A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling <i>in vitro</i> and inhibits insulin-like growth factor-I receptor–dependent tumor growth <i>in vivo</i>

Ji, Qunsheng; Mulvihill, Mark J.; Rosenfeld-Franklin, Maryland; Cooke, Andrew; Feng, Lixin; Mak, Gilda; O’Connor, Matthew; Yao, Yan; Pirritt, Caroline; Buck, Elizabeth; Eyzaguirre, Alexandra; Arnold, Lee D.; Gibson, Neil W.; Pachter, Jonathan A.

doi:10.1158/1535-7163.mct-07-0070

Cited by 140 publications

(122 citation statements)

References 42 publications

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“…Interestingly, we have recently shown that IGF receptor 1 (IGF-1R) is expressed at a significantly higher level in all ER þ tumors (including ER þ /HER2 þ ) compared with ERÀ/HER2 þ tumors (Appl Immunohistochem Mol Morphol; in press). 40 Similar findings were reported by Harris et al 41 If these findings are also supported by additional studies, IGF-1R may be another molecule that could be targeted with available antibodies [42][43][44][45] in these difficult-to-treat ER þ /HER2 þ tumors, despite the presence of two well-known targets.…”

Section: Discussionsupporting

confidence: 74%

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

et al. 2011

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Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptornegative/HER2 þ tumors is seen in 27-45% of cases. In contrast, estrogen receptor (ER) þ /HER2 þ tumors demonstrate pathologic complete response in B8% of cases and is generally limited to weak-to-moderate ER þ /HER2 þ tumors. It is speculated that addition of trastuzumab to neoadjuvant chemotherapy regimen will increase the pathologic complete response rates in all HER2 þ tumors. A list of HER2 þ patients who received neoadjuvant chemotherapy (with trastuzumab) in the years 2007-2010 was obtained from our hospital database. The 104 HER2 þ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results as follows: ERBB2 (ER-/PR-[H-score r10]/HER2 þ ), Luminal B-HER2 Hybrid (LBHH; weak to moderate ER þ [H-score 11-199]/HER2 þ ), and Luminal A-HER2 Hybrid (LAHH; strong ER þ [H-score Z200]/ HER2 þ ). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and in the lymph nodes. Percentage tumor volume reduction was also calculated based on pretherapy size and detailed evaluation of the resection specimen. In all, 52% (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33%; 10 of 30) and LAHH (8%; 2 of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86%), followed by LBHH (74%) and LAHH (64%) tumors. We conclude that addition of trastuzumab to neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2 þ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be utilized to counsel patients considered for neoadjuvant chemotherapy and the same principle could be applied in the adjuvant setting.

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Section: Discussionsupporting

confidence: 74%

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

et al. 2011

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“…Most of these factors are associated with carcinoma growth and metastasis. IGF-I is believed to regulate carcinoma cell proliferation and to influence tumor growth (98,99). BMPs have been associated with high-risk premalignant and malignant lesions of oral epithelium, with salivary gland tumors, and with the promotion of tumor cell migration (100,101).…”

Section: Discussionmentioning

confidence: 99%

Emdogain® in carcinogenesis: a systematic review of in vitro studies

2010

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Emdogain is a commercial product of unknown composition and is clinically used to induce periodontal regeneration. This study aims to review current knowledge of the in vitro effects of Emdogain on oral tissues and, in particular, factors related to carcinoma. A systematic approach was used to review studies from the Embase and Pubmed databases; a total of 76 studies were included. These comprised in vitro studies of the cytokines in, or regulated by, Emdogain and assays designed to study the effects of EMD on human cells in oral tissues or malignant cells. Several studies have shown that EMD regulates the proliferation, migration, adhesion, gene expression, and cytokine production of (pre-)osteoblasts, periodontal fibroblasts, and gingival fibroblasts. However, the effects of EMD on malignant oral cells are not well understood. EMD seems to have broad regulatory effects on malignant cells and on several carcinoma-related factors. Evidence suggests that patients with premalignant or malignant mucosal lesions should not be treated with EMD. (J Oral Sci 52, 1-11, 2010)

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“…Cells were harvested and implanted s.c. in the right flank of nu/nu CD-1 mice as described previously (29). Tumors were allowed to establish to 200 AE 50 mm 3 in size before randomization into various treatment groups with 8 mice per group.…”

Section: In Vivo Antitumor Efficacy Studiesmentioning

confidence: 99%

Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

Bhagwat

Gokhale

Crew

et al. 2011

Molecular Cancer Therapeutics

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The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC 50 values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Ka, PI3Kb, PI3Kg, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling.

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A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor–dependent tumor growth in vivo

Cited by 140 publications

References 42 publications

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

Emdogain® in carcinogenesis: a systematic review of in vitro studies

Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

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