Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; In the light of completed trials

Korkmaz, Taner; Seber, S.; Başaran, Gül

doi:10.1016/j.critrevonc.2015.10.006

Cited by 45 publications

(40 citation statements)

References 36 publications

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“…1 The cure rate for ovarian cancer has not changed appreciably in the past forty years, underscoring the need for better treatment strategies. 26 Ovarian serous carcinoma (OSC) is the most common subtype of ovarian cancer, accounting for some 90% of ovarian cancer cases. OSC is characterized by a poor five year survival rate due to late detection and poor clinical response.…”

Section: Discussionmentioning

confidence: 99%

“…OSC is characterized by a poor five year survival rate due to late detection and poor clinical response. 26 OSC is often responsive to initial platinum-based chemotherapy, but relapse with therapy-resistant disease is common. 27 Therefore, there is a need for increased understanding of signaling mechanisms that drive OSC tumor behaviors that can be translated into novel therapeutic intervention approaches.…”

Section: Discussionmentioning

confidence: 99%

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PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis

et al. 2016

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Atypical protein kinase Cι (PKCι) is an oncogene in lung and ovarian cancer. The PKCι gene PRKCI is targeted for frequent tumor-specific copy number gain (CNG) in both lung squamous cell carcinoma (LSCC) and ovarian serous carcinoma (OSC). We recently demonstrated that in LSCC cells PRKCI CNG functions to drive transformed growth and tumorigenicity by activating PKCι-dependent cell autonomous Hedgehog (Hh) signaling. Here, we assessed whether OSC cells harboring PRKCI CNG exhibit similar PKCι-dependent Hh signaling. Surprisingly, we find that whereas PKCι is required for the transformed growth for OSC cells harboring PRKCI CNG, these cells do not exhibit PKCι-dependent Hh signaling or Hh-dependent proliferation. Rather, transformed growth of OSC cells is regulated by PKCι-dependent nuclear localization of the oncogenic transcription factor, YAP1. Lentiviral shRNA-mediated knock down (KD) of PKCι leads to decreased nuclear YAP1 and increased YAP1 binding to angiomotin (AMOT), which sequesters YAP1 in the cytoplasm. Biochemical analysis reveals that PKCι directly phosphorylates AMOT at a unique site, Thr750, whose phosphorylation inhibits YAP1 binding. Pharmacologic inhibition of PKCι decreases YAP1 nuclear localization and blocks OSC tumor growth in vitro and in vivo. Immunohistochemical analysis reveals a strong positive correlation between tumor PKCι expression and nuclear YAP1 in primary OSC tumor samples, indicating the clinical relevance of PKCι-YAP1 signaling. Our results uncover a novel PKCι-AMOT-YAP1 signaling axis that promotes OSC tumor growth, and provide a rationale for therapeutic targeting of this pathway for treatment of OSC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis

et al. 2016

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Section: Ovarian Cancer Landscapementioning

confidence: 99%

“…Furthermore, the clinical experience in advanced and relapsed EOC has shown that addition of a third cytotoxic compound to existing chemotherapeutic regimens results in increased toxicity without improving disease control [19][20][21]. Maintenance therapy with conventional cytotoxic agents has not demonstrated any meaningful OS benefit, yet cumulative toxicity associated with long-term chemotherapy has emerged as a major clinical concern [22].More recently, an increased understanding of the biological and genomic complexity of EOC has prompted the exploration of molecularly targeted strategies designed to advance the field beyond the limitations of broadbased cytotoxic therapy [4,8]. In this regard, two new classes of targeted agents have been approved for EOC therapy in the last 5 years -angiogenesis inhibitors (bevacizumab) and PARP inhibitors (olaparib, rucaparib and niraparib) [23] -each of which selectively impact oncogenic pathways linked to ovarian tumorigenesis [24,25].…”

mentioning

confidence: 99%

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

et al. 2017

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Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody-drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansine's mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease. Ongoing Phase III monotherapy and Phase Ib/II combination trials evaluating its activity in the setting of platinum resistance are emphasized, which will help define its role in the evolving landscape of ovarian cancer therapy. Ovarian cancer landscapeOvarian cancer remains a leading cause of gynecological cancer mortality, responsible for 152,000 deaths annually worldwide [1]. In the USA alone, it is estimated that 22,440 women will be diagnosed with ovarian cancer in 2017 and more than 14,000 will die due to this disease [2]. The remarkable degree of cellular and molecular heterogeneity exhibited by tumors of the ovary (including those arising from the fallopian tubes and primary peritoneum) is such that ovarian cancer is no longer considered a single disease entity with variable morphology, but rather a collection of neoplasms each associated with their own distinct histological subtypes and response to therapy [3,4]. Among these, epithelial ovarian cancer (EOC) accounts for approximately 95% of ovarian cancer malignancies [5,6]. The foundation of current standard-of-care treatment for women diagnosed with EOC is cytoreductive (debulking) surgery and chemotherapy using a platinum-based combination regimen, most commonly the carboplatin-paclitaxel doublet. This strategy has largely reached a plateau of effectiveness in improving overall patient survival [7,8]. The continuing high mortality is associated, at least in part, with the fact that EOC is overwhelmingly diagnosed at an advanced stage. Furthermore, while EOC is highly chemosensitive and most individuals achieve remission with front-line therapy, up to 80% of patients relapse and require further treatment without the expectation of cure [9].The development of platinum resistance in EOC appears to be a dynamic and multifactorial process, although the underlying molecular mechanisms remain poorly defined [10,11]. Recurrent EOC is classified based on the length Drug Evaluation Moore, Martin, O'Malley et al. of time, empirically divided into 6-month blocks, since receiving treatment with a platinum agent, known as the platinum-free interval [7,12]. The classification is as follows:r Refractory: progression during or within 4 weeks of platinum-based chemotherapy; r Primary resistant: relapse within 6 months of completing initial platinum therapy; r Partially platinum sensitive: relapse between 6 and 12 months; r Platinum sensitiv...

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“…First-line treatment for EOC includes debulking surgery followed by taxane/platinum-based regimens. Despite promising initial response, the majority of patients with advanced disease relapse and exhibit resistance to both chemotherapeutics and targeted therapies2.…”

mentioning

confidence: 99%

Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells

Momeny

Sabourinejad

Zarrinrad

et al. 2017

Sci Rep

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Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies.

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Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; In the light of completed trials

Cited by 45 publications

References 36 publications

PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis

PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells

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