Targeting glucose metabolism in cancer: a new class of agents for loco-regional and systemic therapy of liver cancer and beyond?

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and the third leading cause of cancer-related deaths worldwide. In patients with unresectable disease, loco-regional catheter-based intra-arterial therapies (IAT) can achieve selective tumor control while minimizing systemic toxicity. As molecular features of tumor growth and microenvironment are better understood, new targets arise for selective anticancer therapy. Particularly, antiglycolytic drugs that exploit the hyperglycolytic cancer cell metabolism – also known as the ‘Warburg effect’ – have emerged as promising therapeutic options. Thus, future developments will combine the selective character of loco-regional drug delivery platforms with highly specific molecular targeted antiglycolytic agents. This review will exemplify literature on antiglycolytic approaches and particularly focus on intra-arterial delivery methods.

Practice points.

• Image-guided intra-arterial therapies provide the dual benefit of selective tumor targeting and reduced systemic toxicity and represent a fully accepted therapeutic modality for unresectable hepatocellular carcinoma (HCC).

• According to the ‘Warburg effect’, tumor cells undergo a genetically driven shift in glucose metabolism that results in a hyperglycolytic phenotype and glucose dependency as hallmarks of malignant transformation.

• Improved molecular understanding of the ‘Warburg effect’ has become an organizing principle for drug discovery with the ultimate goal of introducing antiglycolytic agents for the therapy of cancer.

• 3-Bromopyruvate (3-BrPA) is a potent antiglycolytic agent that primarily functions through the inhibition of the glycolytic enzyme GAPDH in cancer cells.

• Strong preclinical evidence exists in support of the anticancer effects of 3-BrPA. While fully evaluated for local intra-arterial delivery, promising initial data on drug micro-encapsulation may open a new frontier for systemic delivery of 3-BrPA and other antiglycolytic agents.

Hepatocellular carcinoma & intra-arterial therapies

Hepatocellular carcinoma (HCC) constitutes one of the most common cancers and represents the third leading cause of cancer-related deaths worldwide [1]. Curative approaches primarily include resection and liver transplantation, which are only indicated in patients with very early and early stage HCC [2]. However, the continuous evolution of minimal-invasive loco-regional therapies has achieved substantial progress for prognosis improvement in patients with unresectable HCC. In particular, catheter-based intra-arterial therapies (IATs) have gained wide acceptance in the treatment of intermediate and advanced stage HCC [3]. The scientific rationale of IAT is based on the fact that healthy liver tissue is almost exclusively supplied from the portal vein, whereas the feeding vessels of the hypervascular tumors primarily branch from the hepatic artery [4]. Conventional transarterial chemoembolization (cTACE) is the most commonly used IAT modality and its broad clinical application has established this technique as an effective and safe treatment option for liver malignancies (Figure 1). The outstanding advantage of IAT compared with systemic chemotherapy is the highly selective targeting of the tumor through the blood supply while reducing systemic toxicity to a minimum [5]. In addition to the palliative setting, IAT have proven their potential for down-staging and bridging of patients to resection or liver transplantation [6]. The concept of IAT experiences continuous innovation and novel therapeutic options are being evaluated to achieve an ideal combination of different tumoricidal mechanisms for a complete and selective tumor kill. One such approach involves the combination of loco-regional therapies with the use of antiglycolytic agents to exploit the glucose dependence of most tumor cells. The following paragraphs will discuss the underlying mechanisms and provide the rationale for targeting tumor metabolism.

Figure 1. . Transarterial chemoembolization.

(B) and (C) demonstrate a fluoroscopy and a schematic image of a hepatocellular carcinoma (HCC) after treatment with conventional transarterial chemoembolization (cTACE). Preprocedural angiographic evaluation reveals a centrally located hypervascular tumor (A). Subsequently, an emulsion of oily lipiodol and chemotherapeutic agents is administered through the catheter into the feeding arteries of the tumor via the femoral and hepatic artery. This step is followed by the injection of embolic spheres to prevent the wash out of the drug cocktail and to devascularize the tumor.

• Tumor metabolism & tumor hypoxia

As early as 1956, Otto Warburg was the first to describe a characteristic shift in cancer cell metabolism toward a hyperglycolytic phenotype [7]. The ‘Warburg hypothesis’ implies the switch toward glycolysis as the major pathway of energy production in cancer cells, even in the presence of oxygen where oxidative phosphorylation would be biochemically most efficient [8]. Thus, this mechanism is also referred to as ‘aerobic glycolysis’. Since the update of the widely accepted hallmarks of cancer in 2011, the ‘reprogramming of energy metabolism’ has gained new interest as a principal feature of tumorigenesis and brought the ‘Warburg effect’ back into scientific limelight [9].

On a molecular level, the hyperglycolytic phenotype of tumor cells is defined by alterations of the expression levels of metabolic proteins and emerges concomitant with malignant transformation. In order to quickly generate sufficient amounts of energy solely by glycolysis, the glucose-uptake is substantially increased in cancer cells [10]. As blood supply soon becomes insufficient in highly proliferating tumors, cancer cells are often exposed to hypoxia [11]. As such, the main molecular driver of hypoxia, the hypoxia-inducible factor-1 (HIF-1) helps adapting the cell metabolism to environmental changes and mediates the overexpression of glycolytic enzymes and upregulation of glucose transporters, such as subtype GLUT-1 [10,12,13]. Accelerated glycolysis also implies the synthesis of large amounts of lactate, which is transported via proton-coupled monocarboxylate transporters (MCT) leading to an acidification of surrounding tumor microenvironment [14].

With this in mind, recent oncologic research increasingly utilizes novel techniques such as gene expression analysis in order to characterize the molecular profile of cancer cells. These studies aim at the early detection of accessible tumor types for targeted therapies and strive for the determination of tumor response to treatment in various tumor entities [15,16]. Within the scope of personalized medicine, molecular tumor analysis would further allow for individually matched targeted therapy regimens for each patient in the future.

Targeting cancer metabolism

As a result of the improved understanding of the underlying mechanisms of ‘reprogrammed glucose metabolism’, oncologic research is markedly driven toward the development of pharmacological agents for antiglycolytic tumor therapy [17]. As a result of this trend, a number of drugs are currently under investigation with the ultimate goal of exploiting the tumor-specific hyperglycolytic phenotype of cancer cells. So far, approaches to target glucose metabolism either focus on glucose-uptake via GLUT-1 (e.g., Phloretin, WZB117) or glycolytic enzymes such as hexokinase (HK; e.g., lonidamine, 2-deoxy-D-glucose), glyceraldehyde 3-phosphate dehydrogenase (GAPDH; e.g., 3-bromopyruvate), lactate dehydrogenase (e.g., Oxamete) or pyruvate dehydrogenase kinase (PDK; e.g., dichloroacete) [18].

This review will discuss available preclinical and clinical experience with exemplified antiglycolytic drugs in the treatment of solid tumors and point out future directions of antiglycolytic therapy with particular respect to IAT in HCC.

• 2-deoxy-D-glucose

Among the large number of potential antiglycolytic drugs, 2-deoxy-D-glucose (2-DG) is one of the longest known agents and well studied. 2-DG is a glucose analog that competitively inhibits glucose-uptake in cancer cells and interferes with HK, the first and rate-limiting step of glycolysis [19,20]. Once it has entered the cell, it is phosphorylated by HK to 2-DG-6-phosphate, which cannot be further metabolized and accumulates intracellularly. Subsequently, 2-DG at a therapeutic dose causes ATP depletion as well as oxidative stress and eventually facilitates cell death [21,22]. Moreover, these features of 2-DG in combination with the increased glucose uptake in cancer cells provide the rationale for the detection of tumors by positron emission tomography (PET) using ¹⁸F-labeled 2-deoxy-D-glucose (FDG) [23,24].

Inhibition of proliferation by 2-DG has been reported for many cancer cell lines in vitro, whereas animal studies report heterogenous effects of 2-DG [25,26]. After daily administrations of 2-DG at therapeutic doses, hypoglycemia-like symptoms are very likely to occur and appear to limit the potential for single-agent therapy in vivo [27,28]. However, a Phase I dose-escalation trial investigated the safety of orally administered 2-DG in patients with castrate-resistant prostatic cancer. In this study, 45 mg/kg was identified as the recommended dose and 2 days after therapy, correlative FDG-PET scan in five of eight patients demonstrated reduced signal intensity of the tumor [29]. Overall, initial results from clinical trials were inconclusive, thus rendering 2-DG unsuitable for monotherapy.

In an attempt to resurrect 2-DG for clinical use, more recent preclinical and clinical investigations primarily focused on combination approaches and used 2-DG at lower doses as a potentially beneficial combination partner with other systemically applicable chemotherapeutic agents. In this setting, current literature suggests synergistic effects of 2-DG with some agents in vitro as well as in a Phase I clinical trial with docetaxel [30,31].

Moreover, it is hypothesized that 2-DG functions as a radiosensitizer by preventing cancer cells from recovery after radiation damage [32,33]. Numerous preclinical studies have demonstrated enhanced killing of malignant cells when 2-DG was administered in combination with irradiation [34,35]. The first clinical trial to examine the feasibility and safety of orally administered 2-DG was conducted in cerebral glioma patients [36]. Subsequent dose-escalation trials in glioblastoma patients revealed a favorable toxicity profile for 2-DG at a dose of 250 mg/kg, administered up to seven-times weekly in combination with hypofractioned radiotherapy. At higher doses, dose-limiting side effects occurred in two of six patients [37]. Adapting the recommended treatment schedule in another clinical trial, surgical re-exploration and histological tumor analysis in 13 of 20 patients revealed extensive tumor necrosis with surrounding tissue being well-preserved [38].

Overall, good local tumor control was achieved in combined treatment regimens with protection of healthy parenchyma and improved quality of life in more than 100 patients with brain tumors [39]. However, loco-regional delivery could help reducing systemic toxicity after monotherapy and may facilitate the applicability of 2-DG in other solid tumors.

• Dichloroacetate

One of the more recently presented candidates for antiglycolytic therapy is dichloroacetate (DCA). DCA has been used in the therapy of congenital disorders with inadequate mitochondrial function for over 25 years [40]. The impact of DCA is based on its ability to disinhibit mitochondrial pyruvate dehydrogenase (PDH) by a specific blockade of its regulator PDK. PDH catalyzes the conversion of pyruvate to acetyl-CoA and thereby links glycolysis to the aerobic citric acid cycle [27]. Hence, DCA supports the redirection of energy production toward oxidative phosphorylation with further utilization of pyruvate and reduced lactate accumulation [41].

The compelling concept of potentially reversing the ‘Warburg effect’ in cancer cells prompted several oncologic studies to be initiated with the purpose to investigate the use of DCA in antiglycolytic tumor therapy. One of the first studies was performed in rats bearing subcutaneous lung cancer cells. In contrast to intraperitoneal injections, orally administered DCA was reported to induce apoptosis and decrease proliferation of cancer cells in this setting [42]. Moreover, encouraging anticancer effects were reported for DCA application in neuroblastoma cells [43]. However, in recently published data on murine and human neuroblastoma as well as human breast cancer cell lines, DCA could not prevent or even accelerated tumor cell proliferation. A tumor-promoting effect was additionally observed in a subcutaneous xenograft mouse model for neuroblastoma when DCA was administered with drinking water [44].

As for clinical experience, a prospective single-arm trial was designed to examine the occurrence of dose-limiting toxicity of oral DCA in 15 patients with brain malignancies. Eight patients completed at least one 4-week cycle revealing no acute toxicity. The patients remained with stable disease according to radiographic and clinical evaluation and received DCA for an average of 75.5 days. Two patients experienced grade 0–1 distal paresthesia [45]. In a subsequent dose-escalation study enrolling 24 patients with solid tumors, 6.25 mg/kg was determined to be a safe oral treatment dose of DCA. At 12.5 mg/kg, three patients experienced dose-limiting fatigue, vomiting and diarrhea. FDG-PET demonstrated no tumor response and stable disease in eight patients [46].

While clinically promising, Shen et al. found that DCA was able to overcome sorafenib-resistance in a subcutaneous xenograft mouse model with sorafenib-resistant HCC cells [47]. Regarding oral combination therapy, enhanced cytotoxic effects were recently reported for adriamycin with simultaneously administered DCA in hepatoma cells in vitro as well as in subcutaneous mouse xenografts [48].

Overall, preclinical results for single use of DCA in antiglycolytic tumor therapy appear to be ambiguous. As for the clinical experience, results should be regarded as preliminary and beneficial data exists in support of a favorable toxicity profile rather than anticancer efficacy.

• 3-Bromopyruvate

One of the most promising antiglycolytic drugs currently under evaluation is 3-Bromopyruvate (3-BrPA), a pyruvate analog and alkylating agent. Its ability to deactivate GAPDH was first described in the year 1993 and autographic evidence was provided in 2010 [49,50]. As a multifunctional enzyme that is often upregulated in cancer cells, GAPDH is reported to support tumorigenesis and chemoresistance and therefore constitutes a promising target for antitumoral therapy [51,52]. Hence, 3-BrPA was also reported to enhance cytotoxic drug effects in the setting of combination therapy, thus providing an encouraging strategy to overcome drug resistance in cancer [53–56]. Yet, the predominant mechanism of action is the inhibition of GAPDH through alkylation of the active site, which catalyzes the sixth step of glycolysis. The inhibition of GAPDH then leads to massive intracellular ATP depletion, which is followed by a ‘vicious cycle’ of redox imbalance and finally results in cell death [57–60] (Figure 2).

Figure 2. . Metabolic targets of 3-bromopyruvate in cancer cells.

The figure illustrates the metabolic targets of 3-bromopyruvate (3-BrPA) in a tumor cell underlying its anticancer effects. Transport of 3-BrPA is mediated by MCTs. The primary intracellular target of 3-BrPA is glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which is subsequently inhibited by alkylation causing severe depletion of adenosine triphosphate (ATP) in hyperglycolytic cancer cell phenotypes. Additionally, induction of oxidative and endoplasmatic reticulum (ER) stress lead to apoptosis in tumor cells. By modulation of ABC–transporters with drug efflux capacity, chemosensitivity of cancer cells is increased by 3-BrPA in combination therapy.

GLUT: Glucose transporter; LDH: Lactate dehydrogenase; MCT: Monocarboxylate transporter; ROS: Reactive oxygen species; TCA: Tricarboxylic acid cycle.

A central characteristic of cellular 3-BrPA-uptake is the transmembrane transport of this molecule, which is mediated via MCT-1. This particular circumstance is especially important in the light of the fact that MCT-1 transporters are significantly overexpressed in cancer cells, thus allowing for a nearly cancer-specific uptake of the drug. The preferential uptake of 3-BrPA by MCT-1 is hypothesized to facilitate selective targeting of cancer cells, which has been recently demonstrated for this otherwise toxic agent [61]. However, the rather unspecific alkylating properties of 3-BrPA imply nontarget toxicity which limited the in other respect high anticancer potency of 3-BrPA. This circumstance prompted the concept of using loco-regional catheter-based drug delivery platforms to circumvent the undesired side effects.

As 3-BrPA has proven its anticancer properties in a variety of cancer entities in vitro, numerous animal studies were initiated. These concepts mainly focused on establishing 3-BrPA as a locally applicable drug for the treatment of hepatic malignancies. Hence, the majority of those studies were conducted using the well-established VX2 liver tumor model in New Zealand rabbits [62,63]. Other loco-regional approaches included ultrasound-guided intra-tumoral delivery of 3-BrPA in a murine orthotopic pancreatic cancer model as well as an orthotopic breast cancer model [64,65]. As for the intra-arterial delivery method, one of the early studies established the efficacy of 3-BrPA in a total of 32 VX2 liver tumor bearing rabbits receiving a single transcatheter bolus injection of 3-BrPA via the femoral and hepatic artery under fluoroscopy guidance. Response to treatment was assessed by histopathological analysis of the liver 4 days after treatment. The results showed complete necrosis in all treated animals with no evidence of damage to surrounding liver and no drug-related toxicity in other organs [66]. This result prompted a subsequent dose-escalation study in eight VX2 tumor-bearing rabbits. As a result, this study identified 1.75 mM 3-BrPA as an optimal therapeutic concentration to achieve complete selective tumor destruction if injected intra-arterially. At concentrations of 2.5 mM 3-BrPA, peripheral liver necrosis was observed. Moreover, continuous intra-arterial infusion of 3-BrPA for the duration of 1 h was determined to be the favorable method of delivery as compared with bolus injections [67].

Another large-scale tracer study analyzed the bio-distribution of ¹⁴C-labeled 3-BrPA after intravenous and intra-arterial delivery in a total of 60 VX2 tumor-bearing rabbits. Accordingly, quantitative tracer uptake measurements revealed accumulated ¹⁴C-labeled 3-BrPA within tumor-infiltrated regions of the liver and only minimal radiographic uptake was detected in nontarget tissues. Additionally, following FDG-PET scans demonstrated reduced signal intensity in treated tumors indicative of a highly effective blockade of cancer metabolism by 3-BrPA. Hence, this study confirmed the favorable pharmacokinetic profile of local 3-BrPA injections over systemic delivery. In addition, the high local tumor control rate was confirmed by FDG-PET scans and yielded significant survival benefits for intra-arterially treated animals [68]. This rare ability of an investigative drug to achieve survival benefits in an animal tumor model was also confirmed in other animal studies, making 3-BrPA a promising candidate for clinical trials [69,70]. Additionally, another comparative trial demonstrated the encouraging potential of intra-arterial 3-BrPA infusions to effectively prevent intra-abdominal metastatic spread of VX2 tumors, known for a aggressive growth pattern [71].

In order to validate FDG-PET as a glucose metabolism-related biomarker for tumor response to antiglycolytic therapy, another study included a total of 23 VX2 tumor-bearing rabbits into their experimental group. One week after intra-arterially delivered 3-BrPA, FDG-uptake on PET scans was significantly reduced in treated tumors compared with controls. Ex vivo analyses demonstrated complete tumor necrosis and thereby confirmed the radiological results. Consequently, FDG-PET can be considered as a useful tool in the follow-up of tumor therapy with 3-BrPA [72].

As for the clinical application, the ministry of health in Israel granted permission to use 3-BrPA under the compassionate use protocol in two clinical patients who received the drug intra-arterially. In both cases, patients were diagnosed with end-stage liver cancer (HCC and cholangiocarcinoma, respectively). As a result, both treatments were technically successful and no drug-related toxicities were recorded. More importantly, the US FDA recently accepted an investigational new drug application for the use of 3-BrPA for a Phase I clinical trial in the setting of IAP of liver cancer [73]. This clinical trial is scheduled to start in 2015.

In the light of the promising data for the safety and efficacy of 3-BrPA in the scenario of loco-regional application, many authors considered drug toxicity to be the main obstacle for a systemic use of the drug. As such, the molecular instability of the 3-BrPA components was identified as the central issue to impede its use for systemic delivery. Recently, this frontier was approached by a study that was designed to investigate the role of 3-BrPA for systemic delivery in an orthotopic xenograft mouse model for pancreatic cancer. The concept of this study was to micro-encapsulate 3-BrPA using a molecular carrier, β-cyclodextrin (β-CD), as a vehicle for systemic administration. The purpose of 3-BrPA micro-encapsulation was to achieve molecular stability of 3-BrPA, thus reducing the nontarget toxicity of this alkylating agent. As a result, the micro-encapsulated drug formulation (ß-CD–3-BrPA) demonstrated identical anticancer efficacy as compared with free 3-BrPA in in vitro experiments. Subsequently, efficacy and safety of daily percutaneous injections were investigated in vivo. Tumor-bearing mice were treated systemically with daily intraperitoneal injections with up to 5 mg/kg 3-BrPA as well as comparable doses of the micro-encapsulated drug. Weekly follow-up using bioluminescence imaging (BLI) revealed minimal or no tumor progression under ß-CD-3-BrPA treatment, whereas ß-CD alone had no effect on tumor growth. BLI results were confirmed by histopathological analysis which demonstrated extensive tumor necrosis and in some cases even tumor eradication under daily systemic 3-BrPA therapy. Interestingly, drug microencapsulation achieved a significant reduction of systemic toxicity and therapy-related mortality as compared with the free 3-BrPA [74] (Table 1).

Table 1. . Key reports on the anticancer efficacy of 3-bromopyruvate in vivo.

Study (year)	Tumor model	Objective	Treatment with 3-BrPA	Outcomes	Toxicities	Ref.
Geschwind et al. (2002)	VX2 rabbits (n = 22)	Efficacy and feasibility	IA: infusion (compared with embolization)	Histopathology: complete necrosis of treated tumors	Histopathology: no effects on surrounding liver parenchyma	[63]
				All animals had developed lung metastases that were successfully treated with systemic 3-BrPA
				Embolization caused severe peripheral liver necrosis
Vali et al. (2007)	VX2 rabbits (n = 8+30)	Dose-escalation	IA: dose-escalation; single vs serial bolus injection vs 1 h infusion (compared with controls)	Maximum tolerated dose: 25 ml	Histopathology: peripheral liver necrosis at maximum dose	[64]
				Recommended therapeutic dose = 1.75 ml
				Favorable method of delivery = continuous 1 h infusion
Vali et al. (2008)	VX2 rabbits (n = 60)	Biodistribution and efficacy (14c-labeled 3-BrPA)	IA vs IV (compared with controls)	IA: 14c-labeled 3-BrPA accumulated selectively within the tumor	No nontarget distribution of 3-BrPA	[65]
				IA: FDG-PET showed reduced uptake, prolonged survival (55 vs 18.6 days controls)	No altered FDG uptake in healthy tissue
				IV: no significant differences in FDG uptake
Vossen et al. (2008)	VX2 rabbits (n = 20)	Efficacy and feasibility of metastatic VX2 tumor model	IA: infusion vs partial hepatectomy vs TACE	VX model is feasible to investigate drug influence on metastatic profile	N.A.	[68]
				Less abdominal dissemination and kidney metastases compared with both TACE and surgery
				All animals developed lung metastases
Liapi et al. (2011)	VX2 liver tumor model in rabbitxenografts (n = 23)	Effects of 3-BrPA on tumor metabolism imaged with FDG-PET	IA vs control	FDG uptake was reduced 7days after therapy	N.A.	[69]
				Histopathology revealed tumor necrosis confirming imaging results
Ganapathy et al. (2012)	subcutaneous HCC model in mice (Hep 3B cells) (n = 24)	Efficacy and mechanistic analysis	Percutaneous intratumoral injections (for 3 days) (compared with shRNA and controls)	Decreased BLI signal 3 days after treatment	N.A.	[67]
				Inhibition of tumor progression, induction of apoptosis, inhibition of GAPDH activity
Ota et al. (2013)	orthotopic pancreatic cancer model in mice (Panc-1 cells) (n = 13)	Efficacy, safety and establishment of a new tumor model	US-guided percutaneous intratumoral injections, (compared with controls)	Weekly us measurement and histology after 4 weeks: 1 animal progressed, 5 tumors decreased in size	Ex vivo: no signs of toxicity in pancreas or other organs	[62]
Chapiro et al. (2014)	orthotopic pancreatic cancer model in mice (MiaPaCa2 cells)	Feasiblity, efficacy, safety (microencapsulated 3-BrPA)	Daily intraperitoneal injections (compared with gemcitabine and free 3-BrPA)	Establishment of microrencapsulated 3-BrPA for systemic delivery	Ex vivo: no signs of toxicity in other organs	[70]
				Inhibition of tumor progression on weekly BLI scans	No acute adverse events
				Histopathology: tumor necrosis	No deaths in contrast to free 3-BrPA

BLI: Bioluminescence; 3-BrPA: 3-Bromopyruvate; FDG: 18F-2-Deoxy-D-glucose; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; HCC: Hepatocellular Carcinoma, IA: intra-arterial; IV: Intravenous; PET: Positron emission tomography; TACE: Transarterial chemoembolization; US: Ultrasound; VX2 Rabbits: VX2 Liver-Implanted Tumor Model In Rabbits.

Conclusion & future perspective

Selectively targeting tumor metabolism has long been considered as a desirable therapeutic option but it has not yet been translated into clinical practice. The altered metabolic profile of cancer cells has been explained through the principles of the ‘Warburg effect’. Aerobic glycolysis and glucose dependency of cancer cells are mainly understood as the mechanism to maintain the excessive need of energy for tumor growth. More recently, this hallmark of cancer became an organizing principle of drug discovery, leading to the introduction of several antiglycolytic agents. However, dose-related systemic toxicity is a feared hazard that poses a significant barrier to antitumor efficacy in this new class of agents. Hence, 2-DG – the veteran drug among antiglycolytic agents – has recently re-entered clinical trials after disappointing initial results due to extensive toxicities at therapeutic doses. 2-DG is currently being resurrected in the setting of combination therapies with irradiation in attenuated doses. DCA is a rather new antiglycolytic agent that is still under investigation. Previous findings suggest a favorable safety profile for oral delivery but results on anticancer efficacy remain equivocal.

As opposed to 2-DG and DCA, 3-BrPA has been successfully tested for monotherapy in hyperglycolytic cancers such as HCC. In experiments using the VX2 liver tumor model in rabbits, 3-BrPA exhibited exceptional anticancer efficacy and the ability to prolong survival when administered locally. Intra-arterial delivery of the drug maximized drug concentrations within the tumor while circumventing systemic toxicity and leaving healthy liver parenchyma and other organs unharmed. However, the concept of local drug delivery has significant limitations with regard to patients with systemic spread of the disease. Thus, novel ‘out-of-the-box’ solutions as exemplified by the micro-encapsulation of 3-BrPA will lead the way toward finally achieving the goal of antiglycolytic cancer therapy in clinical trials.