Ovarian cancer: strategies for overcoming resistance to chemotherapy

Key Points

  • The standard care for ovarian cancer is a combination of surgery and chemotherapy.

  • Carboplatin and paclitaxel form the cornerstone of chemotherapy in ovarian cancer.

  • In patients with tumour-cell dissemination beyond the ovaries, most relapse and ultimately die due to the development of drug resistance.

  • Drug resistance can arise due to pharmacokinetic, tumour micro-environmental and cancer-cell-specific abnormalities.

  • A number of resistance mechanisms have been defined in vitro. However, the importance of these in patients remains unclear.

  • Novel experimental approaches for analysis of clinical samples, such as comparative genomic hybridization, expression profiling and tissue microarrays, are likely to improve our understanding of drug resistance in patients.

  • Pharmacokinetic approaches to overcoming drug resistance, such as intraperitoneal chemotherapy and high-dose chemotherapy, are under evaluation.

  • A number of novel cytotoxic agents and drugs that target cell survival, drug resistance and apoptotic pathways are now entering clinical trials, and are aimed at overcoming drug resistance.

Abstract

Ovarian cancer is responsible for 4% of deaths from cancer in women. Treatment comprises a combination of surgery and chemotherapy, but patients typically experience disease relapse within 2 years of the initial treatment. Further treatment can extend survival, although relapse eventually occurs again. A better understanding of the mechanisms that underlie this drug resistance should allow treatment to be optimized, so that substantial improvements in the outlook for women with this disease can be achieved.

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Figure 1: Drug-resistance mechanisms.
Figure 2: Models of treatment failure in ovarian cancer.
Figure 3: Signalling pathways involved in taxane and platinum-therapy-induced apoptosis and cell-cycle arrest.
Figure 4: Strategies for identifying mechanisms of drug resistance.

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Acknowledgements

The authors are grateful to CRUK, the Kidani Trust and the Sir John Egan Trust for their support.

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DATABASES

Cancer.gov

ovarian cancer

LocusLink

BAD

BAK

BAX

BCL-2

BCL-XL

BIM

BMF

c-ABL

CD95

ERBB2

EGFR

GST

HIF1

JNK

KIP1

MLH-1

MAPK

PI3K

p53

PKC

TRAIL

Glossary

PROGRESSION-FREE SURVIVAL

The time interval from the start of treatment to disease progression. It is a measure of the clinical benefit from therapy.

OVERALL SURVIVAL

The time interval from the start of treatment to death is a more objective measure of clinical benefit than progression-free survival. However, it is also affected by treatments that might be given after the failure of the treatment under evaluation.

META-ANALYSIS

A statistical technique that is used for combining the results of several randomized clinical trials.

RESPONSE RATE

The percentage of patients in whom treatment results in a significant reduction in tumour size.

COMPLETE RESPONSE

Clinical and radiological resolution of all evidence of a tumour following treatment.

NUCLEOTIDE EXCISION REPAIR

DNA repair in response to damaged bases or the spatial configuration of DNA. The abnormal sequence is excised and replaced by newly synthesized DNA.

MISMATCH REPAIR

DNA repair in response to incorrect pairing of bases.

INTRINSIC APOPTOTIC PATHWAY

Activation of programmed cell death by intracellular signals that are mediated by BAX and BCL2, resulting in the release of cytochrome c and APAF1 from the mitochondrial membrane, with subsequent activation of caspase-9 and downstream effector caspases such as caspase-3.

MAPK PATHWAY

(Mitogen-activated protein kinase pathway). Signal-transduction pathway that is crucial for the integration of mitogenic signals. Activation of this pathway is involved in many cellular processes, including cell-cycle progression.

PROGRESSIVE DISEASE

At least a 20% increase in the sum of the maximum diameter of target tumour lesions, or the appearance of one or more new lesions.

THERAPEUTIC INDEX

Measures the clinical benefit of a treatment relative to its toxicity.

PHARMACOKINETICS

Processes that are involved in the distribution and metabolism of a drug in an organism.

FIRST-PASS METABOLISM

Initial inactivation of a drug following administration, usually by the liver.

PI3K PATHWAY

The phosphatidylinositol 3- kinase (PI3K) family of enzymes are activated in response to a wide variety of stimuli and catalyse the phophorylation of inositol lipids at the D-3 position of the inositol ring. These phosphoinositides act as second messengers; a primary target is the serine/threonine kinase AKT, which phosphorylates several cellular targets, including proteins involved in cell survival, proliferation and migration.

MICROSATELLITE INSTABILITY

Alterations of the length of simple repetitive genomic sequences due to mutations in MMR genes MSH2 or MLH1.

IAP

(Inhibitor of apoptosis proteins). A class of proteins that inhibit caspases and thereby block activation of the effector caspase cascade that is responsible for cell death.

ASCITES

Accumulation of fluid in the peritoneal cavity.

PARACENTESIS

Drainage of ascitic fluid via a percutaneously inserted abdominal catheter.

COMPARATIVE GENOMIC HYBRIDIZATION

(CGH). A method for simultaneously measuring gains or losses in cellular DNA at all chromosomal loci relative to normal genomic DNA

SUBTRACTIVE HYBRIDIZATION

A technique that is used for identifying differentially expressed transcripts between two sources. cDNA from one source is hybridized to mRNA from another source to remove comparably expressed transcripts, and the resulting differentially expressed cDNAs are separated by chromotography.

mRNA EXPRESSION PROFILING

A method for measuring the global pattern of mRNA levels within a cell by hybridization to a preformed array that contains cDNA or oligonucleotides representative of known genes or expressed sequence tags.

LIPOSOMAL DRUGS

Drugs that are encapsulated in a lipid bilayer to alter their pharmacokinetic properties.

ADEPT

A method for the selective delivery of a drug to tumour cells. This is achieved by attaching an enzyme to a tumour-cell-specific antibody, which, in turn, can catalyse the conversion of a systemically administered non-toxic pro-drug to its active form at the tumour-cell surface.

GDEPT

A method for the selective delivery of a drug to tumour cells. This is achieved by using gene-therapy approaches to express a foreign enzyme specifically in tumour cells. The enzyme, in turn, can then catalyse the conversion of a systemically administered non-toxic pro-drug to its active form in the tumour cell.

PARTIAL RESPONSE

At least a 30% reduction in the sum of the maximum diameter of target tumour lesions, with no new lesions or increase in the size of an existing lesion.

STABLE DISEASE

Change in size of tumours not sufficient to be classified as partial response or progressive disease.

RT-PCR

(Reverse transcriptase polymerase chain reaction). Allows the amplification and quantitation of specific mRNA species.

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Agarwal, R., Kaye, S. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 3, 502–516 (2003). https://doi.org/10.1038/nrc1123

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