Molecular Mechanisms of Cardiotoxicity Induced by ErbB Receptor Inhibitor Cancer Therapeutics

The introduction of the so-called “targeted therapies”, particularly those drugs that inhibit the activity of tyrosine kinases, has represented a remarkable progress in the treatment of cancer. Although these drugs improve survival rates in cancer, significant cardiotoxicity, manifesting as left vertricular dysfunction and/or heart failure, has emerged. The ErbB receptor tyrosine kinases are being pursued as therapeutic targets because of their important roles in normal physiology and in cancer. Besides the fact that the ErbB receptors are indispensable during development and in normal adult physiology, epidermal growth factor (EGFR) and ErbB2 in particular have been implicated in the development of many human cancers. This review focuses on the rationale for targeting members of ErbB receptor family and numerous agents that are in use for inhibiting the pathway. We summarize the current knowledge on the physiological role of ErbB signaling in the ventricle and on structural aspects of ErbB receptor activation in cancer and cardiac cells. We examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of ErbB inhibitors, which can influence the design of future anticancer therapies

Analysis of Phenotype and Outcome in Essential Thrombocythemia with CALR or JAK2 mutations

The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and the Calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30 % of essential thrombocythemia cases. In a retrospective study, we have examined the frequency of MPL and CALR mutations in JAK2 V617F negative essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant essential thrombocythemia with a cohort of JAK2 V617F positive essential thrombocythemia (n=57). CALR positive cases represented 63.7% of double negative essential thrombocythemia, and most carried CALR Type 1 or Type 2 indels. However, we also identified one patient, who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, lower leukocyte counts, hemoglobin, hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR Type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F positive patients, in particular patients of age 60 years or younger. In conclusion, this study on a Belgian cohort supports and extends the growing body of evidence that CALR mutant is phenotypically distinct from JAK2 V617F positive essential thrombocythemia, with regard to its clinical and hematological presentation as well as the overall survival.status: publishe

Analysis of phenotype and outcome in essential thrombocythemia with CALR or JAK2 mutations.

The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival

Elastin fragmentation inatheroscleroticmice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death

AIMS: There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/−)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(−/−)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(−/−)Fbn1(C1039G+/−) mice and was associated with myocardial infarction, stroke, and sudden death. METHODS AND RESULTS: Female ApoE(−/−)Fbn1(C1039G+/−) and ApoE(−/−) mice were fed a WD for up to 35 weeks. Compared to ApoE(−/−) mice, plaques of ApoE(−/−)Fbn1(C1039G+/−) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(−/−)Fbn1(C1039G+/−) mice. In ApoE(−/−) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(−/−)Fbn1(C1039G+/−) mice died suddenly, whereas all ApoE(−/−) mice survived. ApoE(−/−)Fbn1(C1039G+/−) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke. CONCLUSIONS: Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(−/−)Fbn1(C1039G+/−) mice represent a unique model of acute plaque rupture with human-like complications