From the discovery of tubulin to the approval of vinblastine for anticancer treatment, it has been more than half a century.
Microtubules play an extremely important role in cell division, and disruption of the formation of mitotic spindles affects all dividing cells. For cancer cells that proliferate faster than most normal cells, anti-mitotic drugs can preferentially kill cancer cells when used in anti-tumor therapy. The development and application of such drugs is also an important part of the anti-cancer history of human drugs.
Figure 1 The main mechanism of action of microtubule inhibitors
Gift of nature
From land to sea, natural products play an important role in the history of human disease treatment. More than 50% of the anti-tumor drugs currently used are obtained from natural products. Microtubule inhibitors are the most representative of them.
The first antitumor drug derivative to enter clinical use was the vinca alkaloid, which was obtained from the vinca flower of Madagascar in the 1960s. Aboriginal people in Madagascar were among the first to discover the medicinal properties of periwinkle, but initially used plant extracts to treat diabetes. After less than 10 years, paclitaxel was successfully isolated from the bark of Pacific yew, but it was not until 1979 that Monroe Wall and Mansukh Wani discovered that it inhibited microtubule activity, and the medicinal purification yield was very low. In 1981, French scientist Pierre Potier isolated 10-DAB from the leaves of the British yew, using it as a substrate for semi-synthetic paclitaxel, which eventually led to the commercialization of paclitaxel by BMS.
Although the ocean covers about 70% of the Earth’s surface, less than 5% of the deep sea area is explored, and Daejeon of the marine sponge Halichondria okadai collected from five different regions, including the Central Pacific Ocean to the Indian Ocean to the New Zealand Sea. Natural analogues, followed by the Kishi R&D team at Harvard University in 1992 to complete the full synthesis of Otarubin B. Japan Eisai participated in the research and development of its anti-tumor activity, and finally launched the most complicated chemical synthesis method on the market.
Vincristine – accidental cooperation between academic and industrial circles
From the successful extraction of vinca alkaloids in plants, to the final Oncovin vincristine and Velban vinblastine in the United States in 1963 and 1965, respectively, became the first microtubule inhibitors for anti-tumor treatment, in addition to persistence The power of luck.
Vincristine is widely used to treat acute lymphoblastic leukemia and Hodgkin’s lymphoma; vinblastine is most commonly used to treat bladder cancer, but it is also effective against other blood and solid cancers, including Hodgkin’s lymphoma. The anti-tubulin activity of vinblastine was 6 times higher than that of vincristine.
Since the 1950s, Lilly has been testing the biological activity of hundreds of plant extracts every year, hoping to develop a new drug. Gordon Svoboda added Madagascar Periwinkle to the Eli Lilly study list based on his recollection of reports of the use of periwinkle products in the Philippines during the Second World War to treat diabetes. In January 1958, the extract was found to exhibit in anti-cancer tests.
Figure 3. Robert Noble and Charles Beer
At the same time, two research scientists at the University of Western Ontario in Canada, Robert Noble and Charles Beer, also found that the extract of Madagascar periwinkle can kill white blood cells. They also presented their findings on the discovery of new cancer activity at a scientific seminar in New York in March 1958. Coincidentally, the meeting was released at midnight due to time problems, and the audience had been reduced to only a few. The audience, most of them are from Lilly. Since then, the two teams have established cooperation to speed up the introduction of vincristine and vinblastine. The extraction of natural products must also depend on the yield of periwinkle, and the cost of early extraction from wild plants is still quite large, until the supply cost of large-scale farm cultivation is reduced in the later period. Vindesine and vinorelbine, which were developed after the chemical modification of vinblastine, were finally listed in countries such as Europe and Japan.
From paclitaxel to docetaxel – the second generation of market disputes
About 30 years later, the first paclitaxel drug, Taxol (Paclitaxel), was approved in the United States as a second-line therapy for ovarian cancer in 1992, and its indications have continued to expand. Four years later, French pharmaceutical giant Sanofi developed the second-generation taxane drug Taxotere (docetaxol, docetaxel).
Docetaxel is also based on 10-DAB synthetic structural modification. There are two main differences from paclitaxel: one is the two positions of the chemical structure, and docetaxel replaces the acetate of paclitaxel with a hydroxyl functional group on carbon 10, and The presence of tert-butyl carbamate on the side chain of the phenylpropionate rather than the benzamide in paclitaxel; a change in the carbon 10 functional group results in more paclitaxel being more soluble in water than paclitaxel, thereby increasing the efficacy. Second, the docetaxel solvent is polysorbate 80 and alcohol. If the patient is allergic to paclitaxel in the media, castor oil or polysorbate, the doctor will be more likely to recommend docetaxel.
Previously, due to incomplete toxicity data, the FDA rejected the Taxotere listing application in 2014, but Taxotere quickly became the largest competitor of Taxol after being approved for marketing. But behind the huge commercial success, Sanofi’s marketing approach to Taxotere has been controversial. As a result, the FDA issued a warning letter to Sanofi on the marketing of Taxotere in 2009, stating that “if the promotional materials suggest or suggest that a drug is safer or more effective than another drug without substantial clinical experience, It is misleading material.” But Sanofi’s promotion of Taxotere was more effective and safer than Taxol, but in a number of long-term studies, there was no statistically significant difference in survival between Taxotere and Taxol in patients with metastatic breast cancer.
Taxotere also has a very important adverse reaction, permanent hair loss, which occurs in 3%-15% of patients who complete Taxotere treatment. Sanofi also realized the risk of permanent hair loss in 2005, the instructions in the EU and Canada. It is pointed out that in some cases, “hair may not grow again”, but the severity is still flashing. Many women with breast cancer have previously preferred to choose to treat the “safer” Taxotere, but permanent or disfiguring alopecia is a pain that can never be healed even for women who successfully fight breast cancer.
Iteration of paclitaxel preparations – behind the legend and decline of Abraxane and Cynviloq
Whether it is paclitaxel or docetaxel, its solvent is easy to stimulate histamine in patients, causing severe allergic reactions in 2% – 4% of patients, so patients taking paclitaxel must be treated with steroids and antihistamines beforehand. And the economic burden has increased. Improved dosage forms have opened up the iterative journey of paclitaxel formulations to improve drug efficacy and reduce adverse reactions.
Figure 4. Paclitaxel formulation technique iteration
One of the most important products is Abraxane, the world’s only listed albumin-bound paclitaxel nanoparticles. The albumin-binding nanotechnology has increased the drug loading of paclitaxel by half, and may also help more paclitaxel into cancer cells. Listed in the United States in 2005, the indication range is similar to that of paclitaxel. In 2013, the FDA newly approved first-line treatment for pancreatic cancer increased its sales. Samyang’s Cynviloq is the world’s only listed paclitaxel polymer micelle with a maximum tolerated dose 40 times that of Taxol. It was first marketed in Korea under the trade name Genexol-PM in 2007.
Neither requires a solvent like Cremaphor, with reduced side effects and shorter dosing times. Cynviloq has two important advantages over Abraxane. One is that Abraxane uses albumin from human blood, is susceptible to contamination, and is “sticky” to plastic infusion bags and catheters, but Cynviloq uses micellar copolymers (synthesizers) to dissolve API paclitaxel, avoiding these two problems; Cynviloq has a higher maximum tolerated dose.
But micellarized paclitaxel did not compete with Abraxane as expected, all of which was related to a famous Chinese doctor investing in Chinese – Huang Xinxiang. Initially, his invented albumin paclitaxel was sold to Celgene for $2.9 billion in 2010 and became Celgene’s largest individual shareholder. Abraxane has almost no rivals after its launch. The high price is one of Celgene’s pillar products for a period of time, Sanyo’s Partner Sorrento is responsible for the approval of Cynviloq in the United States. It is foreseeable that its price advantage will pose a threat to Abraxane’s sales. In November 2014, Huang Xinxiang saw that Cynviloq’s competitive landscape has been formed, so that its assets are not greatly Shrinking, taking the initiative to contact Sorrento to propose the idea of buying Cynviloq, saying that his experience in pushing Abraxane will definitely make Cynviloq commercially successful. On the one hand, Celgene is worried that the US Federal Trade Commission will not approve the antitrust. Sandoz also offered a very sincere price to Sorrento. Finally, in 2016, Huang Xinxiang purchased the sales rights of Cynviloq from Sorrento through his personal company NantPharma for $1.3 billion. I thought that Huang Xinxiang would also develop Cynviloq into the next blockbuster drug like Abraxane, but the plot of Sorrento was reversed in April this year. It was said that Huang intentionally bought Cynviloq and then patented it. Expired to continue to profit from Abraxane, but also to wait for the final court to judge the results, but this is not the first time Huang Xinxiang has been caught in a similar investment scandal, in any case this is a major loss to Sanyo’s opportunities in the North American market.
Ammunition loaded into the ADC
In addition to improved dosage forms, another strategy to improve the accurate delivery of drugs is to load these microtubule inhibitors into a single antibody as an antibody conjugate ADC, but early tubulin inhibitors, including paclitaxel, vincristine, etc. The limitations of resistance and low cytotoxicity require the development of a new generation of tubulin inhibitors with greater potency. Derivatives of microtubule polymerization inhibitors Maytansine maytansine and Auristatin are now widely used as ADC cytotoxic payloads.
Figure 6. Efficacy of cytotoxic drug payload (IC50, M)
Among them, maytansine is one of the first compounds with IC50 reaching picomolar value and higher (100 to 1000 times) efficacy than doxorubicin and paclitaxel. It was first isolated from Maytenus serrata in Ethiopian plants around 1960. It showed good anti-tumor effects before the clinic, but the clinical trial failed in the 1980s and the development was discontinued. Kadcyla developed by Immunogen uses dexamethasone derivative DM1 as a payload and was successfully approved in the United States, the European Union and other regions in 2013.
Auristatin is a water-soluble synthetic analogue of the marine natural product (dolastatin 10) isolated from the extract of the sea rabbit (Dolabella auricularia). Seattle Genetics developed the two most representative auristatin derivatives (MMAE and MMAF), and the FDA approved the ADC targeting CD30. Bentuximab vedotin uses MMAE as a payload.
Strong combination of strategies
Microtubule inhibitors are used in combination with most other types of cytotoxic drugs, such as paclitaxel and carboplatin for first-line treatment of metastatic NSCLC. The traditional combination of concepts has different cytotoxic mechanisms and non-cross-resistance mechanisms. The drug, which increases the lethality to cancer cells when toxicity is acceptable, regulates the dosing regimen to overcome the toxicity associated with drug exposure.
With the rise of immunotherapy, the mechanism of microtubule inhibitors and its combination is also explored. Paclitaxel can enhance the immune stimulating activity at lower doses, which may be one of the considerations for the combination of immunotherapy and microinhibitors. Recently, The FDA accelerated the approval of albumin paclitaxel combined with Atezolizumab for PD-L1-positive metastatic triple-negative breast cancer is a huge breakthrough. At the same time, in the process of increasing the mechanism of microtubule inhibitors, it was also found that microtubule inhibitors also have anti-angiogenic effects through changes in cell morphology and activity, as well as Mcl by inducing anti-apoptotic Bcl-2 family members. -1, Bcl-2 phosphorylation, etc., to promote apoptosis, may also provide a new idea of the mechanism.
Now that microtubule inhibitors are no longer limited to anti-mitotic effects, there are more unknowns to explore.