scholarly journals Targeting HER 1 and 2 in breast cancer with lapatinib

2011 ◽  
pp. 21-28
Author(s):  
Gerald M. Higa
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Family Members ◽  
Disease Relapse ◽  
Her Family ◽  
Development Of Resistance ◽  
Improved Outcomes ◽  
Insight Into

Numerous clinical trials support the biological relevance of the HER2 oncoprotein in breast cancer. In spite of improved outcomes, overexpression of the receptor is associated with increased risks of disease relapse, even in patients with early, and potentially curable, disease. Until recently, development of resistance to trastuzumab left patients with no therapeutic option other than specifically targeted HER2. This paper provides an in-depth review of lapatinib, a dual HER kinase inhibitor, as well as some insight into three HER family members, in breast cancer.

scholarly journals Evaluation of the association of HER family members with efficacy of trastuzumab therapy in metastatic breast cancer

2016 ◽  
Vol 27 ◽  
pp. vi32 ◽  
Author(s):  
A. Koutras ◽  
V. Kotoula ◽  
G. Kouvatseas ◽  
C. Christodoulou ◽  
D. Pectasides ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Family Members ◽  
Metastatic Breast ◽  
Her Family ◽  
Trastuzumab Therapy

Drug Development: Neoadjuvant Opportunities in Breast Cancer

2013 ◽  
pp. 73-79
Author(s):  
Priya Rastogi ◽  
Charles E. Geyer ◽  
Eleftherios P. Mamounas ◽  
Angela DeMichele
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Biology ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Preoperative Therapy ◽  
New Agents ◽  
Her2 Breast Cancer ◽  
Improved Outcomes

Preoperative therapy allows for a higher rate of breast conserving surgery and has been shown equivalent to adjuvant therapy. Preoperative therapy provides an opportunity to obtain insights into breast cancer biology and to accelerate the evaluation of new therapies. Clinical trials have shown that women who achieve a pathologic complete response (pCR) have substantially improved outcomes compared with those who do not achieve a pCR. The U.S. Food and Drug Administration (FDA) meta-analysis demonstrated that the association of pCR and long-term outcomes is greater in women with aggressive breast cancer subtypes. In patients with HER2+ breast cancer, the addition of trastuzumab to chemotherapy in the neoadjuvant setting has doubled pCR and correlated with improved outcomes. Clinical trials will evaluate tailoring the use of radiation therapy in patients who have received neoadjuvant therapy. Trials have established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich breast cancer. The neoadjuvant setting allows for evaluation of endocrine therapies in combination with newer targeted therapies in the appropriate patient populations. The neoadjuvant setting provides opportunity to accelerate the evaluation of new agents, improve pCR rates, and identify predictive biomarkers for response. This setting provides the opportunity for screening new agents in combination with chemotherapy while obtaining serial biopsies to understand biology of response and resistance. Although current standard therapies provide substantial benefits for patients with a pCR, patients with residual disease are at substantial risk for disease recurrence. New agents are being evaluated in patients with high-risk residual disease following standard treatment regimens.

Diarrhea events in cancer patients (pts) treated with lapatinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9125-9125 ◽  
Author(s):  
M. Koehler ◽  
S. Chan ◽  
B. O. Newstat ◽  
A. Preston ◽  
H. A. Burris
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Kinase Inhibitor ◽  
Median Number ◽  
Low Grade ◽  
Cancer Clinical Trials ◽  
Dose Time ◽  
Delayed Onset ◽  
Gastrointestinal Adverse Events ◽  
Time To Onset

9125 Introduction: Lapatinib (L) is an oral dual ErbB1/ErbB2 tyrosine kinase inhibitor administered to > 5,000 pts in clinical trials. Low grade gastrointestinal adverse events: diarrhea, nausea and vomiting were recorded. We characterize here the diarrhea events related to L. Methods: Diarrhea events were recorded in 1,514 pts from 8 completed MBC and non-breast cancer clinical trials. Non-L treated pts in these trials were the comparator for analysis of toxicity grades, relationship to dose, time to onset, duration, required interventions and outcomes. Results: The L dose ranged from 1,000–1,500mg daily as monotherapy (n=928) or in combination with chemotherapy (n=198). Capecitabine alone (n=191)and tamoxifen alone (n=197) pts served as controls. For L and non-L groups the per pt diarrhea rates were: any grade 50%v33%; of those G1 54%v53%; G2 30%v30%; G3 15%v17%; G4 <1%v0% and SAEs 3% v 3%; respectively. There were no fatal L-related SAEs. For L, early diarrhea presentation <6 days(d) was 2x more frequent (44%v21%). In the non-L grp, diarrhea presented at 6–14 d in 30% pts. Delayed onset (>28 d) was similar: 22% on L v 26%, non-L. Initial G3 diarrhea or progression from G1/G2 to G3 was similar (Lv non-L): 4%v 3% and 4% v3%, respectively. The median number of events/pt (2) was the same for both groups and median duration was 5d (L) v 6d (non-L). Events (L v non-L) resolved in 89%v93%; and resolved with sequelae <1% v 1%; resolution was not recorded in 7%v4%. Events were managed in approximately 30% of pts with standard anti-diarrhea medications (loperimide and lomitil) and when more sever with hydration, octreotide & antibiotics. Majority of G1/G2 events were not treated. Most pts (85%) did not have L interrupted or dose adjusted and both group only 2% (L)v 2% (non-L) discontinued therapy due to diarrhea. Conclusions: Diarrhea related to L therapy (mostly used as monotherapy in this analysis) is usually mild to moderate, frequently does not require intervention, but pts monitoring is crucial. Importantly, L-related diarrhea appears as early events (before day 6) and is generally responsive to standard interventions. Analyses are ongoing to further identify its natural history, characteristics and pts at risk for serious events. No significant financial relationships to disclose.

Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitization

2008 ◽  
Vol 417 (1) ◽  
pp. 361-371 ◽  
Author(s):  
Elizabeth Iorns ◽  
Christopher J. Lord ◽  
Alan Ashworth
Keyword(s):  
Breast Cancer ◽  
Oestrogen Receptor ◽  
Kinase Inhibitors ◽  
Genetic Screen ◽  
Genetic Screens ◽  
Development Of Resistance ◽  
Chemical Screen ◽  
Related Proteins ◽  
Insight Into ◽  
Treat Breast Cancer

Tamoxifen is the most commonly used drug to treat breast cancer and acts by blocking ERα (oestrogen receptor α) signalling. Although highly effective, its usefulness is limited by the development of resistance. Given this, strategies that limit resistance by sensitizing cells to tamoxifen may be of use in the clinic. To gain insight into how this might be achieved, we used chemical and genetic screens to identify targets and small-molecule inhibitors that cause tamoxifen sensitization. A high-throughput genetic screen, using an RNA interference library targeting 779 kinases and related proteins, identified the PDK1 (phosphoinositide-dependent kinase 1) signalling pathway as a strong determinant of sensitivity to multiple ERα antagonists, including tamoxifen. A chemical screen using existing drugs and known kinase inhibitors also identified inhibitors of the PDK1 pathway, including triciribine and tetrandrine. Aside from identifying novel agents and targets for tamoxifen sensitization, this approach also provides evidence that performing chemical and genetic screens in parallel may be useful.

EIndole Compounds Against Breast Cancer: Recent Developments

2012 ◽  
Vol 13 (14) ◽  
pp. 1705-1719 ◽  
Author(s):  
Bernhard Biersack ◽  
Rainer Schobert
Keyword(s):  
Breast Cancer ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Vinca Alkaloids ◽  
Indole Derivatives ◽  
Breast Cancers ◽  
Pertinent Literature ◽  
Synthetic Receptor ◽  
Recent Developments ◽  
Insight Into

Breast cancer is still the leading cause of cancer deaths among women worldwide and new therapies and drugs are continuously being conceived and explored to better control or even cure this disease. Among the most efficacious low-molecular drugs for the treatment of breast cancer are indole derivatives such as 3,3'-diindolylmethane (DIM), the structurally complex antimitotic vinca alkaloids, and the synthetic receptor tyrosine kinase inhibitor sunitinib. This review is to give an insight into the latest developments in the field of indole based drugs against breast cancers with a focus on those derived from natural products and on their targets and modes of action. Pertinent literature is covered from 2007 up to 2012.

scholarly journals Novel Therapies for Relapsed and Refractory Neuroblastoma

Children ◽  
2018 ◽  
Vol 5 (11) ◽  
pp. 148 ◽  
Author(s):  
Peter Zage
Keyword(s):  
Clinical Trials ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Disease Relapse ◽  
Therapeutic Modalities ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Improved Outcomes ◽  
Outcomes For Children ◽  
Novel Treatment Strategies

While recent increases in our understanding of the biology of neuroblastoma have allowed for more precise risk stratification and improved outcomes for many patients, children with high-risk neuroblastoma continue to suffer from frequent disease relapse, and despite recent advances in our understanding of neuroblastoma pathogenesis, the outcomes for children with relapsed neuroblastoma remain poor. These children with relapsed neuroblastoma, therefore, continue to need novel treatment strategies based on a better understanding of neuroblastoma biology to improve outcomes. The discovery of new tumor targets and the development of novel antibody- and cell-mediated immunotherapy agents have led to a large number of clinical trials for children with relapsed neuroblastoma, and additional clinical trials using molecular and genetic tumor profiling to target tumor-specific aberrations are ongoing. Combinations of these new therapeutic modalities with current treatment regimens will likely be needed to improve the outcomes of children with relapsed and refractory neuroblastoma.

scholarly journals HO-1 drives autophagy as a mechanism of resistance against HER2-targeted therapies

2019 ◽  
Vol 179 (3) ◽  
pp. 543-555 ◽  
Author(s):  
Natasha Tracey ◽  
Helen Creedon ◽  
Alain J. Kemp ◽  
Jayne Culley ◽  
Morwenna Muir ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapies ◽  
Proteomic Analysis ◽  
Iron Homeostasis ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Heme Oxygenase 1 ◽  
Her2 Positive ◽  
Her Family

Abstract Purpose Targeted therapies have resulted in major advances in the treatment of HER2-positive breast cancers. Despite this, up to 70% of patients will develop resistance to treatment within 2 years and new strategies for targeting resistant disease are needed. Methods To identify potential resistance mechanisms, we used the mouse MMTV-NIC-PTEN+/− spontaneous model of HER2-positive breast cancer and the pan-HER family kinase inhibitor sapatinib. Vehicle and sapatinib-treated tumors were evaluated by immunohistochemistry and proteomic analysis. In vitro studies were carried out to define the role of heme oxygenase 1 (HO-1) and autophagy in resistance to sapatinib and lapatinib, another pan-HER family kinase inhibitor. Results Treatment of tumor-bearing MMTV-NIC-PTEN+/− mice with sapatinib resulted in delayed tumor progression and increased survival. However, tumors eventually progressed on treatment. Proteomic analysis identified proteins associated with cellular iron homeostasis as being upregulated in the sapatinib-treated tumors. This included HO-1 whose overexpression was confirmed by immunohistochemistry. Overexpression of HO-1 in HER2-expressing SKBR3 breast cancer cells resulted in reduced sensitivity to both pan-HER family kinase inhibitors sapatinib and lapatinib. This was associated with increased autophagy in the HO-1 over-expressing cells. Furthermore, increased autophagy was also seen in the sapatinib-treated tumors. Treatment with autophagy inhibitors was able to increase the sensitivity of the HO-1 over-expressing cells to both lapatinib and sapatinib. Conclusion Together these data indicate a role for HO-1-induced autophagy in resistance to pan-HER family kinase inhibitors.

scholarly journals CSCs in Breast Cancer—One Size Does Not Fit All: Therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1128 ◽  
Author(s):  
Andrew Sulaiman ◽  
Sarah McGarry ◽  
Xianghui Han ◽  
Sheng Liu ◽  
Lisheng Wang
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Triple Negative ◽  
Signal Pathway ◽  
Future Research ◽  
Research Needs ◽  
Disease Relapse ◽  
Differential Signal ◽  
Cancer Subtypes ◽  
Potential Inhibitors

Unlike other breast cancer subtypes, triple-negative breast cancer (TNBC) has no specific targets and is characterized as one of the most aggressive subtypes of breast cancer that disproportionately accounts for the majority of breast cancer-related deaths. Current conventional chemotherapeutics target the bulk tumor population, but not the cancer stem cells (CSCs) that are capable of initiating new tumors to cause disease relapse. Recent studies have identified distinct epithelial-like (E) ALDH+ CSCs, mesenchymal-like (M) CD44+/CD24− CSCs, and hybrid E/M ALDH+/CD44+/CD24− CSCs. These subtypes of CSCs exhibit differential signal pathway regulations, possess plasticity, and respond differently to treatment. As such, co-inhibition of different subtypes of CSCs is key to viable therapy. This review serves to highlight different pathway regulations in E and M CSCs in TNBC, and to further describe their role in disease progression. Potential inhibitors targeting E and/or M CSCs based on clinical trials are summarized for further investigation. Since future research needs to adopt suitable tumor models and take into account the divergence of E and M CSCs for the development of effective treatments, TNBC models for clinically translatable studies are further discussed.

Current trend of breast cancer therapeutics from the U.S. clinical trial database

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17546-e17546
Author(s):  
S. S. Kwok ◽  
J. Tsang
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Kinase Inhibitor ◽  
Current Trend ◽  
Cancer Therapeutics ◽  
Study Phase ◽  
Trial Registry ◽  
Cancer Trial ◽  
The Us

e17546 Background: The standard of breast cancer care has been based on clinical trial results. With the International Committee of Medical Journal Editors (ICMJE) requiring all clinical trials registered in a public trial registry as a condition of publication, the US trials registry “ClinicalTrials.gov” has become a global registry of currently available clinical trials. We aim to explore the current clinical trials to study the trend of breast cancer therapeutics development based on analysis of a comprehensive breast cancer trial database. Methods: We performed a systematic review of all breast cancer therapeutic clinical trials. All data were captured from ClinicalTrials.gov for all “industry-sponsored” phase I-IV trials in October, 2007 including trials that were first registered between October 2005 and September 2007. Essential data was extracted by a tailor-made Statistical Analysis System Program developed by Professor JP Karlberg at the University of Hong Kong. The data included register identity, study phase, study compounds and recruitment status etc. Results: Altogether 443 clinical therapeutic interventional trials were identified and classified into 10 modes of action. The latest five mostly studied compounds accounted for 32.73% of all the therapeutic trials (n = 145). Lapatinib, a dual kinase inhibitor is studied most in 31 trials (9 monotherapy). Docetaxel, a mitotic inhibitor is studied in 27 trials (10 monotherapy) while letrozole, an aromatase inhibitor, currently used in adjuvant setting is tested in 18 out of a total 22 trials as monotherapy. Antimetabolites such as gemcitabine being involved in 24 trials (2 monotherapy) with capecitabine studied in 21 trials (11 monotherapy), were followed by bevacizumab, a VEGF monoclonal antibody which is currently studied in 20 trials, and tested as combinations in 75% of the related trials. Conclusions: According to the US trial registry, current most commonly tested compounds for breast cancer include lapatinib, followed by docetaxel, gemcitabine, letrozole, and capecitabine. There is increasing new therapeutics with combination strategy. This supports the trend of personalized medicine in the management of breast cancer which is a heterogeneous disease. No significant financial relationships to disclose.

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