Navitoclax Explained

Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax.[1] [2]

Mechanism of action

Navitoclax inhibits not only Bcl-2, but also Bcl-XL and Bcl-w proteins.[3] Because navitoclax inhibits Bcl-XL, it reduces platelet lifespan, causing thrombocytopenia, and this makes it dose-limiting.

Effects against senescent cells

In animal studies, navitoclax was found to be a senolytic agent, inducing apoptosis in senescent, but not non-senescent cells.[4] Oral administration of ABT263 to either sublethally irradiated or normally aged mice reduced senescent cells, including senescent bone marrow hematopoietic stem cells and senescent muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice.[5]

On September 19, 2018, an article was published in Nature about using this drug to kill senescent glial cells in mice. The drug had a protective effect against memory loss in mice genetically engineered to simulate Alzheimer's Disease.[6]

Clinical trials

ABT-263 was studied in 2009.[7] In January 2017, Navitoclax was evaluated as a combination treatment against solid tumors together with trametinib in a clinical trial sponsored by the National Cancer Institute.[8] In this phase Ib/II study, patients with RAS-mutant tumors were enrolled to received trametinib plus navitoclax in dose-escalation part followed by multiple dose expansion cohorts.

In ESMO Congress 2023, the final results of 91 patients (including 38 patients from dose escalation part) were reported. At RP2D, 8/49 (16.3%) evaluable patients had a partial response (PR) with disease control rate (DCR) 59.2%. Though 35.2% objective response rate (0RR) and a disease control rate (DCR) of 85.7% was achieved among the 32 patients with GYN cancers, but the median duration of response (DOR) of 8.2 months was only moderately fine and no complete response was achieved.[9]

The product is currently under development by AbbVie. Navitoclax as mono-therapy[10] [11] as well as in combination with chemotherapies (paclitaxel, docetaxel, gemcitabine, and irinotecan), olaparib,[12] erlotinib,[13] venetoclax,[14] and rituximab[15] in advanced hematological malignancies (in both pediatric and adult patients) and solid tumors including ovarian cancer, breast cancer, lung cancer.

In addition, a global multi-center, randomized, open-label, phase 3 study evaluating efficacy and safety of navitoclax in combination with ruxolitinib versus best available therapy in adult patients with relapsed/refractory myelofibrosis was initiated at 31 Aug, 2020 and is no longer recruiting (NCT04468984).

Antisclerotic

Not directly related to cancer, rather as a therapy for scleroderma, Navitoclax appeared to reduce existing fibrosis through inducing apoptosis of myofibroblasts. Further research is required to elucidate the exact mechanisms and confirm studies.

Notes and References

  1. Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM . Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors . Journal of Clinical Oncology . 29 . 7 . 909–16 . March 2011 . 21282543 . 4668282 . 10.1200/JCO.2010.31.6208 .
  2. Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, Belmont LD, Nimmer P, Xiao Y, Ma XM, Lowes KN, Kovar P, Chen J, Jin S, Smith M, Xue J, Zhang H, Oleksijew A, Magoc TJ, Vaidya KS, Albert DH, Tarrant JM, La N, Wang L, Tao ZF, Wendt MD, Sampath D, Rosenberg SH, Tse C, Huang DC, Fairbrother WJ, Elmore SW, Souers AJ . 6 . Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy . Science Translational Medicine . 7 . 279 . 279ra40 . March 2015 . 25787766 . 10.1126/scitranslmed.aaa4642 . 206686917 .
  3. The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo. Molecular Cancer Therapeutics. 10. 12. 2340–9. Mol Cancer Ther. 2011 Dec;10(12):2340-9. doi: 10.1158/1535-7163.MCT-11-0415. Epub 2011 Sep 13.. 21914853. 2011. Chen. J.. Jin. S.. Abraham. V.. Huang. X.. Liu. B.. Mitten. M. J.. Nimmer. P.. Lin. X.. Smith. M.. Shen. Y.. Shoemaker. A. R.. Tahir. S. K.. Zhang. H.. Ackler. S. L.. Rosenberg. S. H.. Maecker. H.. Sampath. D.. Leverson. J. D.. Tse. C.. Elmore. S. W.. 10.1158/1535-7163.MCT-11-0415. free.
  4. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL . 6 . Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors . Aging Cell . 15 . 3 . 428–35 . June 2016 . 26711051 . 4854923 . 10.1111/acel.12445 .
  5. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D . Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice . Nature Medicine . 22 . 1 . 78–83 . January 2016 . 26657143 . 4762215 . 10.1038/nm.4010 .
  6. Bussian . Tyler J. . Aziz . Asef . Meyer . Charlton F. . Swenson . Barbara L. . van Deursen . Jan M. . Baker . Darren J. . October 2018 . Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline . Nature . en . 562 . 7728 . 578–582 . 10.1038/s41586-018-0543-y . 30232451 . 6206507 . 2018Natur.562..578B . 1476-4687.
  7. Hauck P, Chao BH, Litz J, Krystal GW . Alterations in the Noxa/Mcl-1 axis determine of small cell to the BH3 mimetic ABT-737 . Molecular Cancer Therapeutics . 8 . 4 . 883–92 . April 2009 . 19372561 . 10.1158/1535-7163.MCT-08-1118 . 19245418 .
  8. Web site: National Cancer Institute (sponsor). Corcoran. Ryan . vanc . Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors. ClinicalTrials.gov. National Institutes of Health. 24 June 2017. ClinicalTrials.gov Identifier: NCT02079740.
  9. Web site: Corcoran . Ryan . 664P - Final results of a phase I/II study of combined BCL-xL and MEK inhibition with navitoclax and trametinib in KRAS or NRAS mutant advanced solid tumors .
  10. Roberts . Andrew . Substantial Susceptibility of to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease . Journal of Clinical Oncology . 10 February 2012 . 30 . 5 . 488–496 . 10.1200/jco.2011.34.7898 . 4979082 .
  11. Joly . Florence . A phase II study of Navitoclax (ABT-263) as single agent in women heavily pretreated for recurrent epithelial ovarian cancer: The MONAVI - GINECO study . Gynecologic Oncology . 2022 . 165 . 1 . 30–39 . 10.1016/j.ygyno.2022.01.021 . 35123771 . 246499398 .
  12. Mackay . Helen . Exactis-03: A phase I trial of the combination of olaparib and navitoclax in women with high grade serous ovarian cancer and triple negative . Journal of Clinical Oncology . June 2023 . 41 . 16_suppl . TPS5623 . 10.1200/JCO.2023.41.16_suppl.TPS5623 . 259080754 .
  13. Tolcher . Anthony . Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with in patients with advanced solid tumors. Cancer Chemother Pharmacol . Cancer Chemotherapy and Pharmacology . 2015 . 76 . 5 . 1025–1032 . 10.1007/s00280-015-2883-8 . 26420235 . 23878408 .
  14. Pullarkat . Vinod . Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory and Lymphoblastic Lymphoma . Cancer Discovery . 2021 . 11 . 6 . 1440–1453 . 10.1158/2159-8290.CD-20-1465 . free . 33593877 . 9533326 .
  15. Kipps . Thomas . A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without, in previously untreated B-cell chronic lymphocytic leukemia . Leukemia & Lymphoma . 2015 . 56 . 10 . 2826–2833 . 10.3109/10428194.2015.1030638 . 25797560 . 4643417 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Navitoclax".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.