Sorafenib – a small molecule with big promise?

In 1990, a new era in cancer therapy emerged, particularly for CML, with the development of imatinib mesylate, a selective tyrosine kinase inhibitor which is a potent and specific BCR-ABL inhibitor [1] The introduction of imatinib mesylate had a dramatic impact on the development of a new generation of cancer drugs based on the better understanding of the molecular and cellular biology underlying tumor pathogenesis and tumor cell growth [2].

Tyrosine kinases (TKs) were found to be attractive targets for therapy, as their abnormal signaling patterns are linked with tumor growth and progression. Furthermore, these constitutively activated TKs stimulate multiple signaling pathways which are responsible for DNA repair, apoptosis, and cell proliferation. Tyrosine kinase inhibitors are now in general use for the treatment of a variety of human tumors including head and neck, gastric prostate and breast cancer and, of course, leukemia [3,4]. They have a number of very favorable qualities. They tend to stabilize tumor progression and may possibly result in inducing a chronic disease state. Side effects of these agents are minimal compared to more conventional cytotoxic chemotherapeutic agents. In addition, synergism is observed in vitro when TKIs are combined with radiotherapy and/or conventional chemotherapeutic agents [5].

When initially developed, the aim of single targeted therapies was to hit a single molecule expressed in neoplastic cell; however, today the prevailing concept is that it may be more beneficial to inhibit both cancer cells as well as the cells of the stroma supporting the tumor. Together these effects may indeed result in better results in terms of cell kill and disease elimination. Therefore, the concept of single-target therapy is now receding somewhat in favor of a multi-targeted approach. The new generation of TKIs are being selected on the basis of their ability to simultaneously target different molecules within the neoplastic cell [3].

Sorafenib is a novel oral multi-kinase inhibitor initially developed as a potent inhibitor of the Raf/MEK/ERK signaling pathway, and has been approved for use in the management of hepatocellular carcinoma (HCC) and renal cell carcinoma [5,6].

Subsequently it was also found to inhibit other receptor tyrosine kinases, including c-KIT, FLT3, PDGFR, and VEGF, and it is currently being evaluated in a wide spectrum of solid tumors and hematological malignancies.

In the current issue of Leukemia and Lymphoma, Crump et al. report the results of a randomized phase I clinical study of Sorafenib in patients with previously untreated myelodysplastic syndromes (MDS) or relapsed or refractory acute myeloid leukemia (AML) [7]. Reports in the literature on its effects on patients with AML have been mainly based on in vitro analysis, individual case reports, experience with compassionate use [8] and in only one phase I clinical trial involving 16 patients which has been published recently [9]. Although AML and advanced stage MDS perhaps share a similar molecular pathogenesis, only this innovative study by Crump patients has included patients with MDS [7]. Their results demonstrated a different dose limiting toxicity (DLT) and schedule in respect to those already established for the use of Sorafenib in solid tumors. The dose required for AML/MDS appears to be 300 mg orally twice daily, which is lower than the recommended phase II dose of 400 mg given twice daily in patients with solid tumors [7]. While more studies to define the optimal dose and schedule still need to be carried out, it is possible that using a schedule of alternate day or weekly dosing in attempt to limit the toxic side effects may be better.

The toxicity profile of this agent highlights the fundamental differences in the safety profile for patients with poor bone marrow reserve and the necessity of being precise when applying a known compound to patients with bone marrow malignancies [7]. While the most frequently reported side effects of Sorafenib: such as skin rashes, hand-foot syndrome and hypertension, were not seen or were less severe in the study reported by Crump et al. [7], an important warning should perhaps register in our minds in the three patients who experienced arterial thrombosis. This complication indeed needs further precautions and evaluation when conducting future phase II trials.

A preliminary small, but encouraging hint of the possible efficacy of Sorafenib in these disorders was evident in the subpopulation of patients with AML/MDS who had Fms-like tyrosine kinase 3 (FLT3) mutations described in this study. FLT3 mutations occur in about one third of patients with AML and can appear as internal tandem duplication of 3–400 bp in the juxta-membrane domain (in 23% of patents) or as a point mutation mainly involving aspartic acid 835 in the second tyrosine kinase domain (in 7% of patients). The presence of FLT3 internal tandem duplications is associated with a poor prognosis and overall survival in adults and children with AML. Therefore, effective therapy using FLT3 inhibitors indeed holds promise for these patients [4,8,9].

Although further studies are still needed to define the role of Sorafenib in the treatment of a subgroup of patients with AML/MDS, an important message can perhaps be gleaned from this study with some caution and hope. Sorafenib appears to be the first FLT3 inhibitor, used as a single agent, which can potentially induce complete remissions in patients with AML/MDS. This is indeed an exciting observation. More excitement may be in store in the near future as other new inhibitors enter the clinical trial arena. For example, AC220 is a second generation FLT3 inhibitor which combines a number of favorable properties including potency, FLT3 selectivity and pharmacokinetics [10].

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.