Panobinostat

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Panobinostat (LBH-589, trade name Farydak FAYR-ah-dak) is a drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid[2] and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).[3]

On 23 February 2015 it received FDA accelerated approval for use in patients with multiple myeloma who had received at least 2 previous treatments, including bortezomib and an immunomodulatory agent.[4] after clinical trials.[5]

Clinical trials

As of August 2012, it is being tested against Hodgkin's Lymphoma, cutaneous T cell lymphoma (CTCL)[6] and other types of malignant disease in Phase III clinical trials, against myelodysplastic syndromes, breast cancer and prostate cancer in Phase II trials, and against chronic myelomonocytic leukemia (CMML) in a Phase I trial.[7][8]

As of 2014 panobinostat is being used in a Phase I/II clinical trial that aims at curing AIDS in patients on highly active antiretroviral therapy (HAART). In this technique, panobinostat is used to drive the HIV DNA out of the patient's DNA, in the expectation that the patient's immune system in combination with HAART will destroy it.[9][10][11]

As of 2016 panobinostat is being studied in a phase II trial for relapsed and refractory diffuse large B-cell lymphoma (DLBCL).[12]

Preclinical studies

Panobinostat has been found to synergistically act with sirolimus to kill pancreatic cancer cells in the laboratory in a Mayo Clinic study. In the study, investigators found that this combination destroyed up to 65 percent of cultured pancreatic tumor cells. The finding is significant because the three cell lines studied were all resistant to the effects of chemotherapy – as are many pancreatic tumors.[13]

Panobinostat has also been found to significantly increase in vitro the survival of motor neuron (SMN) protein levels in cells of patients suffering from spinal muscular atrophy.[14]

Panobinostat was able to selectively target triple negative breast cancer (TNBC) cells by inducing hyperacetylation and cell cycle arrest at the G2-M DNA damage checkpoint; partially reversing the morphological changes characteristic of breast cancer cells.[15]

Panobinostat, along with other HDAC inhibitors, is also being studied for potential to induce virus HIV-1 expression in latently infected cells and disrupt latency. These resting cells are not recognized by the immune system as harboring the virus and do not respond to antiretroviral drugs.[16]

A 2015 study suggested Panobinostat was effective in preventing diffuse intrinsic pontine glioma cell growth in vitro and in vivo, identifying it as a potential drug candidate.[17]

Mechanism of action

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.[2]

References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 Panobinostat Package Insert
  2. ↑ 2.0 2.1 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Table 3: Select epigenetic inhibitors in various stages of development from Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ FDA.gov announcement about accelerated approval of panobinostat (Farydak)
  5. ↑ Panobinostat chemotherapy regimen for multiple myeloma (MM wiki)
  6. ↑ Clinical trial number NCT00425555 for "Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma" at ClinicalTrials.gov
  7. ↑ ClinicalTrials.gov: LBH-589
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Clinical trial number NCT01680094 for "Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART (CLEAR)" at ClinicalTrials.gov
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Panobinostat May Be Active in Select Patients With Refractory DLBCL. May 2016
  13. ↑ Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ TA Rasmussen, et al. Comparison of HDAC inhibitors in clinical development: Effect on HIV production in latently infected cells and T-cell activation. Human Vaccines & Immunotherapeutics 9:5, 1-9, May 2013.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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