Future Science - Abstract: EGFR/HER-targeted therapeutics in ovarian cancer

Blogger's Note: this is a subscription based ($$$) journal

Future Science - Future Medicinal Chemistry - 4(4):447 - Summary

Review

EGFR/HER-targeted therapeutics in ovarian cancer

"Despite decades of research and evolving treatment modalities, survival among patients with epithelial ovarian cancer has improved only incrementally.
During this same period, the development of biologically targeted therapeutics has improved survival for patients with diverse malignancies.
Many of these new drugs target the human epidermal growth factor receptor (EGFR/HER/ErbB) family of tyrosine kinases, which play a major role in the etiology and progression of many carcinomas, including epithelial ovarian cancer. While several HER-targeted therapeutics are US FDA approved for the treatment of various malignancies, none have gained approval for the treatment of ovarian cancer.
Here, we review the published literature on HER-targeted therapeutics for the treatment of ovarian cancer, including novel HER-targeted therapeutics in various stages of clinical development, as well as the challenges that have limited the use of these inhibitors in clinical settings."

abstract: (in mice) MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model

Blogger's Note: in research (mice)

Abstract

Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is extracellular signal–related kinase (ERK). PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR–ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of 4 CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Furthermore, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model.  
However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss and severe skin peeling) at high doses. Our findings indicate that the MEK–ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC. Mol Cancer Ther; 11(2); 360–9. ©2011 AACR

abstract: Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review

"Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss ($$$ requires subscription) available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity."

HER3 - Turning off cancer's growth signals (pancreatic/ovarian)

Drugs that interfere with HER3’s better-known cousins, EGFR and HER2, have already proven effective in treating many types of cancer, and early-stage clinical trials are underway with antibodies directed against HER3. HER3 is of great interest to cancer biologists because it is commonly involved in two of the deadliest forms of the disease, ovarian and pancreatic cancer, says MIT Professor Linda Griffith, who led the research team with Harvard Stem Cell Institute and Brigham and Women’s cardiologist Richard Lee.
The study, published online May 26 in the Journal of Biological Chemistry....

Expert Opinion on Medical Diagnostics - KRAS mutations - Summary

What the reader will gain: KRAS mutations in mCRC and NSCLC primary tumors predict resistance to EGFR-targeted therapy. In pancreatic cancer, KRAS may prove useful as a diagnostic biomarker to screen for early neoplasia. Furthermore, quantitative KRAS mutation analysis could have the potential to distinguish pancreatic cancer from other conditions such as chronic pancreatitis.

With respect to ovarian and endometrial cancer, further studies should focus on determining reliable biomarkers for predicting response to EGFR-targeted therapy. Besides EGFR inhibition, KRAS may also serve as a diagnostic and predictive biomarker for evolving therapies directed against mutant RAS proteins.

Take home message: KRAS has been recognized as an outstanding predictive biomarker to select mCRC and NSCLC patients for EGFR-targeted therapies; however, multi-determinant approaches including other molecular markers should facilitate the identification of patients likely to respond to such therapies.

See also blog post:

Wednesday, July 21, 2010

A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk (full access)

Angiogenesis Inhibitors: Current Strategies and Future Prospects

Abstract/Full free access (chapters): 

Introduction
Inhibition of Angiogenesis for Anticancer Purposes 
Process of Carcinogenesis and Subsequent Tumor Angiogenesis
Angiopoietins and TIE Receptors
Delta/Jagged-Notch Signaling
HIF
Antiangiogenesis Compounds
Inhibitors of Growth Factors, RTKs, and Signaling Pathways
Monoclonal Antibodies Directed at EGFRPI3K/AKT/mTOR Pathway Inhibitors
MAPK-Farnesyltransferase Rho and Ras InhibitorsHIF Pathways and Binding...
Known and Potential Side Effects From the Inhibition of AngiogenesisConclusions
References

Conclusions:
The complex molecular pathways that govern tumor angiogenesis are logical targets for pharmacological manipulation given the important role they play in the growth and development of cancers.