The promise of molecular targeted therapies: Protein kinase inhibitors in the treatment of cutaneous malignancies

Kondapalli, Lavanya; Soltani, Keyoumars; Lacouture, Mario E.

doi:10.1016/j.jaad.2005.02.011

Cited by 47 publications

(28 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The paradigm of imatinib, the ABL kinase inhibitor first introduced in the treatment of chronic myeloid leukemia, was rapidly extended to the development of a variety of new kinase inhibitors for human malignancies with promising results. 29,54,55 Whether PKC-inhibitors may also have a role as therapeutic agents remains to be established. Since T-bet is related directly to the disease activity, T-bet levels can be used as indicators of active disease.…”

Section: Discussionmentioning

confidence: 99%

T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia

Solomou

Keyvanfar

Young

2006

Blood

134

113

View full text Add to dashboard Cite

IntroductionAplastic anemia, the paradigm of bone marrow failure syndromes, is characterized by peripheral blood pancytopenia and an empty bone marrow. 1 In most cases, aplastic anemia is an immunemediated disease with active destruction of hematopoietic cells by T lymphocytes. 2 The aberrant immune response may be triggered by drugs, virus, or chemical exposure, but in the majority of cases there is no obvious etiologic factor. 3,4 The clinical observations that most patients respond to immunosuppressive treatment with cyclosporine and antithymocyte globulin-based regimens 5,6 is the most powerful evidence for the pivotal role of the immune system in the pathophysiology of aplastic anemia. Excessive production of interferon-␥ (IFN-␥), tumor necrosis factor (TNF), and interleukin-2 (IL-2) from patients' T cells suggests that the hematopoietic cells are destroyed through a Th1 T-cell response. [7][8][9][10][11] This Th1 "shift" in aplastic anemia results in both Fas-mediated cell death and inhibition of hematopoietic stem cell proliferation. 2,12 Oligoclonal expansion of cytotoxic T lymphocytes (CTLs) correlates with disease activity. 13,14 In an animal model of aplastic anemia, injection of alloreactive lymphocytes results in bone marrow failure, but pancytopenia can be prevented with anti-IFN-␥ and anti-TNF monoclonal antibody. 15 IFN-␥, the hallmark cytokine of the Th1 immune response, is produced primarily by T cells and natural killer (NK) cells. Following activation, naive T cells differentiate into Th1 CD4 ϩ and cytotoxic CD8 ϩ cells that secrete IFN-␥ and other cytokines, and Th2 CD4 ϩ cells that produce IL-4 and other cytokines. Two transcription factors are responsible for the shift of CD4 ϩ T cells into the Th1 or Th2 phenotype: T-bet for Th1 and GATA-3 for Th2. 16,17 IFN-␥ is also produced when T cells are stimulated with IL-12 or IL-18 secreted by antigen-presenting cells (APCs). Regulation of IFN-␥ production occurs primarily at the level of transcription. 18 The proximal site of the IFN-␥ gene (Ϫ75 to Ϫ45 bp of the IFN-␥ promoter) is a binding site for nuclear factor for activated T cells (NFATs), AP-1, ATF, and CREB transcription factors. 19,20 In the proximal IFN-␥ promoter site, a half T-box sequence allows T-bet binding, resulting in increased IFN-␥ production. 21 T-bet is a member of the T-box family of transcription factors. 22 This family contains a highly conserved DNA binding domain, the T-box. T-box binds to a specific sequence in the promoter of different genes. T-bet is found in Th1 but not in Th2 cells and is the key regulator of Th1 development and function. 16,23 Mice lacking T-bet fail to develop Th1 cells and are driven toward Th2-mediated disease. 24 Overexpression of T-bet in Th2 cells results in loss of the Th2 phenotype and increased production of IFN-␥. 16 Activated T cells result in increased T-bet expression, which induces IL-12R␤2 expression. 25 T-bet also positively regulates its own expression through an autoregulator loop involving Hlx, a homeobox gene. 26 T-cell engagem...

show abstract

Section: Discussionmentioning

confidence: 99%

T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia

Solomou

Keyvanfar

Young

2006

Blood

134

113

View full text Add to dashboard Cite

show abstract

“…Research is also focusing on molecular targeted strategies and tailored chemotherapy. Success will depend on the discovery of the valid receptor and predictive markers for (multi)targeted agents [5,6]. In our patient, for example, the following targets were negative: herceptin (Her2/neu), CD 117 (c-kit often expressed in Merkel cell carcinoma [7]), epidermal growth factor receptor; transmembrane proteins, receptor kinases and cytoplasmatic receptors involved in critical functions (such as tumor growth, angiogenesis, inhibition of apoptosis).…”

Section: Discussionmentioning

confidence: 92%

Merkel Cell Carcinoma – a Rarity in the Urogenital Tract

Schwindl

Meißner

Giedl³

et al. 2006

Oncol Res Treat

View full text Add to dashboard Cite

Merkel cell carcinoma - a rare, aggressive cancer of the skin integument - is being increasingly diagnosed but represents an absolute rarity in the urogenital tract. Case Report: We report on a 70-year-old man who was referred to us with suspected testicular cancer. The pathology report revealed a metastasized Merkel cell carcinoma. Fulminant disease progression under chemo-therapy (regimen as for small cell lung cancer) resulted in death 5 months later. Conclusion: The patient described is considered to be the first to develop testicular metastasis derived from Merkel cell carcinoma. Besides neuroendocrine and epithelial antigen tests, somatostatin receptor scintigraphy is a helpful diagnostic tool. New receptor-associated therapies may allow more effective and less toxic treatment modalities in the mostly elderly or immune deficient patients.

show abstract

“…However, the exact function of ligand-mediated activation of KIT in MCC has to be clarified in further studies. The potential use of KIT kinase inhibitor-based therapies, as already applied in other tumors, should be also considered in MCC [38]. Support for this strategy is provided by the observation that imatinib inhibits growth of MCC cells in vitro [31].…”

Section: Discussionmentioning

confidence: 99%

Co-Expression of KIT Receptor and Its Ligand Stem Cell Factor in Merkel Cell Carcinoma

Krasagakis¹,

Krüger‐Krasagakis²,

Eberle

et al. 2008

Dermatology

View full text Add to dashboard Cite

Background/Aims: KIT receptor has been implicated in the pathogenesis of cancer, either by mutation or autocrine activation. Merkel cell carcinoma (MCC) is a rare KIT-positive cutaneous tumor. We investigated the co-expression of KIT and its ligand stem cell factor (SCF) in MCC. Methods: Sixteen specimens from 13 MCC patients of various tumor stages were examined by immunohistochemistry for SCF, KIT, Ki67/MIB-1 and cleaved caspase 3 expression, and for apoptosis by TUNEL. Results: KIT was expressed in 13 of 16 tumors, and SCF in 15 of 16 specimens. Co-expression of KIT and SCF was detected in 12 of 16 tumors. KIT and SCF immunoreactivity scores were independent of tumor stage. Ki67/MIB-1 proliferation rates were high, whereas apoptosis rates were low, and did not depend on KIT or SCF expression. Conclusion: Co-expression of KIT and SCF in a high percentage of MCC tumors hints to an autocrine mechanism. KIT and SCF expression in primary tumors and in metastases suggests an early event in Merkel cell transformation.

show abstract

The promise of molecular targeted therapies: Protein kinase inhibitors in the treatment of cutaneous malignancies

Cited by 47 publications

References 86 publications

T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia

T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia

Merkel Cell Carcinoma – a Rarity in the Urogenital Tract

Co-Expression of KIT Receptor and Its Ligand Stem Cell Factor in Merkel Cell Carcinoma

Contact Info

Product

Resources

About