In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 43 ( 2012-10-23)
Abstract:
The identification of key CSC pathways and their selective targeting by chemotherapy are important goals of cancer research. The results outlined in the current study will aid in the design of new clinical trials for ovarian cancer that involve a dual combination of Notch pathway inhibitors (GSI or selective anti-Notch antibodies) and platinum-based therapy. In summary, our results show that key pathways, particularly the Notch signaling pathway that we have studied, play an important role in the maintenance of CSCs and platinum chemoresistance in ovarian cancer. Furthermore, this study suggests an important clinical application of Notch pathway inhibitors in newly diagnosed and relapsed ovarian cancer patients. Long-term survival of ovarian cancer patients is low because of high rates of therapeutic failure and tumor relapse. A cure likely necessitates eradication of drug-resistant CSCs in addition to the bulk of non-CSC tumor cells, which commonly are targeted by conventional chemotherapy ( Fig. P1 ). Patient stratification based on their individual genetic make-up and the addition of a front-line therapeutic agent that targets and sensitizes CSCs may result in more effective therapies for ovarian cancer patients. In the current study, we demonstrate that the Notch pathway, especially Notch3, plays a key role in CSC regulation and chemoresistance to platinum-based therapies in ovarian cancer. Our results indicate that overexpression of a constitutively activated Notch3 receptor expands the number of CSCs and increases chemoresistance to platinum compounds. In contrast, inhibition of Notch3 activity, using either siRNAs (short pieces of RNA that silence the Notch3 gene) or γ-secretase inhibitors (GSI), sensitizes ovarian cancer cells to platinum-based therapies. This sensitization is seen in tumor cell lines and patient samples with high levels of Notch3 gene expression but not in lines in which Notch3 is undetected. Furthermore, by targeting both CSCs and non-CSC tumor cells, our study strongly suggests that a dual combination of GSI and platinum (CDDP) therapy is a much more effective treatment than CDDP alone. Our findings demonstrate that GSI and platinum compounds have synergistic cytotoxic antitumor effects and enhance survival in animal models of disease. Interestingly, the synergistic response to GSI/CDDP cotherapy is seen in tumor samples collected from both platinum-sensitive and -resistant patients. The Notch signaling pathway contributes to cancer development and progression by promoting cell survival, motility, and the development of tumor vasculature (angiogenesis). In addition, multiple studies, including ours, have found that Notch plays a key role in the maintenance of CSCs in ovarian, brain, and breast tumors ( 3 – 6 ). Several reports and recent Cancer Genome Atlas data show that dysregulated Notch signaling and Notch3 overexpression occur in a subset of high-grade serous adenocarcinomas, the most common and aggressive ovarian cancer subtype ( 7 ). Resistance to chemotherapy (chemoresistance) is a major obstacle in the treatment of patients with solid carcinomas ( 1 , 2 ). Cancer stem cells (CSCs) are necessary for the development and long-term growth of many of these tumors, including ovarian cancer. CSCs are spared by traditional chemotherapies, including platinum-based compounds, and thus are a major contributor to chemoresistance. We investigated a dual combination therapy that focused on Notch pathway inhibitors, which specifically target drug-resistant CSCs, and standard platinum-based compounds that eliminate the bulk of non-CSC tumor cells. Our results indicate that this combination treatment improves disease outcome and long-term survival.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1206400109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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