Deborah A. Katz

Radiosensitizing effect of anti-HER2/neu agents: Report of 2 cases and review of the literature

The human epidermal growth factor receptors (HERs), including HER1, HER2, HER3, and HER4, are transmembrane tyrosine kinase receptors involved in the regulation of cell growth and survival. Overexpression of HER type 2 (HER2) is seen in approximately 20% to 30% of invasive breast carcinomas. Trastuzumab and pertuzumab (Herceptin and Perjeta, Genentech-Roche, South San Francisco, CA) are humanized recombinant monoclonal antibodies that bind to the extracellular domain of the HER2 receptor and prevent activation of the downstream signaling cascade.1 Pertuzumab and trastuzumab bind to different HER2 epitopes, resulting in a greater antitumor effect through complementary mechanisms of action.2 Multiple randomized clinical trials have demonstrated the efficacy of trastuzumab, pertuzumab, and other antiHER2 agents in early-stage and metastatic HER2-positive breast cancer3-6; therefore, their use has become standard of care in the management of this breast cancer subtype. Trastuzumab remains the first and the best-studied agent in the class of anti-HER2 drugs. Adverse effects of trastuzumab and pertuzumab have been observed primarily when these antibodies were coadministered with chemotherapy. These adverse effects include infusion-

The relationship between ehrlichiosis and the development of hematologic malignancies

Viral and bacterial infections cause chronic inflammation and produce bacterial metabolites that may lead to carcinogenesis. Ehrlichiosis is an intracellular infection that primarily infects white blood cells. Given that infections can lead to cancer, and that Ehrlichia has tropism for white blood cells, it can be deduced that Ehrlichia may cause hematologic malignancies, such as acute leukemia. A prospective study was performed that tested the blood of ten patients with acute leukemia for prior exposure to Ehrlichia. The RT-PCR that was performed did not detect Ehrlichia DNA in any of the ten samples. Therefore, based on this small study, one cannot conclude that Ehrlichia can lead to hematologic malignancies.

Potential role of enzastaurin in the treatment of patients with relapsed or refractory advanced cutaneous T-cell lymphomas: a review

Correspondence: Lydia Usha Rush University Medical Center, 1725 West Harrison Street – Suite 809, Chicago, IL 60612, USA Tel +1 312 563 2200 Fax +1 312 942 3192 Email lydia_usha@rush.edu Abstract: Cutaneous T-cell lymphomas (CTCLs) are rare extranodal non-Hodgkin lymphomas characterized by neoplastic T-lymphocyte accumulation in the skin. The two most common types of CTCLs are mycosis fungoides and the leukemic variant, Sezary syndrome. Prognosis of CTCLs depends on the stage, with a poor prognosis in advanced-stage disease. A number of agents have recently been developed for the treatment of CTCLs: chemotherapeutic agents such as pralatrexate, interferon-alpha, retinoids such as bexarotene, monoclonal antibodies such as alemtuzumab, and histone deacetylase inhibitors such as vorinostat and romidepsin. Nevertheless, there is no cure for CTCLs except for allogeneic stem cell transplant. A promising new drug is enzastaurin. Enzastaurin is a novel serine/threonine kinase inhibitor that binds to protein kinase C-β (PKC-β) and inhibits the phosphoinositide-3 kinase (PI3K)/AKT/phosphatase and tensin homolog (PTEN) signaling pathway. Enzastaurin induces apoptosis and inhibits angiogenesis; it was also shown to suppress growth of CTCL cell lines in vitro. Given its low toxicity, enzastaurin has been tested against both solid tumors and hematologic malignancies. This article is focused on the potential role of enzastaurin in the treatment of CTCLs. A phase II multicenter trial evaluated enzastaurin monotherapy in patients with CTCLs. However, the results from this study were disappointing, demonstrating that enzastaurin had only modest clinical activity. Hence, enzastaurin is not currently developed for treating CTCLs. Potential strategies to improve enzastaurin efficacy against CTCLs are discussed: validation of enzastaurin targets such as PKC-β expression in CTCL lesions and or/blood; measurement of serum vascular endothelial growth factor levels; dose optimization; combining enzastaurin with other antiangiogenic agents, or glycogen synthase kinase inhibitors, or mammalian target of rapamycin (mTOR) inhibitors. Ultimately, developing more potent inhibitors of PKC-β and PI3K/AKT/PTEN/mTOR signaling pathways may be necessary to improve clinical outcomes in CTCLs.