2023-05-26| Interviews

Advancing Next-Generation Cancer Metabolic Therapy by Targeting Critical Amino Acid Metabolic Pathways: An Interview with Brian A. Van Tine, MD, PhD

by Richard Chau
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Alongside immunotherapy, cellular therapy and various new molecular targeted agents, metabolic drugs derived from the unique metabolic mechanisms of cancer cells have been gaining attention in recent years, one of which is ADI-PEG 20, a revolutionary metabolic drug developed by Polaris Pharmaceuticals. As a broad-acting drug that can be used to treat a wide range of cancers, it is currently in clinical trials for indications such as malignant pleural mesothelioma, soft tissue sarcoma, glioblastoma and hepatocellular carcinoma.

GeneOnline is honored to have Prof. Brian A. Van Tine, MD, PhD for an interview. As a medical oncologist with research expertise in metabolic deficiencies in sarcoma and amino acid deprivation therapies, Dr. Van Tine is currently a Professor of Medicine of the Division of Medical Oncology at Washington University in St. Louis. During the interview, he used ADI-PEG 20 as an example to explain how amino acid deprivation therapies could help to fight cancer cells and the clinical application of ADI-PEG 20 in treating soft tissue sarcoma. 

Related article: The Emergence of Metabolic Therapy, Unlocking a Next-Generation Cancer Treatment Strategy 

Silencing of Argininosuccinate Synthetase 1 (ASS1) in Tumors

Tumor cells utilize specific metabolic pathways to support their growth, proliferation and biomass production. One common genetic alteration found in many cancers, including sarcoma, lung cancer, breast cancer, and melanoma, is the silencing of the argininosuccinate synthetase 1 (ASS1) gene. This gene is involved in the urea cycle, which helps produce arginine, an essential amino acid that is required for protein synthesis and cell survival. In particular, cancer cells need high amounts of arginine for growth and proliferation.

Tumors deliberately shut down the arginine biosynthetic pathway because they can obtain arginine from the bloodstream, allowing them to focus on biomass production. According to research findings from Prof. Van Tine’s team, approximately 88% of all sarcoma cases would demonstrate a silenced ASS1 expression, and this loss is associated with reduced overall survival.

Arginine Deiminase: Exploiting Tumor Vulnerabilities

As a potential first-in-class targeted cancer therapy, Polaris Pharmaceuticals’ ADI-PEG 20 (Pegargiminase) is a PEGylated therapeutic protein based on a microbial arginine catabolizing enzyme called arginine deiminase (ADI) with polymer chains of polyethylene glycol (PEG) attached to it. According to Prof. Van Tine, ADI-PEG 20 converts extracellular arginine into citrulline, thus blocking the external supply of this important nutrient to cancer cells. In vitro and mouse models have shown that depriving tumors of circulating arginine halts their growth. 

In addition, Arginine deprivation also gives rise to a host of conditions within cancer cells, including increased autophagy, increased apoptosis, increased eukaryotic stress and altered gene expression. Non-tumor cells are unaffected by the depletion of circulating arginine because they are able to convert citrulline back into arginine through the urea cycle. Therefore, unlike other metabolic approaches that focus on glucose restriction for tumor cells, ADI-PEG 20 provides a unique and specific way to target tumors by exploiting their reliance on arginine.

Metabolic Decision-Making and Adaptations in Tumors

Prof. Van Tine pointed out that research efforts have focused on understanding metabolic adaptations that occur in cancer cells when they are deprived of circulating arginine. Without arginine, tumors would be forced to undergo metabolic adaptations to ensure their survival. Metabolic tracing and metabolomics have made contributions to identify key choices that tumor cells would make to evade cell death, such as switching to glutamine biology and altering their metabolic preferences.

Initial studies revealed that many tumors heavily depend on glucose for their energy needs. However, upon arginine deprivation, tumors undergo a metabolic shift and switch to glutamine metabolism, activating their mitochondria and suppressing the Warburg effect, a hallmark of cancer cells. He added that combining arginine starvation with other metabolic interventions, such as glutaminase inhibitors that suppress the compensatory reliance on glutamine, has shown synergistic effects in inducing tumor cell death.

Prof. Brian Van Tine, MD, PhD interviewed by Thomas Huang, CEO of GeneOnline
Prof. Brian Van Tine, MD, PhD interviewed by Thomas Huang, CEO of GeneOnline

Promising Combinations for Enhanced Therapeutic Efficacy

The primary objective of cancer is to proliferate, and every decision made by cancer cells revolves around this goal. With the uptake of arginine interrupted, tumor cells in a starvation stage have to find other ways to gain biomass in order to sustain their growth and division. According to Prof. Van Tine, research has shown that when sarcoma cells enter the starvation stage, they increase the expression of transporters, including the same transporter used by gemcitabine, a nucleoside analog. This transporter facilitates the entry of nucleotides into cancer cells, making them susceptible to the effects of docetaxel, a mitotic inhibitor. 

By exploiting this mechanism, researchers observed promising results in clinical trials. In particular, Prof. Van Tine quoted a Phase 2 open-label study of ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma. Results showed that sarcoma patients demonstrated improved response rates when combining docetaxel and gemcitabine with arginine starvation. The complete response rate tripled compared to previous trials, and the amount of gemcitabine required could be reduced by a third, reducing the need for high-dose gemcitabine and mitigating toxicity.

These promising findings led to the development of an international Phase 3 registration trial comparing ADI-PEG 20 with docetaxel versus placebo. This trial aims to obtain FDA approval for the combination therapy, further establishing it as a viable treatment option. It is noteworthy that the dosages in both arms differ from standard therapy, highlighting the importance of understanding tumor metabolism in optimizing treatment.

Researchers are continually exploring novel approaches to cancer treatment based on tumor metabolism. Trials are underway in lung cancer, both small cell and non-small cell, using a slightly modified regimen to simplify dosing while maintaining efficacy. Another trial focuses on mesothelioma, targeting metabolic adaptations related to glutamine dependence and folate cycle inhibition. The aim is to identify effective therapies that can overcome tumor adaptation and prevent resistance.

Unraveling Complexities of Tumor Metabolism, Opening New Doors for Metabolic Therapies

Prof. Van Tine also mentioned that the intricate nature of tumor metabolism may pose a substantial challenge to metabolic therapies as tumor cells can rapidly adapt to changing conditions and alter their metabolic pathways in response to therapeutic pressure, making it necessary to develop multi-drug regimens to counter these defense mechanisms of tumor cells and achieve satisfactory therapeutic outcomes. 

Ongoing research and advancements in drug development offer hope for the future, as more targeted drugs acting on specific metabolic pathways are being investigated. On the one hand, researchers are uncovering metabolic vulnerabilities specific to different cancer types, such as the role of glutamine addiction and mitochondrial biology in mesothelioma. The understanding of receptor desensitization and metabolic decisions is also expanding. 

On the other hand, the emergence of new metabolic drugs, such as PKM2 inhibitors (glycolysis), DHFR inhibitors (folate metabolism) and SHMT inhibitors (serine metabolism) offers exciting prospects for personalized cancer treatment. Prof. Van Tine expressed his hope that the field of tumor metabolism will continue to evolve in the next decade, leading to optimized combination therapies and improved patient outcomes.

Apart from the combination of ADI-PEG 20 with conventional chemotherapeutic agents, Prof. Van Tine added that the application of immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 monoclonal antibodies in conjunction with metabolic therapies would also constitute potential new combinations worth exploring in depth. For example, a Phase 1b study investigating ADI-PEG 20 in combination with pembrolizumab (a FDA-approved PD-1 inhibitor) in subjects with advanced solid cancers. Published results showed that the immunometabolic combination was safe and that ADI-PEG 20 treatment increased T cell infiltration in the low PD-L1 tumor microenvironment.

Targeting tumor metabolism, particularly through the combination of arginine deiminase and docetaxel, has shown promise in clinical trials. Understanding the complex interplay between cancer cells and metabolic pathways is vital for developing effective treatments. As researchers continue to unravel the secrets of tumor metabolism, new strategies and therapeutic combinations will emerge, paving the way for more precise and efficient cancer therapies.

Prof. Brian Van Tine, MD, PhD and Thomas Huang, CEO of GeneOnline
Prof. Brian Van Tine, MD, PhD and Thomas Huang, CEO of GeneOnline
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