Saturday, 5 September 2015

ILCA Symposium 3: Advances in Transarterial Treatment of HCC

Targeting Glucose Metabolism: A New Class of Agents for Transarterial Treatment of HCC?

Jean-François Geschwind, MD (USA)

Hepatocellular carcinoma (HCC) is one of the most highly lethal malignancies in the world, making it the third most common cause of cancer related mortality worldwide. In the United States, the incidence of HCC is on the rise, secondary to a concomitant rise in hepatitis C viral (HCV) infection; in the past 2 decades the incidence of HCV-related HCC has tripled. Overall survival remains poor at less than 9 months and largely depends on the stage of the disease; patients with intermediate-stage disease have better 3-year survival expectancies than patients with advanced-stage disease (50% vs. 8%, respectively). In addition, the vast majority of patients are diagnosed at the advanced stage of the disease because of the asymptomatic nature of the disease, as well as because of the lack of an early-detection marker for HCC. Despite recent advances in therapeutic strategies, treating HCC remains a daunting task because of its aggressive nature — more specifically the risk of local invasion, metastatic spread, and the high rate of recurrence after curative therapies — as well as because HCC is largely refractory to systemic chemotherapy. Thus, an effective therapeutic strategy targeting HCC-specific or HCC-related pathway(s) is clearly needed. Furthermore, to make things even more challenging, because HCC typically occurs in the setting of underlying liver disease (cirrhosis), potential new drug candidates would have to also exhibit an extremely favorable toxicity profile.

Tumour metabolism
One of the most important phenotypes exhibited in cancer is the up-regulation of the major energy-producing pathway, glycolysis. This altered tumour-specific glycolytic phenotype, first discovered by the German scientist Otto Warburg decades ago, plays a crucial role in several biosynthetic processes that facilitate uninterrupted tumour growth and is an indispensible “metabolic event” critical for the sustained growth and invasion of tumours. Given the inefficiency of glycolysis compared with oxidative phosphorylation (2 ATP vs. 36 ATP molecules produced per glucose molecule, respectively), one could wonder why cancer cells prefer glycolysis. The main reason for this preference is that the cancer cells are able to generate ATP through glycolysis at a much faster rate than oxidative phosphorylation to meet the energy demands of aggressive malignant growth. Increased glucose metabolism
via glycolysis provides cancer cells with essential substrates for rapid proliferation, ribose for nucleic acid synthesis and pyruvate for cell membrane assembly. Furthermore, an abundant supply of glucose also facilitates the metabolism of glucose via the pentose phosphate pathway (PPP), which is involved in several biosynthetic processes, as well as cellular defense (antioxidants) against reactive oxygen species (ROS). It is well known that HCC cells exhibit the high glycolytic rate of other aggressive malignant tumours through differential expression of enzymes involved in the first step of glucose metabolism. Indeed, whereas normal liver cells rely on glucokinase (type IV hexokinase) to catalyze the first step of glycolysis, HCC cells markedly up-regulate the expression of a different isoform, specifically type II HK (HK II), while substantially down-regulating glucokinase. Similarly, other
glycolytic enzymes such as glyceraldehyde-3 phosphate dehydrogenase (GAPDH), LDH, and others are also upregulated during the malignant transformation of HCC. The disparity in glycolytic rate between tumour cells and normal cells resulting in an increased demand for glucose by cancer cells has already been used diagnostically by positron emission tomography (PET) for tumour imaging with the glucose analog fluorodeoxyglucose (FDG) but has never been exploited as a potential therapeutic target. In fact, because this finding is so ubiquitous in cancer, it is considered a “biochemical signature” of tumour cells. This is why tumour metabolism has been aptly described as “cancer’s Achilles’ Heel,” suggesting it as a possible therapeutic target. Because malignant cells become addicted to glycolysis and dependent on this pathway to generate ATP, inhibition of glycolysis would severely abolish ATP generation in cancer cells and thus preferentially kill the malignant cells while sparing healthy surrounding cells. Targeting glycolysis for the treatment of cancer should, therefore, be a promising novel therapeutic strategy.

Targeting Tumour Metabolism: A New Class of Anticancer Agents
Renewed research interest on tumour metabolism combined with a growing understanding of the molecular mechanisms involved in the regulation of tumour glycolysis contributed to the development of agents targeting glycolysis. Although some of these agents were evaluated in preclinical tumour models for their therapeutic potential, most did not make it into the clinic because of a lack of efficacy and the presence of significant toxicities. Recently however, one such metabolic blocker, 3-bromopyruvate (3-BrPA), a halogenated analog of pyruvic acid, has gained considerable attention because of its significant antitumor effects and its low toxicity profile. The addition of the halogen bromine to the monocarboxylic acid, pyruvate, results in alkylating properties of the compound. As a result, 3-BrPA will bind to its target by forming an irreversible chemical bond. In vitro testing against human
HCC cells demonstrated that 3-BrPA inhibits glycolysis and blocks ATP production, causing apoptosis in a dosedependent manner. Further investigation with radiolabeled 3-BrPA identified the glycolytic enzyme, GAPDH, as the primary intracellular target of this agent. The binding of 3-BrPA to GAPDH caused inhibition of the enzyme activity and, therefore, glycolytic ATP production leading to apoptotic cell death.
Image-guided procedures, especially intra-arterial therapies, play a key role in the treatment of patients with liver cancer. The advantage of locoregional approaches is that they provide not only access to the core but also to the edge of the tumour. In addition, much greater drug concentrations can be achieved within tumours while minimizing systemic exposure. As a result, intra-arterial delivery of 3-BrPA was tested in various animal models of liver cancer. Results were extremely encouraging as tumours were successfully eradicated, in most cases significantly prolonging survival in the process. Some animals were even cured despite the fact these tumours are extremely aggressive. Unlike other alkylating agents, 3-BrPA demonstrated tremendous specificity in molecular targeting, enforcing its antitumorigenic effects by promoting energy depletion, disruption of redox balance, and induction of intracellular stress in a concurrent fashion. Therefore, it appears that 3-BrPA is an extremely promising agent because of its tumour selectivity and ability to promote a multipronged antitumor effect.
In summary, despite cancer’s extreme genetic heterogeneity, the reliance on glycolysis for energy needs and growth is a common pathway that most cancer cells share. As a result, targeting this pathway for therapeutic means is extremely attractive. A new agent 3-BrPA, which specifically inhibits this glycolytic pathway in tumours has already shown great promise in several animal models of liver cancer and could have a significant effect on the survival of patients with liver cancer. Clinical trials are to begin soon.