C-kit, GIST, and Imatinib

Siehl, Jan; Thiel, Eckhard

doi:10.1007/978-3-540-46091-6_12

Cited by 39 publications

(24 citation statements)

References 19 publications

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“…In carcinomas and lymphomas, a higher contingent of apoptotic cells may represent a better response to chemotherapy 30,32 . Unlike many chemotherapeutic agents, imatinib mesylate, used in GIST is not based on a proliferating contingent of cells, but rather a blocking tyrosine kinase receptors and the further induction of cellular proliferation 33 . Therefore, Bcl-2 would not be useful to predict response to imatinib.…”

Section: Discussionmentioning

confidence: 99%

Ki-67 expression score correlates to survival rate in gastrointestinal stromal tumors (GIST)

et al. 2012

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PURPOSE: To evaluate the immunohistochemical expression of p16, Ki-67, p53 and Bcl-2 proteins in gastrointestinal stromal tumors (GIST); to assess the possible association between these variables and clinical and histopathological factors of cancer; and to check for prognostic value of these variables (survival and recurrence). METHODS: A sample of 55 patients treated surgically for GIST in three hospitals was studied. The surgically excised tumors were confirmed as GIST by KIT, vimentin, desmin S100 protein, CD117, 1A4 and CD34 assessment in paraffin blocks. RESULTS: Only 9 (16%) cases of GIST were positive for p53, p16 was positive among 43.6%; 80% of GISTs showed staining for Bcl-2. The proliferative index (expressed as the proportion of positive cells) assessed by immunohistochemical expression of Ki-67 was high in 49% of cases. Elevated Ki-67 scores were associated to high histological grade (p=0.0026) and mitosis index, MI (p=0.0001). High Ki-67 index was associated to death. Expression of p53, p16 and Bcl-2 did not correlate to morphological or clinical variables. CONCLUSIONS: Ki-67 immunohistochemical evaluation should be included in preoperative evaluation of GIST biopsies or surgical specimens as a prognostic tool for clinical staging; and all other proteins studied (Bcl-2, p53 and p16) did not play a role in GIST metabolic or carcinogenic process, remaining without prognostic value.

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Section: Discussionmentioning

confidence: 99%

Ki-67 expression score correlates to survival rate in gastrointestinal stromal tumors (GIST)

et al. 2012

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“…When using molecularly targeted therapy, one plausible approach might be to first identify the molecular ''addiction'' of a specific STS subtype; if such exists, then evaluate the implication of inhibiting that particular target/pathway. This strategy has led to remarkable strides in treatment of gastrointestinal stromal tumor, an STS subtype where activating c-Kit mutations are the major tumorigenesis and progression driver (19), whose inhibition results in significantly improved outcomes (20). However, the rarity of STS makes this approach to discovery and therapeutic efficacy validation of a novel agent extremely challenging.…”

Section: Discussionmentioning

confidence: 99%

Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

Ren

Korchin

Lahat

et al. 2008

Clinical Cancer Research

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Purpose: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. Experimental Design: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). Results: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. Conclusions: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.Available soft tissue sarcoma (STS) chemotherapies have modest response rates with significant toxicities (1). Consequently, new STS therapies must be developed to improve the current STS 5-year survival rates of <50%. However, new STS treatment development and trials validation are hampered by their rarity and remarkable clinical heterogeneity. More than 50 separate STS histologic subtypes are recognized; these possess markedly diverse clinical courses and outcomes, perhaps reflecting the complex and variable array of molecular derangements underlying these STS biological distinctions (2). In the era of targeted therapeutics, exploiting any relevant unifying molecular abnormalities as might exist in STS has appeal. Analogous to solid malignancies, STS consist of both tumor and tumor-associated normal cells; STS growth, migration, and dissemination depend on cross-talk between these two compartments. STS are generally highly vascular and angiogenic, resulting in increased metastatic potential (3). Amidst diversity, these common STS proper...

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“…They most commonly harbor activating mutations of C-KIT or the platelet-derived growth factor receptor alpha oncogene (PDGFRA) [1]. It is believed that mutations leading to independent and uncontrolled activation of KIT cause the development of these tumors [5].…”

Section: Discussionmentioning

confidence: 99%