayers as well as patients and their families, even if approvals are technically based more on safety than cost.