Researchers at the Medical University of South Carolina (MUSC) have found a way to target drug-resistant esophageal cancer cells by exploiting the different energy needs of cancerous versus healthy cells.
This breakthrough is now opening the doorway to new treatments for an otherwise lethal cancer.
The findings of the National Institutes of Health (NIH)-funded study are reported in Nature Communications.
Only about 20 percent of patients diagnosed with esophageal squamous cell carcinoma (ESCC) are still alive five years later, according to the American Cancer Society.
Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality.
Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus there remains a need to elucidate the molecular mechanisms underlying this disease.
There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment, which contains diverse cell populations, signaling factors, and structural molecules that interact with tumor cells and support all stages of tumorigenesis.
In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation.
Anti-tumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), as well as immune checkpoints like programmed death-1 (PD-1).
Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix (ECM) to create a tumor niche and enhance tumor cell migration and metastasis.
Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy.
Unfortunately, this disease is usually found at a late or advanced stage, meaning that, for many patients with ESCC, the cancer has already spread to other parts of their bodies.
The severity of the disease is compounded by its high rate of recurrence.
“[It’s] an aggressive, lethal cancer,” says Shuo Qie, M.D., Ph.D., a postdoctoral fellow at MUSC Hollings Cancer Center and first author on the article.
“[S]urgery is the only and the best choice. But some patients, especially patients with metastasis, need chemotherapy or other additional treatments.”
The overall prognosis of esophageal cancer (EC) is poor with five-year survival rates of 15–34% [1,2].
Neoadjuvant treatment plays a crucial role in management of advanced stage disease [1,2], but not all patients respond to this pre-treatment .
Furthermore, resistance to chemotherapy is often associated with more aggressive tumor biology.
So far, no reliable biomarkers are available to evaluate patients’ individual response to neoadjuvant therapy or tumor biology.
MicroRNAs (miRNAs, miRs) are small non-coding single-stranded, endogenous RNA molecules that might be able to identify and maybe even modulate resistance to treatment.
Development of resistance towards chemotherapeutics is complex and involves multiple aspects such as transmembrane transport of drugs , intracellular drug metabolism  or cellular proliferation and apoptosis [6,7,8,9,10,11].
MiRNAs regulate global gene expression post-transcriptionally  and control many fundamental cellular processes, including cell differentiation, cell proliferation, apoptosis, and metabolism [12,13,14,15]. Most importantly, miRNAs have clearly been linked to cancer  and to sensitivity to chemotherapy [15,17,18].
In our previous work, we were able to identify characteristic miRNA signatures that distinguish cisplatin or 5-FU resistant esophageal squamous cell carcinoma cells (ESCC) from sensitive control cells .
The aim of the current study was to investigate if these specific miRNA signatures of resistant cell lines are in fact responsible for their chemotherapy resistant phenotype.
Moreover, as increasing resistance to chemotherapy clinically often correlates with more aggressive tumor behavior, we further questioned if these miRNA signatures impact biological behavior of cancer cells such as metastatic potential and ability to escape apoptosis.
Finally, we aimed to investigate relevant intracellular pathways that might be regulated by these miRNAs and that might mediate their effects on chemotherapy resistance.
For the study, Qie aimed to further characterize and ideally address the cancer-driving pathway previously discovered by J. Alan Diehl, Ph.D., his mentor and the senior author on the article.
Diehl is the SmartState Endowed Chair in Lipidomics and Pathobiology and Associate Director of Basic Science at MUSC Hollngs Cancer Center.
This pathway, the Cyclin D1 axis, is an intersection at which several cancer-promoting changes occur.
The protein Fbxo4, which usually prevents cancer by controlling cyclin D1 degradation, no longer exerts its protective effects.
This allow cells to spiral out of control.
Qie discovered that the axis activates a metabolic switch that causes ESCC cells to depend much more on glutamine than glucose.
Healthy cells break down both glucose and glutamine for their energy needs, but ESCC cells are virtually addicted to glutamine.
“The cancer cells have to have glutamine. You can bathe them in glucose and they’re still going to die without glutamine,” explains Diehl.
These findings point to a vulnerability in these cancer cells and suggest a new therapeutic possibility – the use of glutaminase inhibitors.
Glutaminase is an enzyme required for the cellular digestion of glutamine.
Inhibiting it effectively blocks the cell’s ability to process glutamine.
The MUSC researchers tested the efficacy of a combination regimen that included a glutaminase inhibitor (Telaglenastat; Calithera, San Francisco, CA) and metformin in cancer cell lines and mice.
They found that the combination regimen effectively treated tumors with the molecular signature that Diehl had previously described.
Importantly, the treatment was effective even against tumors that had developed resistance to CDK4/6 inhibitors. Indeed, the resistant cancer cells were even more vulnerable to this treatment than non-resistant ones.
“It’s quite remarkable that the tumor cells that we have that are resistant to CDK4/6 inhibitors are actually five-, six-fold more sensitive to this combination therapy than they were before they developed resistance,” says Diehl.
The promising findings for this combination regimen in both cellular and animal models suggest that it could have therapeutic potential for patients diagnosed with this traditionally dangerous and difficult cancer.
Having moved this treatment from concept to reality in the laboratory, Qie and Diehl hope to move forward with clinical trials for their combination treatment and are currently seeking funding to do so.
The MUSC researchers’ curiosity about a biological pathway has led to a potential new therapeutic approach for patients with ESCC.
“You’ll hear the term ‘an Achilles heel,'” explains Diehl.
“Can you find the Achilles heel that’s in the cancer but not in the normal cell? And that’s what Qie has done. Just from trying to understand the biology of the pathway, he and I have identified a unique therapeutic opportunity.”
More information: Shuo Qie et al, Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma, Nature Communications (2019). DOI: 10.1038/s41467-019-09179-w
Journal information: Nature Communications
Provided by Medical University of South Carolina