Stem cell factor (SCF) and hypoxia-inducible factor-1α (HIF-1α) both have important functions in pancreatic ductal adenocarcinoma (PDAC). This study aims to analyze the expression and clinicopathological significance of SCF and HIF-1α in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1α expression via Western blot, PCR, chromatin immunoprecipitation (ChIP) assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM) stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05). Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF)-1α in PDAC cells at the protein and RNA levels. When HIF-1α was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1α can directly bind to the hypoxia response element (HRE) region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1α knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1α expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1α and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1α, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC.

/pdf/scf-regulated-by-hif-1a-promotes-pancreatic-ductal-124yevdd7u.pdf

SCF, Regulated by HIF-1α, Promotes Pancreatic Ductal Adenocarcinoma Cell Progression

A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma.

Small molecule tyrosine kinase inhibitors (TKIs) are potent anti-cancer targeted therapies. TKIs are considered safe and efficacious therapeutic modalities, and are generally tolerated well. However, they are associated with certain side effects including hematologic toxicities such as anemia, macrocytosis, neutropenia, thrombocytopenia, hemolytic anemia, bone marrow aplasia and necrosis. Thrombotic microangiopathy, arterial thromboembolism and splenic infarction can also occur following treatment with TKIs. Cytopenias are the most common adverse effects associated with these agents, and other hematologic toxicities are not frequent. It is essential for clinicians to monitor patients closely, and recognize those side effects as early as possible, in order to improve efficacy of small molecule TKIs and optimize outcomes. This article summarizes hematologic toxicities associated with the commonly used small molecule TKIs. It also provides practical strategies for the management of these toxicities.

Hematologic toxicities of small molecule tyrosine kinase inhibitors

Tyrosine kinase inhibitors are novel therapies targeting specific cellular signalling pathways. Sunitinib and sorafenib primarily block tyrosine kinase receptors involved in the progression of many tumours, including clear cell renal cell cancer (ccRCC). Although developed to target selected receptors, it is becoming apparent that they inhibit other kinases; this may result in the development of unexpected side effects. This is potentially dangerous as kinases on noncancerous cells are also inhibited. TKI off-target effects contributing to cardiotoxicity, hypothyroidism, hypertension, fatigue, hair depigmentation, hand-foot syndrome and gastrointestinal perforation have been described. We report three patients (3/412) treated with sunitinib and sorafenib who developed chronic myeloid leukaemia (CML) during treatment for ccRCC, proposing a molecular mechanism of tyrosine kinase inhibitors action on bone marrow cells that might be co-responsible for CML development.

Development of chronic myeloid leukaemia in patients treated with anti-VEGF therapies for clear cell renal cell cancer

Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression-free-survival (PFS) is unknown. We aimed to characterize TKI-associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy-four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib- and sorafenib-treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1-7). Median PFS in sunitinib-treated patients was 11 m (95% CI: 6-19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11-25] vs. 4 m [95% CI: 3-8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib-related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding.

Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma.

Background: The tyrosine kinase inhibitors (TKI) sunitinib and imatinib were shown to induce macrocytosis in patients with renal cell cancer (RCC) and gastrointestinal stromal tumors (GIST), presumably through inhibition of the c-KIT dependent signaling pathway of erythroid progenitor cells of the bone marrow. Patients and Methods: Hematology charts of patients with RCC, breast cancer (BC), GIST, non-small cell lung cancer (NSCLC) and hepatocellular cancer (HCC), receiving single-agent sunitinib, imatinib, sorafenib, erlotinib and BI 2992 (Tovok) at the recommended dose for at least 3 months were reviewed retrospectively for the occurrence of macrocytosis. Results: Macrocytosis occurred in all patients with RCC and BC treated with sunitinib and in all patients with GIST treated with imatinib. The percentage increase of the mean corpuscular volume (MCV) of peripheral red blood cells (RBC) compared with baseline at 3, 6, 9 and 12 months was 12.4%, 16.8%, 16.6%, 12.7% and 0.7%, 5.6%, 5.9%, 5% with sunitinib and imatinib respectively. The values at 3, 6 and 9 months between both groups were significantly different. Sorafenib, erlotinib and BI 2992 did not induce macrocytosis. Conclusion: Sunitinib-induced macrocytosis was not confined to patients with RCC alone but also occurred in patients with BC. Imatinib also induced macrocytosis in patients with GIST but to a significantly lower degree. Because both drugs were used at an effective pharmacodynamic dose inhibiting c-KIT, these data strongly suggest that pathways in addition to c-KIT and not common to both agents are involved in the TKI-induced macrocytosis. Sunitinib, a recently developed tyrosine kinase inhibitor (TKI) targeting vasculoendothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor-B (PDGFR- B) and c-KIT receptor, is currently registered and used as first-line treatment in renal cell carcinoma (RCC) and as second-line treatment in imatinib-resistant gastrointestinal stromal tumors (GIST). The drug is under clinical development in several other solid tumor types and treatment settings such as in the adjuvant or maintenance setting. A large number of clinical and laboratory adverse events with different degrees of severity and incidence have been identified and published for sunitinib. The most frequent are related to the skin, GI tract, thyroid, cardiovascular and hematological systems (1, 2). The toxicities in the hematological system include anemia, leucopenia, neutropenia and thrombocytopenia. Recently a report was published about the induction of macrocytosis, a new, common, laboratory side-effect without clinical relevance to long-term treatment with sunitinib in patients with RCC (3). The mechanism of sunitinib-induced macrocytosis remains unclear and was found not to be attributed to deficiency in vitamin B12, folic acid, nutritional status nor alternative etiologies such as hypothyroidism, alcoholism or liver disease. Rini et al. (3) suggested that sunitinib could be a direct cause of macrocytosis. The mechanism by which sunitinib possibly led to macrocytosis was hypothesized to be mediated by inhibition of the c-KIT receptor of progenitor cells in the bone marrow. The return of the mean corpuscular volume (MCV) to normal values after withdrawal of the agent without other intervention supported the temporary and reversible nature of the phenomenon. Indirect proof of the hypothesis was that sorafenib, a weaker inhibitor of c-KIT, had no effect on the MCV in RCC patients and that treatment with imatinib in GIST specifically inhibiting c-KIT also produced macrocytosis in 42% of the patients receiving the drug (4). We reviewed the hematology charts of patients treated in our institution with several small molecule TKIs in different types of cancer to evaluate their potential for and differences in the induction of macrocytosis and to correlate any differences observed with possible interferences with signaling pathways.

Tyrosine kinase inhibitor-induced macrocytosis.

1253 Tyrosine kinase inhibitor (TKI)-induced macrocytosis

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Tyrosine kinase inhibitor-induced macrocytosis.

1253 Tyrosine kinase inhibitor (TKI)-induced macrocytosis