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Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2616-2618 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.2123
Reversal of Drug Resistance in Ovarian Cancer: Where Do We Go From Here?Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, United Kingdom Disease management in patients with ovarian cancer exemplifies the fundamental problem underlying much of today's cancer chemotherapy: an initial excellent response followed by the eventual evolution of fatal drug resistance. It is therefore understandable that clinicians would seek to address this problem in clinical trials based on the evidence available to them regarding the underlying mechanisms of resistance.1 More than 10 years ago, an intriguing possibility being considered in this context was the pharmacologic reversal of so-called "multidrug resistance." This is the concept behind the trial reported by Lhommé et al2 in this month's issue of Journal of Clinical Oncology, and it involves the agent valspodar, which is a potent inhibitor of the energy-dependent membrane transport protein, P-glycoprotein (P-gp). Overexpression of P-gp (first identified by Victor Ling more than 30 years ago) is responsible for the experimental observation of cross-resistance in cancer cells to various cytotoxic agents, all of which are derived from natural products.3 Reversal can be achieved in experimental models using several types of P-gp inhibitors. What is much less clear is the relevance of these observations to the clinic,4 and the terminology is not helpful. Multidrug resistance based on P-gp is widely misinterpreted as underlying clinical resistance to many drugs, and this is not the case. It has no relevance, for example, to platinum, the key drug in ovarian cancer treatment. So why did the investigators in 1997 hope that a P-gp inhibitor might have an impact in this context? In their defense, the positive evidence was the observation that P-gp–positive cells had been clearly identified in patients with drug-resistant ovarian cancer; indeed, this was the first tumor type in which they were seen.5 Secondly, the laboratory data indicating that taxane resistance may be susceptible to this approach were persuasive,6 and it was not until some years later that the results of randomized clinical trials (Gynecology Oncology Group 132 and International Collaborative Ovarian Neoplasm–3) indicated that, of the two drugs used in first-line treatment, platinum is likely to play a much more important role than paclitaxel.7,8 The trial was therefore completed between 1997 and 1999, and so the negative results represent a mature analysis. It was scrupulously conducted, and it incorporated the inevitable dose reduction of paclitaxel, which is required with cotreatment using a potent P-gp inhibitor such as valspodar, through its physiological inhibition of biliary drug excretion. The high level of normal tissue toxicity in the experimental arm indicates that underexposure to paclitaxel is not the reason for the lack of enhancement of efficacy. The more likely explanation is that resistance to chemotherapy in this patient population is not related to multidrug resistance. In retrospect, this could have been predicted, since we now have a better insight into at least some of the molecular mechanisms underlying drug resistance in this disease. Although we are still some way from a full explanation, the availability of modern techniques to analyze the complete genome in cancer cells, and to correlate aberrations with clinical data, is clearly a step forward. The acquisition of appropriate tumor tissue from ovarian cancer patients is the key, and this may be achieved in several ways. A pretreatment sample on its own can be informative, although when correlations with outcome are made, large numbers are required to take account of other prognostic variables in addition to the response to chemotherapy.9 Paired biopsy samples from the same patient (pretreatment and at relapse) are extremely valuable, but harder to obtain; in this context, tumor cells present in ascites are one obvious source. It may even be possible to obtain meaningful data simply through blood sampling, because we know that in the circulation of ovarian cancer patients, free tumor DNA (and RNA) is present, as well as a variable number of circulating tumor cells. This has been utilized in one analysis of paired blood samples in a large first-line clinical trial in ovarian cancer; the conclusion was that the acquisition of methylation of damage recognition genes (specifically hMLH1) was a potential explanation for the resistance to subsequent chemotherapy in patients whose disease had relapsed.10 Other groups have utilized microarray-based profiling to generate various gene signatures that may correlate with drug resistance or treatment outcome.11-16 These studies have been relatively small (< 100 cases), and there is usually a significant degree of heterogeneity in the circumstances of sample collection that makes comparison difficult. International collaboration is likely needed to maximize the information becoming available using various techniques. A particular challenge will be to identify the different factors relating to platinum and taxanes, because it is very likely that they will not be the same, and modulation approaches will ultimately need to recognize that clinical drug resistance is almost certainly multifactorial. Nevertheless, clinical investigators are already exploring alternative pharmacologic means of resistance reversal, based at least partly on data, albeit incomplete, from clinical material. Considering platinum resistance, these include the demethylation approach, which is capable of reversing resistance in an appropriate ovarian cancer xenograft model.17 A randomized trial involving decitabine is now underway in the United Kingdom following the demonstration in a phase I trial of the feasibility of this approach.18 Phenoxodiol is an inhibitor of the XIAP family of antiapoptotic proteins, and experimental reversal of resistance to both platinum and taxanes has been demonstrated with this agent.19 A randomized trial involving this drug is ongoing in platinum-resistant ovarian cancer patients. Other apoptosis regulators, including those of the BCL-2 family, are promising candidates as targets for resistance modulation, and appropriate clinical trials are under consideration.20 The ability of tumor cells to repair platinum-DNA adducts is clearly an important factor in platinum resistance, but modulation in this context is particularly problematic because the cell has a range of repair pathways available to it. One of these is homologous recombination, and, interestingly, a recent report has linked the acquisition of platinum resistance to the regain of this function in tumor cells with mutations in BRCA2 that were previously characterized by platinum hypersensitivity because of homologous recombination deficiency.21
For resistance to taxanes, as well as platinum, targets for modulation include components of the PI3K/AKT pathway. Amplification of the gene encoding the key catalytic subunit of AKT, P110 Approaches to overcoming taxane resistance are not confined to molecularly targeted agents. Novel cytotoxics have been developed on the basis of activity in paclitaxel-resistant models, in which resistance relates to both P-gp overexpression and beta-tubulin mutations. The most advanced are the epothilones, and initial clinical data indicate a degree of efficacy in paclitaxel-resistant patients.27 So, where does this leave P-gp? Intriguingly, there may yet be a role for resistance modulation based on this approach. Clinicians who manage disease in patients with ovarian cancer have long been aware of the likely existence of a population of tumor cells which remain dormant until signals leading to regrowth eventually lead to fatal drug resistance. These so-called progenitor or tumor stem cells have been identified in various human tumors, and there are a few reports indicating their likely existence in ovarian cancer.28,29 Moreover, it is proposed that an important characteristic of these cells is "self-protection" through the activity of multidrug resistance transporters.30 A high priority, therefore, for future research will be the careful molecular characterization of this cell population in ovarian cancer patients. It is conceivable that this may lead to reversal strategies at an appropriate stage in ovarian cancer management, which may, at least in relation to taxanes, include the inhibition of membrane transport. Ultimately, a successful strategy for overcoming the critical hurdle of drug resistance should come through comprehensive analyses of clinical material linked to high-quality clinical data. It therefore behooves all of us involved in clinical trials to ensure that biologic sample collection becomes a routine aspect of these endeavors. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by Cancer Research UK, and Ovarian Cancer Action. REFERENCES 1. Agarwal R, and Kaye SB: Ovarian cancer: Strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 3:502-516, 2003[CrossRef][Medline] 2. Lhommé C, Joly F, Walker JL, et al: Phase III Study of valspodar (PSC 833) combined with paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer. J Clin Oncol 26:2674-2682, 2008 3. Rothenberg M, Ling V: Multidrug resistance: Molecular biology and clinical relevance. J Natl Cancer Inst 81:907-910, 1989 4. Kaye SB: P-glycoprotein and drug resistance: Time for reappraisal? Br J Cancer 67:641-643, 1993[Medline] 5. Bell DR, Gerlach JH, Kartner N, et al: Detection of P-glycoprotein in ovarian cancer: A molecular marker associated with multidrug resistance. J Clin Oncol 3:311-315, 1985[Abstract] 6. Jachez B, Nordmann R, Loor F, et al: Restoration of taxol sensitivity of MDR cells by the cyclosporin SDZ PSC833 and the cyclopeptide SDZ 280-445. J Natl Cancer Inst 85:478-483, 1993 7. Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 18:106-115, 2000 8. The ICON Group: Paclitaxel plus carboplatin versus standard chemotherapy with either single agent carboplatin or cyclophosphamide, doxorubicin and cisplatin in women with ovarian cancer. Lancet 360:505-515, 2002[CrossRef][Medline] 9. Agarwal R, Kaye SB: Expression profiling and individualisation of treatment for ovarian cancer. Curr Opin Pharmacol 6:345-349, 2006[CrossRef][Medline] 10. Gifford G, Paul J, Vasey PA, et al: The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res 10:4420-4426, 2004 11. Helleman J, Jansen M, Span P, et al: Molecular profiling of platinum resistant ovarian carcinoma. Int J Cancer 118:1963-1971, 2006[CrossRef][Medline] 12. Spentzos D, Levine DA, Ramoni MF, et al: Gene expression signature with independent prognostic significance in epithelial ovarian cancer. J Clin Oncol 22:4700-4710, 2004 13. Bernardini M, Lee CH, Beheshti B, et al: High resolution mapping of genomic imbalance and identification of gene expression profiles associated with response in serous ovarian cancer. Neoplasia 7:603-613, 2005[CrossRef][Medline] 14. Jazaeri A, Awtrey C, Chandramouli G, et al: Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancer. Clin Cancer Res 11:6300-6310, 2005 15. Spentzos D, Levine D, Kolia S, et al: Unique gene expression profile based on pathologic response in epithelial ovarian cancer. J Clin Oncol 23:7911-7918, 2005 16. Dressman HK, Berchuck A, Chan G, et al: An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol 25:517-525, 2007 17. Plumb JA, Strathdee G, Sludden J, et al: Reversal of drug resistance in human tumour xenografts by 2' deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res 60:6039-6044, 2000 18. Appleton K, Mackay HJ, Judson I, et al: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumours. J Clin Oncol 25:4603-4609, 2007 19. Mor G, Fu HH, Alvero AB: Phenoxidiol: A novel approach for the treatment of ovarian cancer. Curr Opin Investig Drugs 7:542-548, 2006[Medline] 20. Witham J, Valenti M, De-Haven-Brundon AK, et al: The Bcl-2/Bcl-XL family inhibitor ABT-737 sensitizes ovarian cancer cells to carboplatin. Clin Cancer Res 13:7191-7198, 2007 21. Edwards SL, Brough R, Lord C, et al: Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111-1115, 2008[CrossRef][Medline] 22. Shayesteh L, Lu Y, Kuo WL, et al: PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99-102, 1999[CrossRef][Medline] 23. Campbell IG, Russell SE, Choong DY, et al: Mutations of the PIK3CA-gene in ovarian and breast cancer. Cancer Res 64:7678-7681, 2004 24. Sain N, Krishnan B, Ormerod MG, et al: Potentiation of paclitaxel activity by the HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, in human ovarian carcinoma cell lines with high levels of activated AKT. Mol Cancer Ther 5:1197-1208, 2006 25. Chen T, Pengetnze Y, and Taylor CC: Src inhibition enhances paclitaxel cytotoxicity in ovarian cancer cells by caspase-9-independent activation of caspase-3. Mol Cancer Ther 4:217-224, 2005 26. Rosan ò L, DiCastro V, Spinella F, et al: ZD 4054, a specific antagonist of the endothelin A receptor, inhibits tumour growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo. Mol Cancer Ther 6:2003-2011, 2007 27. Larkin JM, Kaye SB: Epothilones in the treatment of cancer. Expert Opin Investig Drugs 15:691-702, 2006[CrossRef][Medline] 28. Bapat SA, Mali AM, Koppikar CB, and Kurrey NK: Stem and progenitor-like cells contribute to the aggressive behaviour of human epithelial ovarian cancer. Cancer Res 65:3025-3029, 2005 29. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al: Ovarian cancer side-population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proc Natl Acad Sci U S A 103:11154-11159, 2006 30. Donnenberg VS, and Donnenberg AD: Multiple drug resistance in cancer revisited: The cancer stem cell hypothesis. J Clin Pharmacol 45:872-877, 2005
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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, is seen in 40% of ovarian cancer,
