Jose Baselga

..Numerous studies are underway or planned to evaluate other Herceptin combinations and regimens in the metastatic and adjuvant settings...

..The pharmacokinetics of trastuzumab were evaluated in these studies and the results are summarized...

..These exciting results and plans are further complemented by an emerging number of compounds in clinical development, including both monoclonal antibodies (ie, IMC-C225) and other tyrosine kinase inhibitors, directed at the EGFR...

..It may also be a helpful means of delivering a highly active cytotoxic drug in combination with radiation therapy, other proven chemotherapy agents such as doxorubicin, and new, highly promising biological agents such as HERCEPTIN:..

..1 months following administration of single-agent trastuzumab. Notably, 2% of patients were free of disease progression at 6 months. The safety profile of trastuzumab either given alone or in combination was favourable...

..Thus, the rationale for EGFR-targeted approaches to cancer treatment is apparent and now well established, and there is increasing evidence that they may represent a significant contribution to cancer therapy...

..In addition, compounds that inhibit receptor tyrosine kinases have shown significant preclinical activity and are potential candidates for clinical testing...

..We evaluated the pharmacokinetics and toxicity of C225 in patients with advanced tumors overexpressing EGF receptors...

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..Early data show that they are generally well tolerated and have provided evidence of antitumor activity. HER-TK inhibitors are exciting agents that are likely to have a substantial impact on the way we treat patients with cancer...

..The results of ongoing studies with these agents in diverse indications and tumor types may establish the role of these promising therapies to our current cancer treatments...

..Clinical trials that are built on these results are under way...

..Based on these promising results, additional phase II and phase III trials are currently underway in head and neck and colorectal cancer...

..2%). These results reveal a mechanism of ER regulation mediated by HER2, which suggests a new strategy to improve responses to endocrine therapy in breast cancer...

..We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting...

..In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and results in antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha...

..Our results show that USP15 regulates the TGF-β pathway and is a key factor in glioblastoma pathogenesis...

..The hypothesis is that the suppression of this pathway results in sensitization to anti-HER2 agents. However, this combinatorial strategy has not been comprehensively tested in models of trastuzumab and lapatinib resistance...

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..This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001)...

..Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors...

..Nonetheless, as with other recent studies, a favorable interaction between PIK3CA KD mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained...

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..Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations...

..Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone...

..To evaluate the antitumor activity and pharmacodynamic/biologic effect of gefitinib 500 mg/day monotherapy in patients with previously treated, advanced breast cancer...

..Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors...

..These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis...

..These results suggest that cortactin is a target of 611-CTF involved in the regulation of cell migration and, thus, in the metastatic behavior of breast tumors expressing this CTF...

..The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways...

..This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose...

..Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance, which can be effectively reversed by NVP-BEZ235...

..Inhibition of the EGFR pathway is a useful strategy in the treatment of patients with advanced NSCLC. The aim of this study is to assess predictive clinical parameters of efficacy...

..This phase II trial assessed the efficacy and safety profile of the combination in patients with HER2-positive breast cancer whose disease had progressed during prior trastuzumab-based therapy...

..Thus, the kinase domain seems necessary for the activity of HER2 CTFs and the presence of these HER2 fragments could account for the resistance to treatment with antibodies...

..Together, this extensive program, which includes analysis of predictive molecular and pathologic makers, will establish the efficacy, safety, and role of trastuzumab in early breast cancer...

..To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non-small cell lung cancer patients refractory to platinum-based chemotherapy...

..High CD44 and Id1 levels confer poor prognosis in GBM patients...

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..These new therapies include tyrosine kinase inhibitors, antibody-chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2-ERBB3 dimers...

..IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer...

..Together these observations suggest that therapeutic interventions targeting CDK8 may confer a clinical benefit in beta-catenin-driven malignancies...

..In order to identify a rationally based dose and schedule for cancer treatment, we have conducted a tumor pharmacodynamic phase I study in patients with advanced solid tumors...

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..Overall, results from clinical trials are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk:benefit ratio demonstrated in these studies...

..We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate...

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..Pharmacodynamic analyses in mitotic cells of both skin and tumor provided proof of mechanism for Aurora A kinase inhibition. A more potent, selective, second-generation Aurora A kinase inhibitor, MLN8237, is in clinical development...

..Further investigation into this concept may identify additional funnel factors in the oncogenic pathways and provide potential therapeutic targets...

..The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies...

..Underscoring the functional relevance of the p95HER2-induced senescence secretome, we show that p95HER2-induced senescent cells promote metastasis in vivo in a non-cell-autonomous manner...

..A phase I study was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), establish a safety profile, and to evaluate pharmacokinetics and efficacy of the drug...

..These findings will have to be considered in the design and interpretation of clinical trials with inhibitors of the PI3K pathway...

..Thus, the overall management of breast cancer will increasingly require an understanding of breast cancer heterogeneicity, the biological nature of any given tumor as well the existence of increased personalized treatment options...

..We will present these novel therapies and will analyse for each target the developmental status of some of the agents as well as target-specific challenges...

..Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma...

..Combining trastuzumab and pertuzumab therefore provides a more comprehensive blockade of the HER signaling pathways, resulting in greater antitumor efficacy...

..The epigenetic regulation of the PDGF-B gene dictates whether TGFbeta acts as an oncogenic factor inducing PDGF-B and proliferation in human glioma...

..These data suggest that cytoplasmic p27 can exert oncogenic functions by modulating Akt stability, cell survival, and tumorigenicity...

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..Although both schedules were well tolerated, weekly docetaxel appears to have a more favourable toxicity profile...

..We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors...

..In addition, we tested the new proposed early CA-125 signal of progressive disease (EPD) criterion in the same study population...

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..The lack of clinical response or suggestion of prolonging time to progression compared to historical data with interferon-alfa supports no further study of single-agent C225 in patients with metastatic RCC...

..This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events...

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..The ability of trastuzumab to inhibit HER2 cleavage may correlate with the clinical anticancer activity of the multifunctional HER2-targeting antibody...

..We propose that the inhibition of HER2 cleavage and prevention of the production of an active truncated HER2 fragment represent a novel mechanism of action of trastuzumab...

..Poor survival rates in extensive-stage small-cell lung cancer (SCLC) patients prompted us to evaluate a sequential dose-dense schedule of paclitaxel followed by topotecan...

..To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium...

..The aim of this retrospective study is to analyze the prognostic value of the CA-125 nadir after the completion of an optimal primary treatment...

..Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival...

..Based on these data, a randomised trial in the framework of the EORTC-Genitourinary (GU) group of gemcitabine/carboplatin versus carboplatin/methotrexate/vinblastine (MCAVI) is ongoing...

..The potential clinical benefit of these new three-drug combinations in the treatment of TCC needs to be tested in future phase III studies...

..The significance of these mechanisms for selection of concomitant chemotherapy is also considered...

..This schedule merits further investigation in a phase-II trial...

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..There is preliminary clinical evidence suggesting that the in vivo synergy seen between Ad5CMV-p53 and cisplatin may also occur in patients. Phase II trials are justified and have been started...

..Dose-dense chemotherapy is predicted to be a superior treatment plan. Therefore, we studied dose-dense doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) as adjuvant therapy...

..HSP90 inhibition is therefore a potentially effective therapeutic strategy for p95-HER2-mediated Trastuzumab-resistant breast cancer...

..The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated...

..To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy...

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..Based on these encouraging results, studies assessing activated EGFR, activated MAPK, and other selected markers in phase II trials in tumors from patients treated with ZD1839 are currently planned or ongoing...

..Increasing life expectancy in the general population has led to a rise in the incidence of cancer and new challenges with regard to the diagnosis, therapy and prognosis of this disease...

..We found serial liver biopsies using Tru-Cut to be a safe and easy procedure. In our series, we could evaluate samples for molecular changes that influence the optimal dose, sequence, and schedule of the new antineoplastic agents...

..A new generation of PI3K inhibitors is now entering early clinical trials, with much anticipation that they will add to the growing armamentarium of targeted cancer therapeutics...

..The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of EC and GC that will probably translate into efficacy advantage in the treatment of these common malignancies...

..The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed...

..Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted...