Phase II Trials of Imatinib Mesylate and Docetaxel in Patients with Metastatic Non-small Cell Lung Cancer and Head and Neck Squamous Cell Carcinoma

Tsao, Anne S.; Liu, Suyu; Fujimoto, Junya; Wistuba, Ignacio I.; Lee, John; Marom, Edith M.; Charnsangavej, Chusilp; Fossella, Frank V.; Tran, Hai T.; Blumenschein, George R.; Papadimitrakopoulou, Vassiliki A.; Kies, Merrill S.; Hong, Waun Ki

doi:10.1097/jto.0b013e31822e7256

Cited by 26 publications

(29 citation statements)

References 41 publications

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“…In concequence, we set up the above study to analyze its potency in HNSCC cell lines to confirm these effects. The concentrations of imatinib used in our experiments were within the range that is achieved in a clinical trial (37). Similarly, the concentrations of carboplatin used in this study are clinically relevant.…”

Section: Discussionmentioning

confidence: 59%

“…In former studies imatinib also showed inhibitory impact on the PTK receptor c-kit and on its PTK activity (33,35). Thus, imatinib has antitumor activities towards adenocarcinoma, e.g., colon cancer, and its antitumoral effects have also been shown in non-small cell lung cancer and HNSCC (36,37). In concequence, we set up the above study to analyze its potency in HNSCC cell lines to confirm these effects.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the concentrations of carboplatin used in this study are clinically relevant. As current phase II clinical trials in aerodigestive tumors were undertaken to evaluate the efficacy of imatinib mesylatedocetaxel, which hypothesized that imatinib mesylate would inhibit platelet-derived growth factor receptor (PDGFR) on pericytes and increase docetaxel uptake, showed partial poor outcome in HNSCC patients (37) we find it very important to put emphasis on cell culture experiments. Imatinib can be administered orally to the patients and comparatively limited toxic side effects have been reported (38).…”

Section: Discussionmentioning

confidence: 99%

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Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

et al. 2012

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Abstract. Head and neck squamous cell carcinoma (HNSCC)is an aggressive epithelial malignancy. It is known to be the most common neoplasm appearing in the upper aerodigestive tract. The poor 5-year survival rate has remained unchanged in the last decades even though improved techniques in surgery, radiation and chemotherapy have been established. In contrast to the overall decreasing incidence of head and neck cancer in the US, the incidence of HPV-associated oropharyngeal cancer is increasing, indicating the importance of viral etiology. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). Matrix metalloproteinases (MMP) have been shown to play key roles in the remodeling of the ECM. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. But it also has an inhibitory impact, e.g., on the protein-tyrosine-kinase (PTK) receptor c-kit and on its PTK activity in HNSCC. In this study, we incubated the HNSCC cell lines HNSCC 11A and 14C and the p16-positive SCC line CERV196 with increasing concentrations of imatinib or carboplatin. After an incubation time of up to 10 days, we evaluated MMP-2 and -14 expression by ELISA techniques and immunohistochemistry. MMP-2 and -14 expression was demonstrated in all incubated tumor cell lines. Especially incubation with imatinib resulted in a significant decrease in MMP expression in incubated cell lines. Our results indicate that the expression of MMP-2 and -14 is suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially keeping in mind the moderate toxicity of imatinib.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

et al. 2012

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“…Imatinib also showed an inhibitory effect on the catalytic activity of PDGFR and c-kit tyrosine kinases. It is used for the treatment of several malignancies, such as colon adenocarcinoma and non-small cell lung cancer (37)(38)(39). The aim of the present study was to investigate the effects of imatinib and 5-FU on HPV16-associated HNSCC compared to non-HPVinduced HNSCC and their impact on the expression of MMP-2 and MMP-14 in order to examine the potency of chemotherapeutic agents in HNSCC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Imatinib-associated matrix metalloproteinase suppression in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro

et al. 2014

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. The growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM), which is modified by matrix metalloproteinases (MMPs). The MMP family is still relevant to cancer research, as it promotes malignant transformation, cell proliferation and modulation of angiogenesis even in the early stages of cancer. The proteolytic processing of bioactive molecules by MMP-14 (MT1-MMP) causes severe abnormalities in connective tissue, defective angiogenesis and premature death. MMP-2 (gelatinase A) and MMP-14 also play a role in degradation of basement membrane and cell carcinoma invasion. Imatinib blocks the PTK receptor c-kit and forestalls its PTK activity. The aim of the present study was to investigate the expression pattern of MMP-14 and MMP-2 in human papilloma virus (HPV)-negative and p16-positive SCC and to evaluate the chemosensitivity of the tumour cells to the chemotherapeutic agents, imatinib and 5-fluorouracil (5-FU). We incubated the SCC cell lines with imatinib (18 and 30 µmol/ml) and 5-FU (1 and 5 µmol/ml) and detected MMP-14 and MMP-2 by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) after 48, 72, 120, 192 and 240 h. We detected expression of MMP-2 and MMP-14 in all incubated tumour cell lines. With imatinib in particular, we found a reliable trend towards decreased MMP-2 and MMP-14 expression levels in p16-positive and p16-negative SCC tumour cell lines in addition to an induced apoptotic effect. We found statistically significant imatinib-induced suppression of MMP-2- and MMP-14, dependent on the incubation time and the cell line. We detected a significant suppression of MMP-2 and MMP-14 especially in p16-negative HNSCC14C cells after prolonged treatment time with imatinib. Dose escalation of imatinib and 5-FU had no statistically significant effect on the expression of MMP-2 or MMP-14. The p16-positive SCC cells exhibited higher expression of total protein. We detected a significant suppression of MMP-2 and MMP-14 in all the incubated SCC cell lines, partially after treatment with imatinib. We found higher suppression of MMP-2 in the CERV196 cells after incubation with imatinib. We detected a reliable trend towards increased chemosensitivity of p16-positive tumour cells in vitro after treatment with imatinib. Extended studies and clinical trials are needed to further investigate these findings in HPV-associated HNSCC.

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“…It has been also demonstrated that PDGF overexpression is associated with increase of melanoma cells proliferation and increased pericyte abundance (Furuhashi et al, 2004). Unfortunately, treatment with imatinib (TKR inhibitor specific to PDGFRβ) has not produced encouraging results in patients with metastatic non-small cell lung cancer (Tsao et al, 2011). Conversely, dual PDGFRβ/VEGFR inhibition is effective for treating multiple stages in tumorigenesis, particularly in solid tumors with high pericyte coverage (Bergers and Hanahan, 2008).…”

Section: Need For Pro-angiogenic Therapy?mentioning

confidence: 99%

Anti-angiogenic Therapy in Cancer: Downsides and New Pivots for Precision Medicine

et al. 2017

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Primary solid tumors originate close to pre-existing tissue vasculature, initially growing along such tissue blood vessels, and this phenomenon is important for the metastatic potential which frequently occurs in highly vascularized tissues. Unfortunately, preclinic and clinic anti-angiogenic approaches have not been very successful, and multiple factors have been found to contribute to toxicity and tumor resistance. Moreover, tumors can highlight intrinsic or acquired resistances, or show adaptation to the VEGF-targeted therapies. Furthermore, different mechanisms of vascularization, activation of alternative signaling pathways, and increased tumor aggressiveness make this context even more complex. On the other hand, it has to be considered that the transitional restoration of normal, not fenestrated, microvessels allows the drug to reach the tumor and act with the maximum efficiency. However, these effects are time-limited and different, depending on the various types of cancer, and clearly define a specific “normalization window.” So, new horizons in the therapeutic approaches consist on the treatment of the tumor with pro- (instead of anti-) angiogenic therapies, which could strengthen a network of well-structured blood vessels that facilitate the transport of the drug.

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Phase II Trials of Imatinib Mesylate and Docetaxel in Patients with Metastatic Non-small Cell Lung Cancer and Head and Neck Squamous Cell Carcinoma

Cited by 26 publications

References 41 publications

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

Imatinib-associated matrix metalloproteinase suppression in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro

Anti-angiogenic Therapy in Cancer: Downsides and New Pivots for Precision Medicine

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