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Beyond chemotherapy: targeted therapies in ovarian cancer

Key Points

  • Although the results of treatment with conventional chemotherapy and surgery for advanced ovarian cancer have gradually improved, the majority of women still die with drug-resistant disease after 5 years. Our improved understanding of the underlying biology of ovarian cancer is now leading to the development of molecular targeted therapies, which aim to address this major clinical need.

  • Anti-angiogenic cancer therapies such as bevacizumab have shown efficacy in early-phase ovarian cancer clinical trials and are likely to become part of standard therapy for advanced ovarian cancer in the future.

  • A poly (ADP-ribose) polymerase inhibitor has shown substantial anti-tumour activity as a single-agent therapy in germline BRCA-deficient patients with ovarian cancer in early clinical trials; further studies assessing its role in sporadic ovarian cancers are now underway.

  • Genetic and epigenetic aberrations that drive ovarian cancer have been discovered. These drive key oncogenic signalling pathways, such as the PI3K–Akt pathway, and might be potential targets for anticancer therapeutics, either as monotherapy or in combination with established cytotoxic chemotherapies.

  • Pharmacodynamic biomarkers, which provide proof-of-principle of target modulation and predictive biomarkers, which could be used for patient selection, are essential in the development of novel molecular targeted therapies for ovarian cancer.

  • It is expected that the development of novel anticancer therapies, particularly as maintenance treatments, might lead to the prolonged survival of patients with ovarian tumours in the future.

Abstract

Ovarian cancer is the leading cause of death from gynaecological malignancies in the Western world. Despite the evolution of surgical techniques and meticulously designed chemotherapy regimens, relapse remains almost inevitable in patients with advanced disease. In an age when great advances have been made in understanding the genetics and molecular biology of this heterogeneous disease, it is likely that the introduction of novel targeted therapies will have a major impact on the management of ovarian cancer. Importantly, such strategies might allow selection of treatments based on the molecular characteristics of tumours and bring us closer to an era of personalized medicine.

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Figure 1: Key signalling pathways involved in the progression of ovarian cancer and potential targets for anticancer therapy.
Figure 2: Angiogenesis and functional imaging in ovarian cancer.
Figure 3: Potential triage strategy for the allocation of targeted agents to ovarian cancer patients.

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Acknowledgements

The Drug Development Unit is supported by Cancer Research UK through a programme grant to the Section of Medicine, Institute of Cancer Research, and through an Experimental Cancer Medical Centre (ECMC) grant (C51/A7401). It is also supported by the Department of Health through the ECMC grant and as part of the National Institutes of Health Research Biomedical Research Centre at the Royal Marsden Hospital. T.A.Y., C.P.C. and S.B.K. are employees of The Institute of Cancer Research. T.A.Y. and C.P.C. are Cancer Research UK Clinical Research Fellows (C309/A8274 and C1178/A7851). We would like to thank L. Readings for her invaluable assistance with the preparation of the manuscript.

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Competing interests

Stan B. Kaye serves on advisory boards for the following companies: AstraZeneca, Genentech, OSI Pharmaceuticals Inc. and PharmaMar. Timothy A. Yap and Craig P. Carden do not have any competing interests.

Supplementary information

Supplementary information S1 (table)

Novel targets in ovarian cancer (PDF 350 kb)

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DATABASES

ClinicalTrials.gov

NCT00429793

NCT00523432

NCT00610714

NCT00628251

NCT00753545

National Cancer Institute Drug Dictionary

aflibercept

AZD0530

carboplatin

cediranib

cetuximab

combretastatin 4A phosphate

deforolimus

doxorubicin

erlotinib

etoposide

everolimus

gefitinib

gemcitabine

imatinib

matuzumab

olaparib

paclitaxel

panitumumab

patupilone

pazopanib

pertuzumab

rapamycin

sorafenib

sunitinib

temsirolimus

topotecan

trabectedin

trastuzumab

FURTHER INFORMATION

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Glossary

FIGO stages

(The International Federation of Gynecology and Obstetrics stages). This system describes a classification of the stage of ovarian cancer as determined by surgical and pathological findings.

Platinum-sensitive disease

Recurrence of disease on platinum chemotherapy after more than 6 months.

Platinum-resistant disease

Recurrence of disease on platinum chemotherapy after less than 6 months.

Platinum-refractory disease

Recurrence of disease during or on completion of platinum chemotherapy.

CTCAE

(Common Terminology Criteria for Adverse Events).

This is a descriptive terminology which can be used for adverse event reporting. A grading scale is provided for each adverse event term and the grade refers to the severity of the adverse event.

Hand–foot syndrome

A condition marked by pain, swelling, numbness, tingling or redness of the hands or feet. It sometimes occurs as a side effect of certain anticancer drugs. It is also called palmar–plantar erythrodysaesthesia.

Fistula

An abnormal opening or passage between two organs or between an organ and the surface of the body.

Cancer antigen 125

(CA125). A tumour biomarker that is clinically approved for monitoring the response to anticancer treatment and predicting prognosis following treatment in ovarian cancer and other malignancies.

Synthetic lethality

A lethal synergy between two otherwise non-lethal events.

IC50

The half maximal inhibitory concentration is the concentration of a drug that is required for 50% inhibition in vitro and is commonly used as a measure of drug potency in pharmacological research.

BRCAness

A term that describes the traits that some sporadic cancers share with those that occur in carriers with mutations in BRCA1 or BRCA2. This sharing of characteristics might have important implications for the clinical management of these cancers.

Pharmacological audit trail

This describes a framework that systematically traces all phases of drug development, from target identification to clinical outcome and permits rational 'go' or 'no-go' decisions to be made in a hypothesis-testing manner, guiding the successful development of modern therapeutics.

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Yap, T., Carden, C. & Kaye, S. Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer 9, 167–181 (2009). https://doi.org/10.1038/nrc2583

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