Novel Tubulin-Targeting Therapies Make Headway

Publication
Article
Oncology Live®Vol. 21/No. 23
Volume 21
Issue 23
Pages: 57-58

Clinical findings have recently been reported for 2 of the more advanced emerging tubulin-targeting agents, VERU-111 and plinabulin.

Microtubules, which are cytoskeletal proteins that are integral to cell functions, have represented an attractive target for anticancer drug development for more than 60 years. The first microtubule-targeting agents (MTAs) were introduced in the late 1950s, beginning with vinca alkaloids and followed several years later by taxanes.1-4 Since then, many MTAs have been developed for the treatment of numerous cancer types.

Now advances in understanding the role of the microtubule cytoskeleton in cancer cells have generated optimism that novel MTAs will provide increased efficacy with less toxicity. Clinical findings have recently been reported for 2 of the more advanced emerging tubulin-targeting agents, VERU-111 and plinabulin.5,6

The Role of Microtubule Function

Microtubules are polymers of tubulin heterodimers, each of which consists of an α- and β-tubulin monomer. These heterodimers bind in chains to form 13 protofilaments that bind laterally to create a hollow microtubule 24 nm in diameter.7

The dynamics between intracellular pools of tubulin heterodimers and microtubule polymers are highly regulated. Microtubule dynamics are determined by the guanine triphosphate (GTP) nucleotide bound to each tubulin heterodimer. When GTP is hydrolyzed to guanine diphosphate (GDP) during polymerization, the affinity of GDP-bound tubulin for adjacent tubulin molecules weakens, and this dynamic instability of microtubules results in periods of polymerization and depolymerization. During polymerization, GTP-bound tubulin is added to the growing “plus” end of the microtubule to form a stable GTP cap. During depolymerization, GDP-bound tubulin rapidly disassembles from the microtubule.8

In initial preclinical research, investigators

noted that MTAs arrest the cell cycle by

inhibiting mitotic spindle formation, leading to cell death.9 However, in human tumors, in which cell growth is slower when compared with that of cultured cells, mitotic disruption may not play as large a role in the activity of MTAs because fewer cells will be in mitosis at any given time. In addition to mitotic disruption, MTAs can have antiangiogenic and antimetastatic activity. However, the complex environment of a human tumor makes it difficult to determine the exact mechanism of MTA-induced cell death.8

Microtubule-Targeting Agents

MTAs can be classified into 2 broad groups: those that stabilize microtubule formation and those that destabilize microtubule formation (FIGURE10) Microtubule-stabilizing agents (MSAs) include taxanes and epothilones whereas microtubule-destabilizing agents (MDAs) include vinca alkaloids and colchicines.10 Taxanes bind to the inner, luminal side of the microtubule, stabilizing it by strengthening the longitudinal tubulin binding affinity.10 Epothilones mimic the microtubule-stabilizing effect of the taxols, act as competitive inhibitors of taxol binding,and have similar microtubule affinity.11 By contrast, in the MDA group, vinca alkaloids cause depolymerization by forming tubulin paracrystals whereas colchicine blocks microtubule function by binding tubulin and blocking polymerization.10 Although all MTAs have distinct binding sites and actions, most of these compounds show notably similar effects on microtubules, especially at the lowest effective drug concentrations.10

Diverse Binding Sites for Therapies Aimed at the Microtubule

FIGURE. Diverse Binding Sites for Therapies Aimed at the Microtubule10

FDA-Approved MTAs

The FDA has approved at least 8 microtubule inhibitors for use in cancer.12,13 MSAs include paclitaxel and docetaxel, which are approved for use in a number of cancer types. Cabazitaxel (Jevtana), also an MSA, is indicated in combination with prednisone for patients with metastatic castration-resistant prostate cancer (mCRPC),14 and nab-paclitaxel (Abraxane) is approved for metastatic breast cancer, non–small cell lung cancer (NSCLC), and metastatic pancreatic adenocarcinoma.15 The epothilones eribulin mesylate (Halaven) and ixabepilone (Ixempra) are both approved for metastatic or advanced breast cancer;16,17 eribulin also is indicated for unresectable or metastatic liposarcoma.

In the category of MDAs, the vinca alkaloid drug family is comprised of vinorelbine tartrate, used in combination with cisplatin and as monotherapy for metastatic NSCLC, and vincristine sulfate liposome injection (Marqibo), indicated for the treatment of relapsed acute lymphoblastic leukemia.13

As noted, colchicine is a microtubule-destabilizing agent; it induces GTP hydrolysis to convert GTP-bound tubulin to GDP-bound tubulin and promote disassembly. Although the FDA has approved colchicine for the treatment of gout and Mediterranean fever, therapeutic uses have been limited due to its toxicity.18 However, colchicine binding site inhibitors are less susceptible to efflux pumps, a main mechanism for acquired drug resistance. Additionally, colchicine derivatives inhibit angiogenesis, one of the hallmarks of cancer, by disrupting microtubule ability to regulate vasculature network formation.7

Colchicine-Targeting Agents

Several compounds that target the colchicine binding site are currently in clinical development. These include OXi4503 (combretastatin A1 diphosphate; CA1P), for which the FDA has granted a rare pediatric disease designation for development as a treatment for acute myeloid leukemia (AML) due to genetic mutations that disproportionately affect pediatric patients. The agent is a prodrug of combretastatin A1, a chemical originally isolated from a species of willow tree bark, that targets the colchicine binding site to destabilize microtubules. In prior clinical findings, OXi4503 in combination with standard cytarabine elicited 4 complete remissions among 26 evaluable adults with AML.7,19

Other agents in the colchicine class include lisavanbulin (BAL101553) and plinabulin.20,21 Investigators are evaluating lisavanbulin in a phase 1 trial (NCT03250299) in combination with standard radiotherapy for patients with newly diagnosed MGMT promoter unmethylated glioblastoma. Plinabulin (also called NPI-2358 or BPI-2358), which is administered intravenously, is being developed in the United States and China under breakthrough therapy designations for the prevention of chemotherapy-induced neutropenia.6

The agent is being evaluated in the phase 3 Protective 2 trial (NCT03294577) in combination with pegfilgrastim (Neulasta) in patients receiving docetaxel, doxorubicin, and cyclophosphamide and in the phase 3 Protective-1 study (NCT03102606) in patients with advanced solid tumors receiving myelosuppressive chemotherapy.

In topline findings from Protective 2, the combination of plinabulin plus pegfilgrastim met the primary end point by demonstrating a statistically significant improvement in the rate of prevention of grade 4 neutropenia versusnpegfilgrastim alone in cycle 1 of therapy (31.5% vs 13.6%, respectively; P = .0015). Key secondary end points were also met, including duration of severe neutropenia from day 1 to day 8 in the first cycle, and mean absolute neutrophil count nadir during cycle 1 (P = .0002).6

VERU-111

The novel tubulin inhibitor VERU-111 is a first-in-class next-generation oral MTA, which targets both α and β tubulin, binding at the α-β tubulin interface and targeting the colchicine binding pocket.22,23 To date, VERU-111 has shown antitumor activity in several preclinical tumor models.24-27 The preclinical profile of VERU-111 suggests that this agent has high oral bioavailability and a favorable toxicity profile with no neurotoxicity, neutropenia, or myelosuppression. 28 VERU-111 is also not a substrate for multidrug resistance proteins such as P-glycoprotein, MRPs, and BCRP, suggesting the agent may be better able to maintain its inhibition of microtubule activity.22,23

“In preclinical studies, VERU-111 can bind to colchicine, resulting in inhibition of microtubule polymerization,” Mark C. Markowski, MD, PhD, an assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said during a presentation at the European Society for Medical Oncology (ESMO) Virtual Congress 2020. “It can also decrease the production of several β isoforms of tubulin. Unlike other taxane chemotherapy, it’s not a substrate for multidrug resistant proteins or CYP3A4.”5

Markowski and colleagues are evaluating VERU-111 in a phase 1b/2 clinical trial (NCT03752099) in patients with mCRPC whose disease progressed after receiving a novel androgen receptor (AR)-blocking agent.nThe phase 1b portion of the study is assessingnthe safety and tolerability of VERU-111, whereas phase 2 is designed to estimate the prostate-specific antigen (PSA) response rate, defined as a decline greater than or equal to 50% of baseline level, confirmed with a second measurement at least 3 weeks apart.

Continuous administration of VERU-111 proved to be safe and demonstrated antitumor activity, according to phase 1b results reported at the ESMO meeting. At the recommended phase 2 dose of 63 mg daily, 10 men reached at least 4 cycles of continuous dosing; 6 experienced a decrease in PSA—4 experienced a decline of least 30% in PSA, and 2 experienced a decline of least 50% in PSA. Best objective tumor responses consisted of 2 partial responses and 8 cases of stable disease; an additional 2 objective responses occurred in patients who did not reach cycle 4 of treatment.5

The median duration of treatment without radiographic progression was more than 11 months (range, 6-17). At the time of the presentation in September 2020, 5 of 10 of the men were continuing on the protocol. The phase 2 portion of the study has reached its target accrual goal of 40 patients. Radiographic progression-free survival (rPFS) will serve as the primary end point of the study, and investigators also will evaluate safety.5

VERU-111 has demonstrated antitumor activity in preclinical models of other cancer types, such as taxane-resistant cervical, lung, and ovarian cancers and other solid malignancies, as well as in human promyelocytic leukemia.23 Additionally, VERU-111 is being studied in a phase 2 trial (NCT04388826) as a treatment for severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019. The trial is seeking to enroll 40 patients.

References

  1. Dumontet C, Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010;9(10):790-803. Published correction in Nat Rev Drug Discov. 2010;9(11):897.
  2. Nobel RL, Beer CT, Cutts JH. Role of chance observations in chemotherapy: vinca rosea. Ann N Y Acad Sci. 1958;76(3):882-94. doi:10.1111/j.1749-6632.1958.tb54906.x
  3. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;277:665-667. doi:10.1038/277665a0
  4. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971;93(9):2325-2327. doi:10.1021/ja00738a045
  5. Markowski MC, Eisenberger MA, Tutrone R, et al. Phase 1b/2 study of VERU-111, novel, oral tubulin inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen blocking agent. Ann Oncol. 2020;31(suppl 4):S510-S511. doi:10.1016/j.annonc.2020.08.874
  6. BeyondSpring announces positive topline results from its PROTECTIVE-2 phase 3 registrational trial of plinabulin in combination with pegfilgrastim for prevention of chemotherapy-induced neutropenia. News release. BeyondSpring Therapeutics. November 16, 2020. Accessed November 17, 2020. https://bit.ly/35BVosZ
  7. McLoughlin EC, O’Boyle NM. Colchicine-binding site inhibitors from chemistry to clinic: a review. Pharmaceuticals (Basel). 2020;13(1):8. Published correction in Pharmaceuticals (Basel). 2020;13(4):72.
  8. Bates D, Eastman A. Microtubule destabilising agents: far more than just antimitotic anticancer drugs. Br J Clin Pharmacol. 2017;83(2):255-268. doi:10.1111/bcp.13126
  9. Serpico AF, Visconti R, Grieco D. Exploiting immune-dependent effects of microtubule-targeting agents to improve efficacy and tolerability of cancer treatment. Cell Death Dis. 2020;11(5):361. doi:10.1038/s41419-020-2567-0
  10. Karahalil B, Yardım-Akaydin S, Baytas SN. An overview of microtubule targeting agents for cancer therapy. Arh Hig Rada Toksikol. 2019;70(3):160-172. doi:10.2478/aiht-2019-70-3258
  11. Bollag DM, McQueney PA, Zhu J, et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 1995;55(11):2325-2333.
  12. Microtubule inhibitor [drug class]. DailyMed National Library of Medicine. Accessed November 17, 2020. https://bit.ly/3pxwcMh
  13. Vincristine. DailyMed National Library of Medicine. Accessed November 17, 2020. https://bit.ly/3lSBlfm
  14. Jevtana. Prescribing information. Sanofi-Aventis US, LLC; 2020. Accessed November 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/201023s023lbl.pdf
  15. Abraxane. Prescribing information. Celgene Corporation; 2020. Accessed November 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf
  16. Halaven. Prescribing information. Eisai Inc; 2016. Accessed November 17, 2020.
  17. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201532s016lbl.pdf
  18. Ixempra. Prescribing information. Bristol Myers Squibb; 2011. Accessed November 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022065s006lbl.pdf
  19. Kumar A, Sharma PR, Mondhe DM. Potential anticancer role of colchicine-based derivatives: an overview. Anticancer Drugs. 2017;28(3):250-262. doi:10.1097/CAD.0000000000000464
  20. FDA granted pediatric disease designation for OXI-4503. News release. Mateon Therapeutics. September 16, 2020. Accessed November 17, 2020. https://bit.ly/35CjgN9
  21. Kristeleit R, Evans J, Molife LR, et al. Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours. Br J Cancer. 2020;123(9):1360-1369. doi:10.1038/s41416-020-1010-8
  22. La Sala G, Olieric N, Chen AS, et al. Structure, thermodynamics, and kinetics of plinabulin binding to two tubulin isotypes. Chem. 2012;5(11):2969-2986. doi:10.1016/j.chempr.2019.08.022
  23. Chen J, Ahn S, Wan J, et al. Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) analogues targeting tubulin polymerization as antiproliferative agents. J Med Chem. 2012;55(16):7285-7289. doi:10.1021/jm300564b
  24. Veru corporate presentation June 2020. Veru Inc. Accessed November 17, 2020. https://bit.ly/2IOHwCx
  25. Mahmud F, Deng S, Chen H, Miller DD, Li W. Orally available tubulin inhibitor VERU-111 enhances antitumor efficacy in paclitaxel-resistant lung cancer. Cancer Lett. 2020;495:76-88. doi:10.1016/j.canlet.2020.09.004
  26. Kashyap VK, Dan N, Chauhan N, et al. VERU-111 suppresses tumor growth and metastatic phenotypes of cervical cancer cells through the activation of p53 signaling pathway. Cancer Lett. 2020;470:64-74. doi:10.1016/j.canlet.2019.11.035
  27. Deng S, Krutilin RI, Wang Q, et al. An orally available tubulin inhibitor, VERU-111, suppresses triple-negative breast cancer tumor growth and metastasis and bypasses taxane resistance. Mol Cancer Ther. 2020;19(2):348-363. doi:10.1158/1535-7163.MCT-19-0536
  28. Markowski MC, Getzenberg RH, Steiner MS, Azad NS, Eisenberger MA, Antonarakis ES. The effect of VERU-111, a novel oral inhibitor of α and β tubulin, on tumor growth in the human castration-resistant, AR-variant prostate cancer (PCa) model 22Rv1. J Clin Oncol. 2019;37(suppl 7):167. doi:10.1200/JCO.2019.37.7_suppl.167
  29. Li CM, Lu Y, Chen J, et al. Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer. Pharm Res. 2012;29(11):3053-3063. doi:10.1007/s11095-012-0814-5
Related Videos
Emmanuel Antonarakis, MD, associate director, Translational Research, Masonic Cancer Center, University of Minnesota, Clark Endowed Professor of Medicine, University of Minnesota Medical School
Gautam Jha, MD, medical director, M Health Fairview Masonic Cancer Clinic and the Advanced Treatment Center at the M Health Fairview Clinics and Surgery Center—Minneapolis, chair, cancer committee, M Health Fairview Ridges Hospital
Minesh Mehta, MD
Minesh Mehta, MD
Ruben Olivares, MD
Phillip J. Koo, MD
Daniel Spratt, MD
Daniel Spratt, MD
Arya Amini, MD
Philip J. Koo, MD