New mouse models may accelerate multiple myeloma research
Studies with the models point to MYC protein as therapeutic target
More than a dozen new mouse models of multiple myeloma, which researchers hope will advance understanding and treating the disease, were described in a new study.
“We have generated artificial mice that accurately reflect key aspects of the origin and development of multiple myeloma in humans,” Marta Larráyoz, the study’s first author at CIMA (Center for Applied Medical Research) University of Navarre, Spain, said in a university press release. “This allows us to study the progression of the disease, test therapeutic alternatives, and predict the response to combinations of immunotherapy drugs in the clinic.”
Studies using the models point to the protein MYC as a potential therapeutic target for myeloma and may explain why certain immune-modulating therapies haven’t had good results in trials.
The models were described in “Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma,” in Nature Medicine.
Multiple myeloma is a cancer caused by the uncontrolled growth of plasma cells, or antibody-producing immune cells, in the bone marrow. This abnormal cell growth is driven by a variety of genetic mutations, making it difficult to assess the “key genetic drivers that initiate and sustain the [cancerous] process,” the researchers wrote, noting a “paucity of experimental mouse models recapitulating the principal clinical, genetic, and immunological characteristics of MM [multiple myeloma]” limits the ability to understand the “mechanisms that underlie the discrepant outcomes to different immunotherapeutic approaches.”
To address this, an international team led by scientists in Spain used genetic engineering to create mice with “eight MM genetic drivers that recapitulate the most common changes observed in human MM.” They then crossed the mice to create different combinations of mutations and assessed which ones led to developing multiple myeloma.
New mouse models with a ‘range of disease severities’
This resulted in 15 new mouse models, which displayed a range of disease severities.
“We have developed a panel of 15 mouse models encompassing MM genetic heterogeneity, including the standard-risk and high-risk genetic subgroups,” the scientists wrote.
In myeloma, overt cancer is usually preceded by an early stage where increased plasma cell growth is detectable, but isn’t causing notable disease. The scientists found a similar process of disease development in the new models.
“Our genetically diverse mice recapitulate the natural history and clinical evolution of human disease, including models of early and late MM progression from precursor states,” they wrote.
Analyses combining data from more than 500 of these mice and about 1,000 myeloma patients showed overtly cancerous cells tended to exhibit increased activity of a cell growth protein called MYC, but this wasn’t seen in pre-cancer stages.
Increased MYC activity
This suggests “MYC activation is a unifying feature in genetically heterogeneous MM, which distinguishes cases with early and late progression from precursor stages,” the researchers wrote. “Based on these experimental results, we propose that MM is driven by genetically heterogeneous [mutations] that converge in a common MYC [cancer-driving] pathway.”
This pathway may be a useful target for potential treatments and several molecules that suppress MYC and related cellular pathways are “currently being tested in cancer patients,” wrote the researchers who used the models to assess the effectiveness of immune checkpoint blockade (ICB) therapies such as Keytruda (pembrolizumab). This group of medications are designed to block mechanisms used by cancer cells to evade immune system attacks, promoting anti-tumor effects.
ICBs have shown very good results in some cancer types, but findings in multiple myeloma have generally been lackluster.
The researchers found, in their models, the efficacy of ICBs was dependent on the immune cell profile in the bone marrow. Specifically, ICBs were only effective in mice with high levels of CD8 T-cells — a type of immune cell with the ability to destroy cancer cells — and low levels of regulatory T-cells, or Tregs, which normally act to put the brakes on immune activity.
In an analysis of samples from 170 newly diagnosed multiple myeloma patients, only 14% had a ratio of CD8 T-cells to Tregs that was predictive of ICB success in the models.
“Our data can explain why only a small subset of individuals with active MM responded to ICB therapy,” the researchers wrote, adding the results also “provide a potential biomarker to optimize MM immunotherapy in the clinic.”
The researchers have made their new models available to the scientific community in the hope of accelerating myeloma research and projects using them are underway.
“We are testing novel therapies in experimental models at stages of the disease where multiple myeloma cells might be most vulnerable, particularly in early precursor conditions or in the minimal residual disease state (after treatment, when few tumor cells remain),” said José Ángel Martínez Climent, PhD, the study’s senior author and a professor at CIMA. “To do this, we have established numerous scientific collaborations with pharmaceutical companies developing clinical trials in this disease to carry out these same trials in our mice.”
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