Dactolisib Explained

Dactolisib (codenamed NVP-BEZ235 and BEZ-235, also known as RTB101) is an imidazoquinoline derivative acting as a PI3K inhibitor.[1] It also inhibits mTOR.[2] It is being investigated as a possible cancer treatment.[3]

It has been shown to be toxic to Waldenström's macroglobulinemia cells.[4]

It was the first PI3K inhibitor to enter clinical trials, in 2006.[5]

A phase IB/II clinical trial for locally advanced or metastatic HER2 negative breast cancer has completed.[6]

A phase II clinical trial for advanced pancreatic neuroendocrine tumors (pNET) had initially reported results, but was later terminated because insufficient normal tissue tolerance to the drug.[7] A phase I clinical trial of BEZ235 in patients with advanced renal cell carcinoma had to be terminated prematurely due to toxicity and a lack of clinical efficacy .[8] Another Phase Ib study on patients with various solid cancers found severe normal tissue toxicity as well when BEZ235/Dactolisib was administered in combination with the mTOR inhibitor Everolimus. The authors concluded that the combination of both drugs demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity .[9] A phase I study of BEZ-235 to treat acute lymphoid leukaemia was initiated in 2012, but no results were published since then.[10]

A phase 2a randomized, placebo-controlled clinical trial published in 2018 showed that everolimus in combination with dactolisib decreased the rate of reported infections in an elderly population.[11]

Notes and References

  1. Liu . TJ . Koul . D . LaFortune . T . Tiao . N . Shen . RJ . Maira . SM . Garcia-Echevrria . C . Yung . WKA . NVP-BEZ235, a Novel Dual Phosphatidylinositol 3-kinase/Mammalian Target of Rapamycin Inhibitor, Elicits Multifaceted Antitumor Activities in Human Gliomas . Molecular Cancer Therapeutics . 11 August 2009 . 8 . 8 . 2204–10 . 10.1158/1535-7163.MCT-09-0160 . 19671762 . 2752877.
  2. Awasthi . N . Yen . PL . Schwarz . MA . Schwarz . RE . The Efficacy of a Novel, Dual PI3K/mTOR Inhibitor NVP-BEZ235 to Enhance Chemotherapy and Antiangiogenic Response in Pancreatic Cancer . Journal of Cellular Biochemistry . March 2012 . 113 . 3 . 784–91 . 10.1002/jcb.23405 . 22020918 . 23005922 .
  3. Maira . SM . Stauffer . F . Schnell . C . García-Echeverría . C . PI3K Inhibitors for Cancer Treatment: Where Do We Stand? . Biochemical Society Transactions . 1 February 2009 . 37 . 1 . 265–72 . 10.1042/BST0370265 . 19143644.
  4. Sacco . A . Roccaro . A . Ghobrial . IM . Role of Dual PI3/Akt and mTOR Inhibition in Waldenström's Macroglobulinemia . Oncotarget . November 2010 . 1 . 7 . 578–82 . 10.18632/oncotarget.192. 21317453 . 3248138.
  5. Web site: A Phase I/II Study of BEZ235 in Patients with Advanced Solid Malignancies Enriched by Patients with Advanced Breast Cancer . ClinicalTrials.gov . 16 July 2016.
  6. https://clinicaltrials.gov/ct2/show/NCT01495247 Phase Ib/II Trial of BEZ235 With Paclitaxel in Patients With HER2 Negative, Locally Advanced or Metastatic Breast Cancer
  7. https://clinicaltrials.gov/ct2/show/results/NCT01658436 BEZ235 Phase II Trial in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) After Failure of mTOR Inhibitor Therapy.
  8. BEZ235: When Promising Science Meets Clinical Reality . 2016 . The Oncologist . 5016067 . Pongas . G. . Fojo . T. . 21 . 9 . 1033–1034 . 10.1634/theoncologist.2016-0243 . 27566248 .
  9. Web site: A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib(BEZ235) Combined with Everolimus in Patients with AdvancedSolid Malignancies . Target Oncology . 29 March 2017.
  10. Web site: A Phase I, Dose-finding Study of BEZ235 in Adult Patients With Relapsed or Refractory Acute Leukemia . clinicatrials.gov . 29 July 2020.
  11. Zhavoronkov A . Alex Zhavoronkov . Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections . . 12 . 8 . 6492–6510 . 2020 . 10.18632/aging.102988 . 7202545 . 32229705.

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