Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide with an incidence of over 600,000 new cases and almost as many deaths annually.1 Advanced stages of disease at diagnosis often preclude curative treatments, and the overall prognosis of patients diagnosed with advanced HCC remains dismal with median survival of approximately 8 months.2-4 Until recently, systemic therapies for advanced HCC have demonstrated minimal benefit in these patients, largely due to compromised hepatic function from underlying liver disease as well as intrinsic tumor chemoresistance.5-9 In the past year, however, publication of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) phase III trial demonstrated a significant improvement in overall survival (OS) in patients with advanced HCC treated with the biologic agent, sorafenib.4 Despite improvements in outcome with sorafenib, however, the median OS for patients with advanced HCC remains less than a year, and new therapies and combinations are in great need to combat this grim disease. Sorafenib is a small molecule bi-aryl urea with multikinase inhibitor activity. A primary target is the serine-threonine kinase, Raf-1. Sorafenib also has antiangiogenic activity, inhibiting receptor tyrosine kinases including vascular endothelial growth factor (VEGF) receptors 2 and 3 and the platelet derived growth factor receptor (PDGFR).10-12 Preclinical studies in HCC show that Raf-1 kinase signaling along with prolific tumor angiogenesis are common features, providing a molecular rationale for the efficacy of this agent.11,13-16 Radiographically, HCC is a hypervascular tumor, providing additional clinical relevance to the exuberant angiogenesis observed in this tumor type in the preclinical setting.15 The efficacy of sorafenib in the SHARP trial validates the importance of these signaling pathways in HCC. Another signaling pathway which may play a role in hepatocarcinogenesis is the phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3'kinase (PI-3'K)/AKT pathway which activates the mammalian target of rapamycin (mTOR) kinase, in turn triggering multiple downstream cell growth, survival, and angiogenesis signals.26-28 Dysregulated phosphorylation and activation of mTOR signaling may occur due to loss of function of the PTEN tumor suppressor gene, constitutive activation of PI-3'K, or activation of AKT by aberrant upstream growth factor receptor signaling.27 Activated mTOR forms complexes with other proteins, including regulatory associated protein of mTOR (Raptor) and Rictor.26 The mTOR-Raptor complex in turn phosphorylates protein 70 S6 kinase (p70S6K) as well as eukaryotic initiation factor 4E (eIF-4E) binding protein-1 (4E-BP1). P70S6K and 4E-BP1 regulate translation of a host of proteins, including several proteins involved in cell proliferation. Signaling through mTOR also stimulates angiogenesis.26,28-30 Activation of mTOR may induce endothelial cell proliferation as well as increase levels of hypoxia inducible factor (HIF)-1α and HIF-2α, potentially via p70S6K-mediated translation versus decreased oxygen-dependent degradation.31-33 HIFs induce angiogenesis in response to cellular hypoxia by transcriptional activation of target genes including VEGF.32,34,35 The mTOR inhibitor, sirolimus, is a macrocyclic lactone rapamycin produced by the soil bacterium, Streptomyces hygroscopicus. Sirolimus demonstrates fungicidal, immunosuppressive, and antiproliferative properties and is widely used as an immunosuppressant in transplant patients to prevent allograft rejection.26,36 Inhibitors of mTOR are also under investigation as potential anti-cancer agents in multiple human malignancies due to the known proliferative effects of mTOR activation. Temsirolimus, everolimus, and deforolimus are derivatives of sirolimus with similar antiproliferative properties in vitro.26 Temsirolimus is a soluble ester analogue of sirolimus.37 Temsirolimus has been approved by the FDA for treatment of advanced renal cell carcinoma (RCC) and demonstrated a survival benefit as monotherapy by comparison with interferon alpha in a multicenter phase III trial.38,39 In that trial, 626 patients with previously untreated, poor prognosis, metastatic RCC were randomized to receive temsirolimus 25 mg intravenously weekly, 3 million units of interferon alpha subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million units of interferon alpha three times weekly.39 The primary endpoint, overall survival, was 10.9 months in the temsirolimus group, by comparison with 7.3 months with interferon alpha and 8.4 months with combination therapy; both overall survival and progression free survival (PFS) were significantly prolonged in the temsirolimus group by comparison with interferon alpha alone (P = 0.008 and P \< 0.001, respectively). Combination of molecularly targeted therapies offers the theoretical potential for additive or synergistic inhibition of shared targets as well as targets in parallel pathways which may provide escape mechanisms from single-pathway inhibition. In the case of mTOR inhibitors, combination therapy with Ras pathway inhibition may augment efficacy by blocking a pathway upstream of mTOR kinase, while combination with antiangiogenic agents may enhance antiangiogenic effect.26,27