Targeting Nutrient Dependency in Cancer Treatment

Abstract

Metabolic reprogramming is one of the hallmarks of tumor. Growing evidence suggests metabolic changes that support oncogenic progression may cause selective vulnerabilities that can be exploited for cancer treatment. Increasing demands for certain nutrients under genetic determination or environmental challenge enhance dependency of tumor cells on specific nutrient, which could be therapeutically developed through targeting such nutrient dependency. Various nutrients including several amino acids and glucose have been found to induce dependency in genetic alteration- or context-dependent manners. In this review, we discuss the extensively studied nutrient dependency and the biological mechanisms behind such vulnerabilities. Besides, existing applications and strategies to target nutrient dependency in different cancer types, accompanied with remaining challenges to further exploit these metabolic vulnerabilities to improve cancer therapies, are reviewed.

Targeting glutamine dependence with DRP‐104 inhibits proliferation and tumor growth of castration‐resistant prostate cancer

“…Although glutamine is not rate‐limiting in nucleotide synthesis pathway under normal conditions, it is rate‐limiting in nutrient‐poor environments 23,24 . Importantly, none of our in vitro studies were conducted in glutamine depleted or glutamine reduced cell culture media, so the high glutamine levels could also explain why we observed a delayed effect from DRP‐104 treatment Since the tumor microenvironment is a nutrient‐deficient environment, glutamine utilization becomes critical for nucleotide synthesis, thus, cell survival and proliferation 25 . For these reasons, DRP‐104 was expected to be therapeutically more potent in targeting nucleotide synthesis of tumors in vivo and in patients than in nutrient‐rich in vitro conditions.…”

“…23,24 Importantly, none of our in vitro studies were conducted in glutamine depleted or glutamine reduced cell culture media, so the high glutamine levels could also explain why we observed a delayed effect from DRP-104 treatment Since the tumor microenvironment is a nutrient-deficient environment, glutamine utilization becomes critical for nucleotide synthesis, thus, cell survival and proliferation. 25 For these reasons, DRP-104 was expected to be therapeutically more potent in targeting nucleotide synthesis of tumors in vivo and in patients than in nutrient-rich in vitro conditions. This was confirmed by the results of our animal studies, where DRP-104 showed complete stasis of tumor growth in the NCI-H660 NEPC xenograft model.…”

A Meta-analysis on the Effectiveness of Extracellular Vesicles as Nanosystems for Targeted Delivery of Anticancer Drugs

“…Similarly, oncolytic virus, tumour necrosis factor-α (TNF-α), methioninase, and hyaluronidase have been reported as the potential for cancer therapy. − Reports indicated that l -methionine plays an important role in cancer cell survival and the overdependence of cancer cells on methionine as a metabolite for aberrant transmethylation reactions by cancer made it a target for tumor treatment. , Hyaluronan is a long-chain polymer of the extracellular matrix that accumulates in the tumor microenvironment and promotes cancer cell proliferation and metastasis. The report indicated that hyaluronic acid is a target for cancer treatment .…”

RNA Interference against ATP as a Gene Therapy Approach for Prostate Cancer

“…However, previous research works mainly focused on nutrient metabolism and oxidative phosphorylation via inhibiting the availability and usage of glucose, amino acids, and lipids. 9−11 It is possible, but highly challenging, to develop effective strategies to downregulate the ATP level specifically in cancer cells based on differences in nutrient or metabolic dependency in cancer and normal cells, 12 which is an ideal strategy for cancer therapies.…”

“…It exerts a diverse role in the process of tumorigenesis and participates in tumor proliferation, apoptosis, migration, and angiogenesis. , Insufficient ATP supplement impairs the viability of tumor cells via the activation of necrosis and apoptosis pathways. – Increased ATP level is characteristic for tumors and their microenvironment. – Numerous studies have shown that down-regulation of ATP in tumor cells had potent therapeutic potentials. However, previous research works mainly focused on nutrient metabolism and oxidative phosphorylation via inhibiting the availability and usage of glucose, amino acids, and lipids. – It is possible, but highly challenging, to develop effective strategies to downregulate the ATP level specifically in cancer cells based on differences in nutrient or metabolic dependency in cancer and normal cells, which is an ideal strategy for cancer therapies.…”