Arginine Depletion Therapy Shows Promise for Mesothelioma

The following article is an opinion piece written by Jonathan Sharp. The views and opinions expressed in this article are those of the author and do not necessarily reflect the official position of Technology Networks.

The ATOMIC-Meso Trial, which began as a collaboration between multiple research institutions, focused on the effectiveness of pegargiminase, a drug designed to enzymatically deplete arginine from the bloodstream. This strategy capitalizes on the absence of the enzyme ASS1 in mesothelioma cancer cells, which cannot synthesize arginine independently. As arginine is a crucial component of cancer cell metabolism, depleting this amino acid from the blood leads to cancer cell apoptosis but has no effect on healthy cells with an active ASS1 gene.

As reported by the study, when combined with chemotherapy, adding pegargiminase to the treatment schema extended the life of patients by a median of 1.6 months. By 36 months, 4 times the number of patients were alive in the pegargiminase group compared to the group receiving standard chemotherapy. Nevertheless, although positive and hopeful, these results must be considered in the broader context of mesothelioma epidemiology and patient care.

The epidemiology of an orphan cancer

With fewer than 3000 cases identified yearly in the US, mesothelioma is considered an orphan disease. Conditions classified here are characterized by a low number of cases and a subsequent lack of interest in research and treatment developments because any resulting medical product is less likely to be scalable and, by default, profitable. Research led by state organizations and charity institutions is thus generally the main point of progress for treating and diagnosing these conditions.

The pathophysiology of this disease also makes it very hard to diagnose despite existing standards. Mesothelioma emerges almost exclusively in response to asbestos exposure, following a long latency period that can take decades. Nearly all identified cases now occur in veterans exposed to asbestos during their service and among industrial workers exposed to this occupational hazard many years ago.

Patients may easily dismiss these as a less critical condition when initial symptoms are present. With minimal data on presentation, limited experience and heterogeneous manifestations of this cancer in biopsied tissue, pathologists also have a hard time identifying mesothelioma. More often than not, in its early stages, mesothelioma may be wrongfully diagnosed as lung cancer. This leads to delays in treatment, followed by an exponential increase in cancer aggressiveness. Patients at this point may no longer respond to standard systemic therapies and palliative care is the only remaining option.

Since most patients are diagnosed with mesothelioma at later stages, the pegargiminase treatment must work effectively in these advanced stages, especially if it's going to be used as a first-line therapy. In this context, it is essential to clarify that, of the 125 patients randomly assigned to the intervention group, 59 had advanced-stage mesothelioma (Stages 3 and 4). A separate survival analysis was not conducted for these patients. Thus, it is unclear whether patients with advanced mesothelioma may also benefit from the same extended survival rate as the reported median.

Pursuing advances in patient care

As mesothelioma is an orphan disease, advances in treatment are very rare. The US Food and Drug Administration (FDA) approved the first chemotherapy approach in 2004. This treatment consisted of a combination of Alimta^TM (pemetrexed) and cisplatin, demonstrating that both drugs lead to increased survival rates when combined. Almost 20 years later, the CheckMate 743 clinical trials introduced immunotherapy for mesothelioma in 2020. This approach used a combination of nivolumab and ipilimumab and was proposed as a first-line treatment for unresectable malignant pleural mesothelioma. Two years after the publication of the last trial, the FDA approved this treatment scheme and it is now included in the National Comprehensive Cancer Network Clinical Practice Guidelines for mesothelioma treatment.

Now, just four years later, the Atomic-Meso Trial could offer a viable alternative to therapies, with considerably fewer side effects, given that pegargiminase does not impact healthy cell metabolism. However, more data may be necessary before this line of treatment is approved, while additional combination therapies may be needed to overcome mesothelioma cancer cells' adaptability to arginine depletion.

As noted by other researchers, when arginine is depleted from the blood, these cancer cells tend to initially rely on autophagy and recycle intracellular arginine. Once this is no longer an option, these cells use glutamine metabolism and glycolysis to meet energy needs. If arginine deprivation continues, the cells can upregulate ASS1 to synthesize arginine from citrulline, thereby overcoming metabolic stress. Other arginine-dependent cancers experience cellular adaptations that focus on enhancing macropinocytosis and necrocytosis to scavenge arginine from external proteins and concomitantly increase the expression of CAT-1 transporters to enhance arginine uptake.

Therapeutically, targeting these adaptations by combining arginine deprivation with autophagy inhibitors, such as chloroquine, can prevent early cellular adaptations. This further implies that any autophagy inhibitors (or agents targeting different adaptation routes) would have to be administered in a combination therapy. Additionally, addressing glutamine metabolism and CAT-1 transporters could combat later-stage resistance, potentially enhancing the efficacy of treatments.

These innovative strategies to counteract arginine adaptability are still under investigation for other types of cancers but could also apply to mesothelioma. In the meantime, continued research is crucial to fully understand and expand targets focused on cancer cell metabolism. Investigating further into autophagy inhibitors and targeting metabolic pathways like glutamine and CAT-1 transporters will be key in developing more effective treatments. Encouraging robust and continued research will help bring these innovative therapies to clinical practice.