Molecular Pathways

Microtubule Active Agents: Beyond the Taxane Frontier Patrick G. Morris and Monica N. Fornier

Abstract Microtubules are essential to cell transport, signaling, and mitosis. An increasing range of antican- cer drugs interferes with the normal formation and function of microtubules.Vinca alkaloids act as microtubule destabilizers and the taxanes act as microtubule stabilizers. Taxanes are widely used cytotoxic agents that are active in a range of solid tumor malignancies and are routinely used in a variety of settings. Significant limitations with the taxanes exist, including acquired and intrinsic tumor resistance through the expression of multidrug resistance proteins such as P-glycoprotein, risk of hypersensitivity reactions, dose-limiting hematopoietic toxicity, and cumulative neurotox- icity. Hence, there is a need to develop novel agents that act on the microtubules. Epothilones are macrolide antibiotics that bind near the taxane-binding site on microtubules and have been extensively studied in recent and ongoing clinical trials. A variety of other agents that act on the microtubules at different sites with a variety of structures are at varying stages of development.

Background alkaloids interact with the central portion (or Vinca binding site;Fig.2)oftheh-tubulin subunit and thus prevent Microtubules are ubiquitous fibrillar structures that play polymerization into microtubules (3). Colchicine, which is an important role in a variety of cellular processes including used for the treatment of gout, acts at a separate site on a transport, signaling, and mitosis (1). Polymers of - and h-tubulin termed the colchicine-binding site (Fig. 2). h -tubulin combined with microtubular-associated proteins Until recently, the only clinically important microtubule make up microtubules, which are constantly undergoing stabilizers were the taxanes, such as paclitaxel and docetaxel. rearrangement (Fig. 1; ref. 1). The microtubule polymer thus Taxanes are widely used cytotoxic agents that are active in a exists in a dynamic equilibrium with the intracellular pool range of solid tumor malignancies such as breast cancer, a h of - and -tubulin (1, 2). During mitosis, microtubules and NSCLC, ovarian cancer, gastroesophageal cancer, germ cell the mitotic spindle are critical to the separation of chromo- tumors, as well as cancers of the head and neck. They are somes into two daughter cells and so have become a target for routinely used in the neoadjuvant, adjuvant, and metastatic cytotoxic agents (Fig. 1). Through a variety of mechanisms, an setting alone and in combination with drugs with different increasing range of drugs interferes with the normal formation mechanisms of action and nonoverlapping toxicity profiles. and function of microtubules and the mitotic spindle and cause Paclitaxel was originally derived from the bark of the Pacific cells to arrest in metaphase. Cell death then occurs by yew tree but can now, like docetaxel, be partially synthesized apoptosis. Until recently, the most important antimicrotubule from the precursor 10-deactylbaccatin III, derived from needles agents were the taxanes, but many new compounds are at of the European yew (2). The taxanes bind to tubulin, stabilize various stages of development. the microtubule, and inhibit its disassembly leading ultimately Classically, drugs that interfered with microtubular structure to cell death by apoptosis. The clinical use of the taxanes is and function were divided into stabilizers and destabilizers. limited by (a) tumor resistance, (b) risk of hypersensitivity This division is somewhat simplistic and does not account for reactions, and (c) toxicity. all the mechanisms of action such as an effect on tumor Acquired and intrinsic resistance of tumor cells to taxanes vasculature or an effect on microtubule dynamics (2). remains a significant clinical problem. Resistance occurs Microtubule destabilizers consist predominantly of drugs that through a variety of mechanisms. One important mechanism act at the Vinca alkaloid and colchicine-binding sites (Fig. 2). is the expression of multidrug resistance proteins such as The oldest class of cytotoxic agents that interfere with micro- P-glycoprotein, which belongs to a family of ATP-binding tubules are the Vinca alkaloids, such as vincristine, vinblastine, cassette transporters and which is the product of the multidrug and vinorelbine. These agents are active in a variety of resistance-1 gene. The expression of these multidrug resistance malignancies including lymphomas, non-small cell lung cancer proteins leads to the production of transporters that act as drug (NSCLC), and breast cancer. It is thought that the Vinca efflux pumps. These pumps cause the efflux of substrate drugs such as taxanes and Vinca alkaloids from tumor cells and prevent the accumulation of therapeutic intracellular concen- Authors’ Affiliation: Memorial Sloan-Kettering Cancer Center, Breast Cancer trations of active drug. P-glycoprotein is expressed on the Medicine Service, NewYork, NewYork endothelial cells of the capillaries of the central nervous system Received 5/9/08; revised 6/20/08; accepted 6/20/08. and may explain in part why the brain remains a sanctuary site Requests for reprints: Patrick G. Morris, Memorial Sloan Kettering Cancer Center, for many chemotherapeutic agents. Breast Cancer Medicine Service, 1275 York Avenue, Box 457, NewYork, NY 10021. Phone: 646-888-4563; E-mail: [email protected]. Resistance to the taxanes can also occur due to interruption F 2008 American Association for Cancer Research. of the interaction between the drug and the target protein, doi :10.1158/1078-0432.CCR-08-0169 h-tubulin. Tumor cells can overexpress the hIII isoform of

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Fig.1. Structure and function of microtubules.

tubulin leading to demonstrable clinical resistance. Intrinsic delivery to target cells (4). Other limitations to the use of and acquired mutations in the tubulin protein can interfere taxanes include dose-limiting hematopoietic toxicity and with the normal binding of taxanes to the target protein. cumulative neurotoxicity from long-term use. There is therefore Altered expression of microtubule-associated proteins can a need to develop novel taxane delivery systems, taxane also prevent taxane binding. Elucidating the relative importance derivatives, and newer agents to target microtubules to of these mechanisms and circumventing them remains a overcome these problems. significant challenge. The risk of hypersensitivity reactions with the taxanes, Clinical-Translational Advances particularly paclitaxel, results from their poor solubility and the need to dissolve in solvents such as polyoxyethylated castor Microtubule-stabilizing agents oil (Cremophor EL; BASF) or polysorbate. This risk has been Novel taxane formulations. Several advances in the formu- substantially reduced by the use of premedications but remains lation of paclitaxel have occurred, which avoid the need for a clinical problem. It has been suggested that polyoxyethylated polyoxyethylated castor oil and hence lower the risk of castor oil may trap paclitaxel (and other cytotoxic agents hypersensitivity reactions. administered concurrently) in micelles in plasma and may ABI-007 (Abraxane; Abraxis BioScience) is a novel albumin- inhibit the endothelial transcytosis resulting in lower drug bound, 130 nm particle form of paclitaxel that is solvent-free

Fig.2. Microtubule destabilizers and stabilizers and their binding sites on tubulin.

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(4). Preclinical models have suggested that its use is associated Bristol Myers Squibb), which is a semisynthetic derivative of with higher antitumor activity and higher intracellular concen- natural epothilone B. The key modification of a lactone to a trations of active drug compared with paclitaxel. ABI-007 can lactam protects ixabepilone from hepatic degradation by be safely administered without premedication, with shorter esterases. Ixabepilone does, however, need to be dissolved in infusion times than paclitaxel with a greater amount of drug polyoxyethylated castor oil. In vitro studies have shown that the delivered to the target cells. ABI-007 showed superior efficacy to cytotoxicity of ixabepilone is 2.5 times that of paclitaxel and paclitaxel in a phase III study in metastatic breast cancer (5). that activity is maintained in taxane-resistant cell lines (17). As Although ABI-007 use was associated with less neutropenia, its noted above, tumor resistance to taxanes and other drugs is use did increase the risk of peripheral neuropathy (5). ABI-007 often mediated by expression of P-glycoprotein or multidrug is now approved by the Food and Drug Administration for the resistance-associated protein or by mutations within tubulin. treatment of metastatic breast cancer. ABI-007 has also shown The epothilones do not appear to be susceptible to these to be active and safe in advanced NSCLC and in combination resistance mechanisms. Phase I studies in a range of malignan- with carboplatin in melanoma, bladder, esophageal, and cies including patients with tumors refractory to conventional pancreatic cancers (6, 7). A phase II study of ABI-007 in therapy investigated two dosing schedules (once every 21 days combination with trastuzumab and carboplatin in patients or daily for 5 consecutive days out of 21 days) and showed with metastatic breast cancer is ongoing (8). ABI-007 is promising activity (18–20). The recommended dose for phase formulated from human albumin, so a theoretical risk of II studies was 40 mg/m2 every 21 days, which has become the transmission of viruses and prions such as Creutzfeldt-Jakob standard (18, 19). Numerous phase II studies have now been disease exists. No cases of viral transmission from human- reported, which show the activity of ixabepilone in a variety of derived albumin have ever been identified, but this theoretical malignancies and settings, particularly in metastatic prostate risk may limit the broader use of ABI-007 especially in the and breast cancer (21–32). The combination of paclitaxel and adjuvant setting. An adjuvant phase II trial of doxorubicin and estramustine may have a synergistic cytotoxic effect in vitro cyclophosphamide followed by ABI-007, all in combination (24). Estramustine causes microtubule disassembly by binding with bevacizumab, for breast cancer patients has recently to microtubule-associated proteins rather than the taxane- completed accrual (9). The incorporation of ABI-007 into binding site on h-tubulin (24). The combination of estramus- standard taxane-based regimens could potentially remove the tine and ixabepilone is thus rational and has shown promising need for premedication with steroids and could allow more results in a phase II study in metastatic prostate cancer (25). rapid infusion times. In metastatic breast cancer, several phase II studies have CT-2103 (Xyotax; Novartis) is a conjugate of a-poly-L- examined ixabepilone in a variety of settings, including the glutamic acid and paclitaxel. From preclinical data, this drug first-line metastatic setting, for patients that are taxane-naive was expected to improve drug delivery to the target tumor while and in heavily pretreated patients with taxane-resistant disease decreasing toxicity. CT-2103 initially showed promising activity (28–32). in a variety of solid organ tumors including prostate, NSCLC, An international phase III study of 752 patients randomized gastroesophageal, and ovarian cancer (10–13). Neurotoxicity patients to receive ixabepilone with capecitabine or capecita- has, however, been a substantial problem (13–15). Recently, a bine alone and showed a statistically significant prolongation phase II trial in HER-2-negative metastatic breast cancer was in progression-free survival of 4.2 to 5.8 months in favor of the stopped due to a high rate of neurotoxicity and hypersensitivity combination (33). The most common treatment-related reactions, which occurred in 4 of 18 patients (15). Interestingly, toxicities were neutropenia, sensory neuropathy, and fatigue these hypersensitivity reactions occurred after cycle 4, in (33). Although 65% of patients treated with ixabepilone contrast to the hypersensitivity reactions seen with standard experienced neuropathy, this was grade 3/4 in 21% (33). In paclitaxel, which tend to occur after the first dose (15). The October 2007, ixabepilone was approved by the Food and Drug future development of this compound is therefore unclear, Administration for metastatic breast cancer. especially given the myriad of other options. Patupilone. Naturally occurring epothilone B, patupilone Epothilones. Epothilones are macrolide antibiotics and (EPO906; Novartis), is up to 20 times more potent than represent a novel class of antimicrotubule agent. The natural paclitaxel against a variety of cell lines in vitro and this activity is epothilones A and B, produced by the myxobacterium maintained in taxane-resistant cell lines. It has a different side- Sorangium cellulosum, are cytotoxic in vitro (16). By binding effect profile to ixabepilone with minimal neurotoxicity and near the taxane-binding site (Fig. 2), epothilones cause myelosuppression. The main dose-limiting toxicity is diarrhea. microtubular stabilization and cellular arrest in a similar way Although these substances are very similar chemically, their to the taxanes. However, their chemical structure is unrelated; differing side-effect profile is puzzling and likely related to moreover, epothilones bind to the tubulin-binding pocket in a tissue distribution and metabolism (34). This may in part be specific and independent manner, suggesting that rather than a due to the fact that patupilone, unlike ixabepilone, is common pharmacophore for taxanes and epothilones, tubulin inactivated by esterases (34). This different side-effect profile has a promiscuous binding pocket, allowing different mole- of patupilone suggests a possible use in patients with cules to interact according to their unique structures. Early neurotoxicity from prior taxane therapy. clinical use of epothilones was limited by pharmacokinetic Interestingly, patupilone has been shown to cross the blood- difficulties and metabolic instability; therefore, synthetic and brain barrier and has antitumor effects in the central nervous semisynthetic derivatives have been developed to overcome system in animal models (35). Results from a phase II trial of these problems. refractory brain metastases in NSCLC were encouraging (35). A Ixabepilone (BMS-247550). The epothilone most widely phase II trial of patupilone is ongoing in patients with clinically investigated is ixabepilone (BMS-247550, Ixempra; progressive brain metastases from breast cancer following

www.aacrjournals.org 7169 Clin Cancer Res 2008;14(22) November 15, 2008 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2008 American Association for Cancer Research. Molecular Pathways whole-brain radiotherapy.1 These are interesting and important identify their chemical structure and formulate them synthet- studies because of the dearth of therapeutic options for these ically. For many of these agents, research is therefore at an early patients. The brain remains a sanctuary site for many cytotoxic stage. Discodermolide, isolated from the marine sponge agents. With improvements in systemic control of many Discoderma dissoluta, has shown promising activity in vitro malignancies, brain metastases are an increasing clinical and possible synergy with paclitaxel, suggesting that the problem and therapeutic advances in this area are welcome. binding sites are not identical (Fig. 2; ref. 49). Dictyostatin is Patupilone has shown activity in preclinical models of rarer structurally related to discodermolide and was initially isolated malignancies such as in multiple myeloma cell lines, in from a marine sponge of the genus Spongia (50). Dictyostatin hepatocellular carcinoma cell lines, and in a rat glioma model and discodermolide maintain antiproliferative activity in cells in combination with imatinib (36–38). These data offer expressing h-tubulin mutation genes (2, 50). Early clinical possible avenues for further investigation in the future. results with discodermolide were encouraging, but further Other epothilone B analogues. Other semisynthetic ana- clinical development has been limited by unforeseen pulmo- logues of epothilone B are at various stages of development. nary toxicity (2) The possibility of developing structural BMS-310705 is a semisynthetic analogue of epothilone B, analogues remains. which is more water-soluble than ixabepilone (39). BMS- Laulimalide and peloruside. Laulimalide is a structurally 310705 has been safely administered without the need for complex substance derived from marine sponges that also premedications (39). In a phase I study, responses were seen in maintains antimitotic activity against paclitaxel-resistant cells gastric, breast, and ovarian cancer, but difficulties have arisen (51). The interaction of laulimalide and microtubules is with diarrhea and neurotoxicity. Its future use may be limited complex, but there is evidence for a distinct laulimalide- to patients not suitable for treatment with other epothilones binding site on a-tubulin (Fig. 2; ref. 52). Xenograft studies in (39). ABJ-879 is another semisynthetic derivative of epothilone mice have shown that the drug has a narrow therapeutic index B, which has showed superior activity to paclitaxel in various and marked toxicity without evidence of efficacy, probably cell lines and in xenograft tumor models (40). Although ABJ- limiting its further development (51). Peloruside A is a 879 remains active in vitro against multidrug-resistant cell lines, metabolite of the New Zealand marine sponge Mycale hentscheli the absence of clinical studies to date suggest that this with a similar structure to the epothilones (52). It has compound may not be important in the future (40). ZK-EPO, the advantage of being less lipophilic than paclitaxel and a rationally designed derivative of epothilone B and the first binds to a-tubulin on the laulimalide-binding site (52). This fully synthetic epothilone, has shown remarkable activity in a binding site distinct from the taxanes raises the possibility of variety of cell lines as well as an ability to evade the cellular combining drugs that act on laulimalide and taxane-binding efflux pumps responsible for multidrug resistance (41). A phase sites—a synergistic antiproliferative effect has already been seen II study in platinum-resistant ovarian cancer has enrolled 63 in vitro (53). patients with promising early efficacy results (42). The most Other agents. Cyclostreptin was originally recovered from notable toxicity appears to be neurotoxicity (42). the fermentation broth of a bacterium from the Streptomyces Epothilone D derivatives. In vitro studies have suggested that species (54). Although it is less cytotoxic than paclitaxel in vitro, epothilone D and its analogues have substantially less activity it is active in taxane-resistant cell lines possibly because of a that epothilone B (41). KOS-862 is a derivative of epothilone novel mechanism of action involving covalently cross-linking D, which has shown particular activity against taxane-resistant with h- tubulin (54). Eleutherobin and sarcodictyins A and B cells in vitro (43). In phase I studies, KOS-862 has been are chemically related natural compounds derived from coral successfully combined with drugs with differing mechanisms of with potent antimicrotubule activity by binding to the taxane- actions such as carboplatin, gemcitabine, and trastuzumab binding site (55). Further chemical developments are awaited. (43–46). Phase II studies in metastatic breast cancer, platinum- refractory NSCLC, and metastatic hormone-refractory prostate Microtubule-destabilizing agents cancer have shown disappointing efficacy and substantial Colchicine-binding site. Although colchicine itself has no neurotoxicity (43, 47, 48). The future development of this clinical use in malignancy, many orally available compounds compound could lie in taxane-naive patients or at lower doses that act at the colchicine-binding site of tubulin (Fig. 2) are in combination with other cytotoxic agents. Early clinical undergoing investigation for possible cytotoxicity. These agents experience with KOS-1584, also derived from epothilone D, has include 2-methoxyestradiol, sulfonamide derivatives, and been encouraging with responses in NSCLC, ovarian, and head synthetic derivatives of Aspergillus species (56–58). As yet, no and neck cancer (48). Diarrhea has emerged as a dose-limiting dominant compound has emerged, but there is substantial toxicity and antidiarrheal prophylaxis is now routinely given in potential for development of agents that act as this novel site studies (48). and could theoretically be combined with other antimicrotu- Discodermolide and dictyostatin. There has been consider- bule agents and drugs with other mechanisms of action. able interest in substances derived from marine organisms as Vinca-binding site. As noted, Vinca alkaloids have a anticancer agents. For many sedentary marine organisms, the well-established role in a variety of malignancies. Vinflunine production of toxic substances that act on microtubules forms is a synthetic Vinca alkaloid with greater in vitro activity an important defense mechanism. These substances tend to be than older Vinca alkaloids and has now shown clinical efficacy in short supply and considerable time has been needed to in NSCLC (59). Synthetic derivatives of other naturally occurring compounds that act at the Vinca site are undergoing investigation (Fig. 2). Halichondrin B is a large polyether 1Phase II trial of patupilone in patients with brain metastases from breast cancer. macrolide derived from the marine sponge Halichondria okadaic NCT00450866. http://clinicaltrials.gov/ct2/show/NCT00450866. (60) Eribulin mesylate (E7389) is a synthetic derivative of

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halichondrin, which is currently in phase II trials in breast, nucleation at low concentrations and is potentially a more prostate, and NSCLC (60). Cryptophycins are naturally promising drug—phase II studies in melanoma and NSCLC are occurring compounds isolated from blue-green algae (61). ongoing (63). LY355703 is a synthetic cryptophycin derivative, which has shown some activity in platinum-refractory ovarian cancer Conclusion (61). Although the activity of these compounds in refractory malignancies may be modest, a future role in a variety of Many promising agents that interfere with microtubules are at settings is possible. Future synthetic derivatives may also show varying stages of development. The challenges lie in how these greater activity. novel agents can be incorporated into standard management for Dolastatins. Dolastatins were originally isolated from the diseases with many different treatment options as well as for Indian Ocean mollusk, Dolabella auricularia (also known as the diseases with minimal therapeutic options. The use of rational sea hare), and screened for anticancer activity and are thought combinations of drugs with nonoverlapping side-effect profiles to bind near the Vinca binding site (62). Although many and differing mechanisms of action is particularly interesting. compounds have been tested, clinical results have been disappointing. TZT-1027, a derivative of dolastatin-10, showed Disclosure of Potential Conflicts of Interest no activity in NSCLC in a phase II trial despite promising results in preclinical studies (62). Tasidotin (ILX651), a M.N. Fornier: speaker, Bristol-Myers Squibb. P.G. Morris: honoraria, Eisai, synthetic derivative of dolastatin-15, inhibits microtubule Genomic Health, Pfizer, and Haymarket Media.

References 1. Gelfand VI, Bershadsky AD. Microtubule dynamics: esophageal and gastric cancer: a phase I study. Am J Oncology Group trial S0111. J Clin Oncol 2005; mechanism, regulation, and function. Annu Rev Cell Clin Oncol 2006;29:376 ^ 9. 23:8724 ^ 9. Biol 1991;7:93 ^ 116. 13 . SabbatiniP,AghajanianC,DizonD,etal.PhaseII 24. Speicher LA, Barone L, Tew KD. Combined antimi- 2. Rowinsky EK, Calvo E. Novel agents that target study of CT-2103 in patients with recurrent epithelial crotubule activity of estramustine and Taxol in human tubulin and related elements. Semin Oncol 2006; ovarian, fallopian tube, or primary peritoneal carcino- prostatic carcinoma cell lines. Cancer Res 1992;52: 33:421^35. ma. J Clin Oncol 2004;22:4523^ 31. 4433^40. 3. Rai SS, Wolff J. Localization of the vinblastine- 14. Veronese ML, Flaherty K, Kramer A, et al. Phase I 25. Galsky MD, Small EJ, Oh WK, et al. Multi-institu- binding site on h-tubulin. J Biol Chem 1996;271: study of the novel taxane CT-2103 in patients with ad- tional randomized phase II trial of the epothilone B an- 14707 ^ 11. vanced solid tumors. Cancer Chemother Pharmacol alog ixabepilone (BMS-247550) with or without 4. Nyman DW, Campbell KJ, Hersh E, et al. Phase I and 2005;55:497^501. estramustine phosphate in patients with progressive pharmacokinetics trial of ABI-007, a novel nanopar- 15. Lin NU, Parker LM, Come SE, et al. Phase II study of castrate metastatic prostate cancer. J Clin Oncol ticle formulation of paclitaxel in patients with ad- CT-2103 as first- or second-line chemotherapy in 2005;23:1439^46. vanced nonhematologic malignancies. J Clin Oncol patients with metastatic breast cancer: unexpected 26. RosenbergJE,WeinbergVK, KellyWK, et al. Activity 2005;23:7785 ^ 93. incidence of hypersensitivity reactions. Invest New of second-line chemotherapy in docetaxel-refractory 5. GradisharWJ,Tjulandin S, Davidson N, et al. Phase III Drugs 2007;25:369 ^ 75. hormone-refractory prostate cancer patients: ran- trial of nanoparticle albumin-bound paclitaxel com- 16. Gerth K, Bedorf N, Ho« fle G, Irschik H, Reichenbach domized phase 2 study of ixabepilone or mitoxantrone pared with polyethylated castor oil-based paclitaxel H. Epothilons A and B: antifungal and cytotoxic com- and prednisone. Cancer 2007;110:556 ^ 63. in women with breast cancer. J Clin Oncol 2005;23: pounds from Sorangium cellulosum (myxobacteria). 27. Rosenberg JE, Galsky MD, Rohs NC, et al. A retro- 7794 ^803. Production, physico-chemical and biological proper- spective evaluation of second-line chemotherapy re- 6. Green MR, Manikhas GM, Orlov S, et al. Abrax- ties. J Antibiot (Tokyo) 1996;49:560 ^3. sponse in hormone-refractory prostate carcinoma: ane, a novel Cremophor-free, albumin-bound parti- 17. Lee FY, Borzilleri R, Fairchild CR, et al. BMS- second line taxane-based therapy after first-line epo- cle form of paclitaxel for the treatment of 247550: a novel epothilone analog with a mode of ac- thilone-B analog ixabepilone (BMS-247550) therapy. advanced non-small-cell lung cancer. Ann Oncol tion similar to paclitaxel but possessing superior anti- Cancer 2006;106:58 ^ 62. 2006;17:1263 ^ 8. tumor efficacy. Clin Cancer Res 2001;7:1429^ 37. 28. Low JA, Wedam SB, Lee JJ, et al. Phase II clinical 7. Stinchcombe TE, Socinski MA, Walko CM, et al. 18. Abraham J, Agrawal M, Bakke S, et al. Phase I trial of ixabepilone (BMS-247550), an epothilone B Phase I and pharmacokinetic trial of carboplatin and trial and pharmacokinetic study of BMS-247550, analog, in metastatic and locally advanced breast can- albumin-bound paclitaxel, ABI-007 (Abraxane) on an epothilone B analog, administered intravenously cer. J Clin Oncol 2005;23:2726 ^ 34. three treatment schedules in patients with solid on a daily schedule for five days. J Clin Oncol 29. Roche¤ H, Yelle L, Cognetti F, et al. Phase II clinical tumors. Cancer Chemother Pharmacol 2007;60: 2003;21:1866^73. trial of ixabepilone (BMS-247550), an epothilone B 759 ^ 66. 19. Mani S, McDaid H, Hamilton A, et al. Phase I clinical analog, as first-line therapy in patients with metastatic 8. Seidman A, Danso M, Bach A, et al. Phase IIstudy of and pharmacokinetic study of BMS-247550, a novel breast cancer previously treated with anthracycline weekly nanoparticle paclitaxel (ABI-007), carboplatin derivative of epothilone B, in solid tumors. Clin Cancer chemotherapy. J Clin Oncol 2007;25:3415^ 20. and trastuzumab as first-line therapy of HER2-positive Res 2004;10:1289 ^ 98. 30. Denduluri N, Low JA, Lee JJ, et al. Phase II trial of metastatic breast cancer. J Clin Oncol 2006 ASCO 20. ShimizuT,Yamamoto N,YamadaY, et al. Phase I clin- ixabepilone, an epothilone B analog, in patients with Annu Meet Proc 2006;24:10650. ical and pharmacokinetic study of 3-weekly, 3-h infu- metastatic breast cancer previously untreated with 9. Dickler M,TrainaT, Panageas K, et al. Adjuvant beva- sion of ixabepilone (BMS-247550), an epothilone B taxanes. J Clin Oncol 2007;25:3421 ^ 7. cizumab (B) plus dose-dense doxorubicin/cyclo- analog, in Japanese patients with refractory solid 31. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety phosphamide (AC) followed by nanoparticle tumors. Cancer Chemother Pharmacol 2008;61: of ixabepilone (BMS-247550) in a phase II study of albumin- bound paclitaxel (nab-p) in early stage 751 ^ 8. patients with advanced breast cancer resistant to an breast cancer patients: cardiac safety. J Clin Oncol 21.Whitehead RP, McCoy S, Rivkin SE, et al. A phase II anthracycline, a taxane, and capecitabine. J Clin Oncol 2007 ASCO Annu Meet Proc 2007;25:567. trial of epothilone B analogue BMS-247550 (NSC 2007;25:3407^14. 10. Khan M, Sharef S, Amato RJ. Phase II study of xyo- #710428) ixabepilone, in patients with advanced 32.Thomas E,Tabernero J, Fornier M, et al. Phase II clin- tax (PPX) for androgen independent prostate cancer pancreas cancer: a Southwest Oncology Group study. ical trial of ixabepilone (BMS-247550), an epothilone (AIPC). J Clin Oncol 2006 ASCO Annu Meet Proc Invest New Drugs 2006;24:515^ 20. B analog, in patients with taxane-resistant metastatic 2006;24:14624. 22.Vansteenkiste J, Lara PN, Jr., Le Chevalier T, et al. breast cancer. J Clin Oncol 2007;25:3399 ^ 406. 11. Nemunaitis JJ, Leighl N, Miller W, Cormier Y, Phase II clinical trial of the epothilone B analog, ixabe- 33. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone Bernareggi A, Oldham F. Paclitaxel poliglumex (PPX) in pilone, in patients with non small-cell lung cancer plus capecitabine for metastatic breast cancer pro- combination with carboplatin (carb) for the first-line whose tumors have failed first-line platinum-based gressing after anthracycline and taxane treatment. treatment of patients with advanced non-small cell lung chemotherapy. J Clin Oncol 2007;25:3448 ^ 55. J Clin Oncol 2007;25:5210^ 7. cancer (NSCLC): preliminary data. J Clin Oncol 2005 23. Hussain M, Tangen CM, Lara PN, Jr., et al. Ixa- 34. Goodin S, Kane MP, Rubin EH. Epothilones: mech- ASCOAnnu Meet Proc 2005;23:7230. bepilone (epothilone B analogue BMS-247550) is anism of action and biologic activity. J Clin Oncol 12. DipetrilloT, Milas L, Evans D, et al. Paclitaxel poliglu- active in chemotherapy-naive patients with hor- 2004;22:2015^ 25. mex (PPX-Xyotax) and concurrent radiation for mone-refractory prostate cancer: a Southwest 35. Abrey L, Wen P, Govindan R, et al. Activity of

www.aacrjournals.org 7171 Clin Cancer Res 2008;14(22) November 15, 2008 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2008 American Association for Cancer Research. Molecular Pathways

patupilone for the treatment of recurrent or pro- 45. Cortes J, Climent M, Gomez P, et al. Phase I trial of 55. Hamel E, Sackett DL, Vourloumis D, Nicolaou KC. gressive brain metastases in patients (pts) with weekly combination KOS-862 (epothilone D) and The coral-derived natural products eleutherobin and non-small cell lung cancer (NSCLC): an open-label, trastuzumab in HER-2 overexpressing malignancies. sarcodictyins A and B: effects on the assembly of pu- multicenter, phase II study. J Clin Oncol 2007 J Clin Oncol 2006 ASCO Annu Meet Proc 2006;24: rified tubulin with and without microtubule-associat- ASCO Annu Meet Proc 2007;25:18058. 2028. ed proteins and binding at the polymer taxoid site. 36. LinB,CatleyL,LeBlancR,etal.Patupilone(epothi- 46. Marshall J, Ramalingam S, Hwang J, et al. Phase 1 Biochemistry 1999;38:5490 ^ 8. lone B) inhibits growth and survival of multiple myelo- and pharmacokinetic (PK) study of weekly KOS-862 56. KamathK,OkounevaT,LarsonG,PandaD,WilsonL, ma cells in vitro and in vivo. Blood 2005;105:350 ^ 7. (epothilone D) combined with gemcitabine (GEM) in Jordan MA. 2-Methoxyestradiol suppresses microtu- 37. MokTS, Choi E, Yau D, et al. Effects of patupilone patients (pts) with advanced solid tumors. J Clin bule dynamics andarrests mitosis withoutdepolymeriz- (epothilone B; EPO906), a novel chemotherapeutic Oncol 2005 ASCO Annu Meet Proc 2005;23:2041. ing microtubules. Mol CancerTher 2006;5:2225^33. agent, in hepatocellular carcinoma: an in vitro study. 47. Overmoyer B,Waintraub S, Kaufman P,et al. Phase II 57. Yee KW, Hagey A,Verstovsek S, et al. Phase 1study Oncology 2006;71:292 ^ 6. trial of KOS-862 (epothilone D) in anthracycline and of ABT-751, a novel microtubule inhibitor, in patients 38. O’ReillyT, Wartmann M, Maira SM, et al. Patupilone taxane pretreated metastatic breast cancer. J Clin with refractory hematologic malignancies. Clin Cancer (epothilone B, EPO906) and imatinib (STI571,Glivec) Oncol 2005 ASCO Annu Meet Proc 2005;23:778. Res 2005;11:6615 ^ 24. in combination display enhanced antitumour activity 48. Stopeck A, Moulder S, Jones S, et al. Phase I trial of 58. Nicholson B, Lloyd GK, Miller BR, et al. NPI-2358 is in vivo against experimental rat C6 glioma. Cancer KOS-1584 (a novel epothilone) using two weekly a tubulin-depolymerizing agent: in-vitro evidence for Chemother Pharmacol 2005;55:307 ^ 17. dosing schedules. J Clin Oncol 2007 ASCO Annu activity as a tumor vascular-disrupting agent. Antican- 39. Sessa C, Perotti A, Llado' A, et al. Phase I clinical Meet Proc 2007;25:2571. cer Drugs 2006;17:25 ^ 31. study of the novel epothilone B analogue BMS- 49. Mita A, Lockhart A, ChenT, et al. A phase I pharma- 59. Bennouna J, Breton JL, Tourani JM, et al. Vinflu- 310705 given on a weekly schedule. Ann Oncol cokinetic (PK) trial of XAA296A (discodermolide) ad- ninean active chemotherapy for treatment of ad- 2007;18:1548^53. ministered every 3 wks to adult patients with vanced non-small-cell lung cancer previously treated 40.Wartmann M, Loretan J, Reuter R, et al. Preclin- advanced solid malignancies. J Clin Oncol 2004 with a platinum-based regimen: results of a phase II ical pharmacological profile of ABJ879, a novel ASCO Annu Meet Proc 2004;22:2025. study. Br J Cancer 2006;94:1383 ^ 8. epothilone B analog with potent and protracted 50. Madiraju C, Edler MC, Hamel E, et al.Tubulin assem- 60. JordanMA,KamathK,MannaT,etal.Theprimary anti-tumor activity. Proc Am Assoc Cancer Res bly, taxoid site binding, and cellular effects of the mi- antimitotic mechanism of action of the synthetic hali- 2004;45:abstract 5440. crotubule-stabilizing agent dictyostatin. Biochemistry chondrin E7389 is suppression of microtubule 41. Klar U, Buchmann B, SchwedeW, et al.Total synthe- 2005;44:15053^63. growth. Mol CancerTher 2005;4:1086 ^ 95. sis and antitumor activity of ZK-EPO: the first fully 51. Liu J,Towle MJ, Cheng H, et al. In vitro and in vivo 61. D’Agostino G, del Campo J, Mellado B, et al. A mul- synthetic epothilone in clinical development. Angew anticancer activities of synthetic (-)-laulimalide, a ma- ticenter phase II study of the cryptophycin analog Chem Int Ed Engl 2006;45:7942 ^ 8. rine natural product microtubule stabilizing agent. LY355703 in patients with platinum-resistant ovarian 42. Rustin G, Reed N, Jayson G, et al. Phase II trial of Anticancer Res 2007;27:1509 ^ 18. cancer. Int J Gynecol Cancer 2006;16:71 ^ 6. the novel epothilone ZK-EPO in patients with platinum 52.Wilmes A, Bargh K, Kelly C, Northcote PT, MillerJH. 62. Riely GJ, Gadgeel S, Rothman I, et al. A phase 2 resistant ovarian cancer. J Clin Oncol 2007 ASCO Peloruside A synergizes with other microtubule stabi- study of TZT-1027, administered weekly to patients Annu Meet Proc 2007;25:5527. lizing agents in cultured cancer cell lines. Mol Pharma- with advanced non-small cell lung cancer following 43. BeerTM, Higano CS, Saleh M, et al. Phase II study col 2007;4:269 ^ 80. treatment with platinum-based chemotherapy. Lung of KOS-862 in patients with metastatic androgen in- 53. Hamel E, Day BW, Miller JH, et al. Synergistic Cancer 2007;55:181 ^ 5. dependent prostate cancer previously treated with effects of peloruside A and laulimalide with taxoid site 63. McDermott D, Hersh E, Weber J, et al. ILX651 docetaxel. Invest New Drugs 2007;25:565 ^ 70. drugs, but not with each other, on tubulin assembly. administered daily for five days every 3 weeks 44. Monk J, Calero-Villalona M, Dupont J, et al. Phase 1 Mol Pharmacol 2006;70:1555^ 64. (qdx5dq3w) in patients (pts) with inoperable locally trial of KOS-862 (epothilone D) in combination with 54. Buey RM, Calvo E, Barasoain I, et al. Cyclostreptin advanced or metastatic melanoma: phase II experience. carboplatin (C) in patients with solid tumors. J Clin binds covalently to microtubule pores and lumenal J Clin Oncol 2005 ASCO Annu Meet Proc 2005;23: Oncol 2005 ASCO Annu Meet Proc 2005;23:2049. taxoid binding sites. Nat Chem Biol 2007;3:117^ 25. 7556.

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Patrick G. Morris and Monica N. Fornier

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