Toward a Personalized Use of Paclitaxel

Send Orders for Reprints to [email protected] 296 Recent Patents on Anti-Cancer Drug Discovery, 2019, 14, 296-297

COMMENTARY

Gian L. Russo*

National Research Council, Institute of Food Sciences, Avellino 83100, Italy

When Wall and Wani presented in 1967, for the first time and its cause-effect relationship with toxicity and therapeutic at the 153rd National Meeting of the American Chemical efficacy in 295 patients affected by different solid tumors, Society, their preliminary data on the structure of a new namely ovarian, esophageal, breast cancers, and NSCLC compound, that they called Taxol, possessing novel anti- under three different chemotherapeutic regimens with PTX leukemic and antitumor agent [1], they probably did not pre- representing the key consistent agent. TC > 0.05 indicates the dict that in the following 50 years, Taxol would become the time at which the plasma concentration of PTX exceeds largest cancer drug ever manufactured, with an annual sale 0.05µM. Previous works from the same group demonstrated that peaked in 2000, reaching $1.6 billion (source that this parameter was associated with chemotherapeutic https://dtp.cancer.gov). Taxol was originally isolated from efficacy or severe toxicity in ovarian cancer patients treated the bark of the Pacific yew tree Taxus brevifolia and its with PTX plus carboplatin depending on the threshold con- clinical success became soon the emblem of naturally- centration of PTX exposure [14]. Chen and Zhang identified derived anticancer drugs. The structure was published on three ranges of TC > 0.05 distribution (26 to 30h; below 26h May 5, 1971 [2]. Following an agreement signed in 1991 and above 30h) and correlated them to the efficacy of the between NCI and Bristol-Myers Squibb (BMS) for the isola- chemotherapeutic treatment. In fact, they showed that in tion and formulation into drug of taxol from the bark of the 65.6% of PTX, TC > 0.05 in CR (Complete Remission) and PR Pacific yew tree [3], BMS changed the original name from (Partial Remission) were in the range of 26-30h, suggesting “Taxol” to “Paclitaxel” (PTX) and the drug was sold under that monitoring the PTX TC > 0.05, other than simply the blood the trademark name in US of “Taxol®” [3]. Foreign brand concentration of the agent, is essential to optimize individual names are: Anzatax, Asotax, Bristaxol, Praxel and Taxol treatment in different forms of solid cancers [13]. In the sec- Konzentrat. Paclitaxel has been approved to be used alone or ond part of their work, the authors focused on the correlation in combination with other drugs against solid tumors, such as between PTX TC > 0.05 and several indicators of drug toxicity, AIDS-related Kaposi Sarcoma (KS), breast cancer, Non- namely: leukopenia and leukopenic fever; neutropenia and Small Cell Lung Cancer (NSCLC) and ovarian cancer [4, 5], neutropenic fever; anemia and peripheral neurotoxicity. In but it is also being studied for the treatment of other types of all cases, they demonstrated that the higher the PTX TC > 0.05 (> 30h), higher were the degree of all forms of adverse ef- cancer, including esophageal cancer [6], pancreas [7], blad- fects in patients with ovarian cancer, esophageal cancer, der [8], prostate [9], and melanoma [10]. From a molecular breast cancer and NSCLC (Tables 3-6 in [13]). point of view, the pivotal work conducted in the Horwitz’ laboratory demonstrated in 1979 that PTX induces cell cycle The monopoly of PTX practically ended in the first dec- arrest in G2/M Phase promoting microtubule assembly [11]. ade of this millennium with the appearance on the market in As a result, microtubules are resistant to depolymerization 2005 of an innovative formulation of this drug marketed and their dynamicity is inhibited by blocking fundamental under the trade name of Abraxane® and representing a pro- functions in eukaryotic cells, such as mitosis. In cancer cells, tein-bound, injectable formulation of PTX, also known as this mechanism explains the antiproliferative effects associ- nanoparticle albumin-bound paclitaxel (nab-paclitaxel). The ® ated with PTX [11]. In later works, PTX analogues bearing clinical efficacy of Abraxane is significantly higher than photoreactive groups were used to identify the binding sites PTX in terms of response rate, increased time to disease pro- on distinct β-tubulin isotypes [12]. gression, increased survival and reduced toxicity [15]. Abraxane® has been FDA approved to be used alone or with Despite the fact that, surfing PubMed, the term “pacli- other drugs to treat: recurred or metastasized breast cancer, taxel” appears in title/abstract > 26,000 times, this compound advanced or metastasized non-small cell lung cancer (in and its clinical applications are still intensively studied. A combination with carboplatin) and metastasized pancreatic good example comes from the recent article authored by cancer (in combination with gemcitabine hydrochloride) [16- Chen and Zhang groups [13]. Here, the authors investigated 18]. As clearly reported by Sofias et al. (Fig. 2 in [19]), the ® the association of the pharmacokinetic parameter TC > 0.05 Abraxane projected sales by 2020 can raise $1.9 billion, while the prediction for Taxol® is lowering below $100 mil- *Address correspondence to this author at the Consiglio Nazionale delle lion. Based on this evidence, the work by Chen and Zhang Ricerche - Istituto Scienze dell'Alimentazione, via Roma, 64 - 83110 - Avel- [13] appears extremely timing since it inspires the extension lino, Italy; Tel: +39 0825 299331; E-mail: [email protected] of their study to compare the TC > 0.05 parameter between

Abraxane® and PTX. In addition, the application of this [10] Leon-Ferre RA, Markovic SN. Nab-paclitaxel in patients with method can be extended to test the efficacy of the growing metastatic melanoma. Expert Rev Anticancer Ther 2015; 15(12): 1371-7. family of other taxane anticancer agents approved by FDA in [11] Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly monotherapy or in combined chemotherapeutic formulations in vitro by taxol. Nature 1979; 277(5698): 665-7. [20]. [12] Yang CH, Horwitz SB. Taxol: The first microtubule stabilizing agent. Int J Mol Sci 2017; 18(8): 1733-41. REFERENCES [13] Xin DS, Zhou L, Li CZ, Zhang SQ, Huang HQ, Qiu GD, et al. TC > 0.05 as a pharmacokinetic parameter of paclitaxel for therapeutic [1] Wall ME, Wani MC. 153rd National Meeting of the American efficacy and toxicity in cancer patients. Recent Pat Anticancer Chemical Society; Miami Beach (FL)1967. pp. M-006. Drug Discov 2018; 13(3): 341-7. [2] Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant [14] Zhang S, Sun M, Yuan Y, Wang M, She Y, Zhou L, et al. Correla- antitumor agents. VI. The isolation and structure of taxol, a novel tion between paclitaxel TC > 0.05 and its therapeutic efficacy and se- antileukemic and antitumor agent from Taxus brevifolia. J Am vere toxicities in ovarian cancer patients. Cancer Transl Med 2016; Chem Soc 1971; 93(9): 2325-7. 2(5): 131-6. [3] Martin V. Overview of paclitaxel (TAXOL). Semin Oncol Nurs [15] Gradishar WJ. Albumin-bound paclitaxel: A next-generation tax- 1993; 9(4 Suppl 2): 2-5. ane. Expert Opin Pharmacother 2006; 7(8): 1041-53. [4] Mekhail TM, Markman M. Paclitaxel in cancer therapy. Expert [16] Drugs.com. FDA approves abraxane 2005 [Available from: http:// Opin Pharmacother 2002; 3(6): 755-66. www.drugs.com/newdrugs/abraxaneamerican-pharmaceutical- [5] Goodman J, Walsh V. The Story of Taxol: Nature and Politics in partners-inc-american-bioscience-inc-metastaticbreast-cancer- the Pursuit of an Anti-Cancer Drug. 1st ed. Cambridge University 143.html]. Press: New York 2001; 323(7304): 115-25. [17] ClinicalTrials.gov. Albumin-bound paclitaxel (ABI-007) for pa- [6] Van Hagen P, Hulshof MC, Van Lanschot JJ, Steyerberg EW, Van tientswith advanced non-small cell lung cancer 2013 [Available Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative Chemo- from: https://clinicaltrials.gov/ct2/show/study/NCT00540514]. radiotherapy for esophageal or junctional cancer. N Engl J Med [18] ClinicalTrials.gov. Phase III study of ABI-007(Albumin-bound 2012; 366(22): 2074-84. paclitaxel) plus gemcitabine versus gemcitabine in metastatic ade- [7] Ma WW, Hidalgo M. The winning formulation: The development nocarcinoma of the pancreas 2016 [Available from: https://clinical of paclitaxel in pancreatic cancer. Clin Cancer Res 2013; 19(20): trials.gov/ct2/show/NCT00844649]. 5572-9. [19] Sofias AM, Dunne M, Storm G, Allen C. The battle of "nano" [8] Vaughn DJ. Paclitaxel and carboplatin in bladder cancer: Recent paclitaxel. Adv Drug Deliv Rev 2017; 122: 20-30. developments. Eur J Cancer 2000; 36(Suppl 2): 7-12. [20] Ojima I, Lichtenthal B, Lee S, Wang C, Wang X. Taxane antican- [9] Obasaju C, Hudes GR. Paclitaxel and docetaxel in prostate cancer. cer agents: A patent perspective. Expert Opin Ther Pat 2016; 26(1): Hematol Oncol Clin North Am 2001; 15(3): 525-45. 1-20.