M. Markman

Jalid Sehouli

Charles F. Levenback

Dennis S. Chi

Epithelial Ovarian Cancer: Focus on Targeted Therapy

Ovarian cancer affects approximately 25,000 women in the United States each year and remains one of the most lethal female malignancies. A standard approach to therapy is surgical cytoreduction, after which the remaining microscopic residual disease is treated with chemotherapy. The vast majority of patients have disease recurrence, underscoring the crucial need for approaches to control the regrowth, or colonization, of tissues after local treatment. Improved therapies require mechanistic information about the process of metastatic colonization, the final step in metastasis, in which cancer cells undergo progressive growth at secondary sites. Studies of metastasis suppressors are providing insights into events controlling metastatic colonization. This paper reviews our laboratory&#39;s approach to the identification, characterization, and functional testing of the JNKK1/MKK4 metastasis suppressor in ovarian cancer metastatic colonization. Specifically, we demonstrate that interaction of ovarian caner cells with the omental microenvironment activates JNKK1/MKK4 resulting in decreased proliferation without affecting apoptosis. The potential role of the omental microenvironment, specifically milky spot structures, is also described. It is our goal to provide this work as a usable paradigm that will enable others to study metastasis suppressors in clinical and experimental ovarian cancer metastases.

Shaheena Khan

Jennifer L. Taylor

Carrie W. Rinker-Schaeffer

Disrupting Ovarian Cancer Metastatic Colonization: Insights from Metastasis Suppressor Studies

RRR-<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M2" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>-tocopherol derivative <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M3" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>-TEA (RRR-<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M4" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>-tocopherol ether-linked acetic acid analog) has been shown to be a potent antitumor agent both in vivo and in vitro.  In this study, we investigated the effects of <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M5" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg>-TEA on the expression of epidermal growth factor receptor (EGFR) family members, ErbB1, 2 and 3, and the role of ErbB 2 and 3 in <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M6" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg>-TEA-induced apoptosis and suppression of Akt, FLIP and survivin in the cisplatin-sensitive (A2780S) and -resistant (A2780/CP70R) human ovarian cancer cell lines. Data show that <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M7" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>-TEA&#x27;s ability to induced apoptosis was associated with reduced expression of ErbB1 (cisplatin-resistant cells), 2 and 3 (both cell types) and reduced levels of the phosphorylated (active) form of Akt; as well as, reduced levels of FLIP and survivin proteins in both cell types. Ectopic overexpression and siRNA knockdown studies showed that ErbB2, ErbB3, Akt, FLIP and survivin are involved in <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M8" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>-TEA-induce apoptosis and that <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M9" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>-TEA downregulates FLIP and survivin via suppression of pAkt, which is mediated by ErbB2 and ErB3. Thus, <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M10" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg>-TEA is a potent pro-apoptotic agent for both cisplatin-sensitive and -resistant ovarian cancer cell lines in cell culture and it produces cell death, at least in part, by downregulation of members of the EGFR family.

Ming-Chieh Shun

Weiping Yu

Sook-Kyung Park

Bob G. Sanders

Kimberly Kline

Downregulation of Epidermal Growth Factor Receptor Expression Contributes to <svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z"/></g></svg>-TEA's Proapoptotic Effects in Human Ovarian Cancer Cell Lines

In sporadic epithelial ovarian cancer (EOC), the inactivation of BRCA1 through various mechanisms is a relatively common event. BRCA1 protein dysfunction results in the breakdown of various critical pathways in the cell, notably, the DNA damage response and repair pathway. Tumors from patients with <i>BRCA1</i> germline mutations have an increased sensitivity to DNA damaging chemotherapeutic agents, such as cisplatin, due to defective DNA repair. Thus, inhibiting BRCA1 in sporadic EOC using novel targeted therapies is an attractive strategy for the treatment of advanced or recurrent EOC. Several classes of small molecule inhibitors that affect BRCA1 have now been tested in preclinical and clinical studies suggesting that this is a rational therapeutic approach. The aim of this paper is to provide an understanding of how BRCA1 has evolved into a promising target for the treatment of sporadic disease and to outline the main potential small molecule inhibitors of BRCA1 in EOC.

Katherine V. Clark-Knowles

Anna M. O'Brien

Johanne I. Weberpals

BRCA1 as a Therapeutic Target in Sporadic Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.

L. D. Kellenberger

J. E. Bruin

J. Greenaway

N. E. Campbell

R. A. Moorehead

A. C. Holloway

J. Petrik

The Role of Dysregulated Glucose Metabolism in Epithelial Ovarian Cancer

Ovarian cancer is the most common cause of mortality of tumors from gynecologic origin and is often diagnosed after patients have already progressed to advanced disease stage.  The current standard of care for treatment of ovarian cancer includes cytoreductive surgery followed by adjuvant chemotherapy.  Unfortunately, many patients will recur and ultimately die from their disease.  Targeted therapies have been evaluated in ovarian cancer as a method to overcome resistant disease.  Angiogenesis inhibitors have shown success in many tumor types and have also demonstrated promise in trials involving patients with ovarian cancer.  PARP inhibitors may be potentially active agents in patients with BRCA-associated ovarian cancer.  Trials that have evaluated combinations of targeted agents have often revealed untoward toxicities, thus tempering enthusiasm for this approach.

Lyndsay J. Willmott

John P. Fruehauf

Targeted Therapy in Ovarian Cancer

Epithelial ovarian cancer remains a major women's health problem due to its high lethality. Despite great efforts to develop effective prevention and early detection strategies, most patients are still diagnosed at advanced stages of disease. This pattern of late presentation has resulted in significant challenges in terms of designing effective therapies to achieve long-term cure. One potential promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. This review examines three of the most provocative targeted therapies with current or future applicability in epithelial ovarian cancer.

Nicanor I. Barrena Medel

Jason D. Wright

Thomas J. Herzog

Targeted Therapies in Epithelial Ovarian Cancer

Ovarian cancer is the most lethal of all gynecological malignancies, due in part to the diagnosis at an advanced stage caused by the lack of specific signs and symptoms and the absence of reliable tests for screening and early detection. Most patients will respond initially to treatment but about 70% of them will suffer a recurrence. Therefore, new therapeutic modalities are urgently needed to overcome chemoresistance observed in ovarian cancer patients. Evidence accumulates suggesting that the insulin/insulin growth factor (IGF) pathways could act as a good therapeutic target in several cancers, including ovarian cancer. In this paper, we will focus on the role of insulin/IGF in ovarian cancer tumorigenesis and treatment.

Marie-Claude Beauchamp

Amber Yasmeen

Ariane Knafo

Walter H. Gotlieb

Targeting Insulin and Insulin-Like Growth Factor  Pathways in Epithelial Ovarian Cancer

Difficult to detect, ovarian cancer typically presents at an advanced stage. Significant progress has been achieved in the treatment of ovarian cancer with therapeutics focused on DNA replication or cell division. However, despite sensitivity to induction chemotherapy the majority of patients will develop recurrent disease. Conventional agents for recurrent disease offer little in terms of long-term responses. Various targeted therapeutics have been explored in the management of ovarian cancer. These include monoclonal antibodies to epidermal growth factor receptors, small molecule tyrosine kinase inhibitors, monoclonal antibodies directed at the vascular endothelial growth factor (bevacizumab), and the small tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor. Recently, several other agents have come forth as potential therapeutic agents in the management of ovarian cancer. These include monoclonal antibodies to the folate receptor, triple angiokinase inhibitors, PARP inhibitors, aurora kinase inhibitors, inhibitors of the Hedgehog pathway, folate receptor antagonists, and MTOR inhibitors.

Susana M. Campos

Sue Ghosh

A Current Review of Targeted Therapeutics for Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer death in women in North
America, and approximately two-thirds of cases of ovarian cancer are of high-grade
serous type. The remaining cases are comprised of a mix of different
tumor types (e.g., endometrioid, clear cell, mucinous, etc.), with no single tumor
type accounting for more than 10% of ovarian cancer cases. These tumor types
can be reproducibly diagnosed, and each features distinct underlying molecular
events during oncogenesis, with a characteristic natural history and response
rate to conventional cytotoxic chemotherapy. In this review the molecular
abnormalities present in the more common non-high-grade serous subtypes of
ovarian cancer will be presented. Development of targeted therapies for these tumor types will require understanding of the genetic basis of each tumor type, and may lead to subtype-specific therapy.

C. Blake Gilks

Molecular Abnormalities in Ovarian Cancer Subtypes Other than High-Grade Serous Carcinoma

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<p><em>Journal of Oncology</em> publishes research related to breast cancer, lung cancer, gastrointestinal cancer, skin cancer, head and neck cancer, paediatric oncology, neurooncology as well as genitourinary cancer.</p>


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<p>Chief Editor, Professor Bruno Vincenzi, is an Associate Professor of Medical Oncology at University Campus Bio-Medico, Italy. His research interests include urogenital neoplasms and the pathophysiology and treatment of bone metastases.</p>


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Journal of Oncology publishes research related to breast cancer, lung cancer, gastrointestinal cancer, skin cancer, head and neck cancer, paediatric oncology, neurooncology as well as genitourinary cancer.

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Journal of Oncology

Epithelial Ovarian Cancer: Focus on Targeted Therapy

Epithelial Ovarian Cancer: Focus on Targeted Therapy

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